US20030198601A1 - Compositions and methods for the pulmonary delivery of aerosolized medicaments - Google Patents

Compositions and methods for the pulmonary delivery of aerosolized medicaments Download PDF

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Publication number
US20030198601A1
US20030198601A1 US10/313,961 US31396102A US2003198601A1 US 20030198601 A1 US20030198601 A1 US 20030198601A1 US 31396102 A US31396102 A US 31396102A US 2003198601 A1 US2003198601 A1 US 2003198601A1
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United States
Prior art keywords
composition
dry powder
pharmaceutical
particle size
carrier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/313,961
Inventor
Robert Platz
John Patton
Linda Foster
Mohammed Eljamal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma AG
Original Assignee
Nektar Therapeutics
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23679173&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030198601(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US07/910,048 external-priority patent/US5458135A/en
Priority claimed from US08/309,691 external-priority patent/US5785049A/en
Application filed by Nektar Therapeutics filed Critical Nektar Therapeutics
Priority to US10/313,961 priority Critical patent/US20030198601A1/en
Assigned to NEKTAR THERAPEUTICS reassignment NEKTAR THERAPEUTICS CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: INHALE THERAPEUTIC SYSTEMS, INC.
Publication of US20030198601A1 publication Critical patent/US20030198601A1/en
Priority to US11/627,884 priority patent/US20070122418A1/en
Assigned to INHALE THERAPEUTIC SYSTEMS, INC. reassignment INHALE THERAPEUTIC SYSTEMS, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: INHALE THERAPEUTIC SYSTEMS
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF PATENT RIGHTS Assignors: NEKTAR THERAPEUTICS
Abandoned legal-status Critical Current

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    • A61M15/0045Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0051Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0086Inhalation chambers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/06Solids
    • A61M2202/064Powder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/02General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0233Conductive materials, e.g. antistatic coatings for spark prevention
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/07General characteristics of the apparatus having air pumping means
    • A61M2205/071General characteristics of the apparatus having air pumping means hand operated
    • A61M2205/073Syringe, piston type
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00Uses of viruses
    • C12N2799/02Uses of viruses as vector
    • C12N2799/021Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/022Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus

Definitions

  • the present invention relates generally to methods and compositions for the dry powder formulation of pharmaceuticals, including macromolecules, for pulmonary delivery.
  • pulmonary delivery a drug dispersion for oral inhalation
  • Such pulmonary drug delivery compositions are designed to be delivered by inhalation by the patient of a drug dispersion so that the active drug within the dispersion can reach the lung. It has been found that certain drugs delivered to the lung are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of macromolecules (proteins, polypeptides and nucleic acids) which are difficult to deliver by other routes of administration. Such pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
  • Pulmonary drug delivery can itself be achieved by different approaches, including liquid nebulizers, aerosol-based metered dose inhalers (MDI's), and dry powder dispersion devices.
  • Aerosol-based MDI's are losing favor because they rely on the use of chlorofluorocarbons (CFC's), which are being banned because of their adverse effect on the ozone layer.
  • Dry powder dispersion devices which do not rely on CFC aerosol technology, are promising for delivering drugs that may be readily formulated as dry powders. Many otherwise labile macromolecules may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers. The ability to deliver pharmaceutical compositions as dry powders, however, is problematic in certain respects.
  • the dosage of many pharmaceutical compositions is often critical so it is necessary that any dry powder delivery system be able to accurately, precisely, and reliably deliver the intended amount of drug. Moreover, many pharmaceutical compositions are quite expensive. Thus, the ability to efficiently deliver the dry powders with a minimal loss of drug is critical. It is also essential that the powder be readily dispersible prior to inhalation by the patient in order to assure adequate distribution and systemic absorption.
  • a particularly promising approach for the pulmonary delivery of dry powder drugs utilizes a hand-held device with a hand pump for providing a source of pressurized gas.
  • the pressurized gas is abruptly released through a powder dispersion device, such as a venturi nozzle, and the dispersed powder made available for patient inhalation.
  • a powder dispersion device such as a venturi nozzle
  • the dispersed powder made available for patient inhalation.
  • hand-held devices are problematic in a number of other respects.
  • the particles being delivered are less than 10 ⁇ m in size, usually in the range from 1 ⁇ m to 5 ⁇ m, making powder handling and dispersion more difficult than with larger particles.
  • the problems are exacerbated by the relatively small volumes of pressurized gas, which are available using hand-actuated pumps.
  • venturi dispersion devices are unsuitable for difficult-to-disperse powders when only small volumes of pressurized gas are available.
  • Another requirement for hand-held and other powder delivery devices is efficiency. It is important that the concentration of drug in the bolus of gas be relatively high to reduce the number of breaths required to achieve a total dosage.
  • the ability to achieve both adequate dispersion and small dispersed volumes is a significant technical challenge that requires in part that each unit dosage of the powdered composition be readily and reliably dispersible.
  • a dry powder sonic velocity disperser is described in Witham and Gates, Dry Dispersion with Sonic Velocity Nozzles, presented at the workshop on Dissemination Techniques for Smoke and Obscurants, Chemical Systems Laboratory, Aberdeen Proving Ground, Md., Mar. 14-16, 1983.
  • U.S. Pat. Nos. 4,926,852 and 4,790,305 describe a type of “spacer” for use with a metered dose inhaler.
  • the spacer defines a large cylindrical volume which receives an axially directed burst of drug from a propellant-driven drug supply.
  • U.S. Pat. No. 5,027,806, is an improvement over the '852 and '305 patents, having a conical holding chamber which receives an axial burst of drug.
  • U.S. Pat. No. 4,624,251 describes a nebulizer connected to a mixing chamber to permit a continuous recycling of gas through the nebulizer.
  • U.S. Pat. No. 4,677,975 is described above.
  • European Patent Application 347,779 describes an expandable spacer for a metered dose inhaler having a one-way valve on the mouthpiece.
  • International Patent Publication No. WO 90/07351 describes a dry powder oral inhaler having a pressurized gas source (a piston pump) which draws a measured amount of powder into a venturi arrangement.
  • a MDI for delivering insulin into a spacer for regulating inhalation flow rate is described in U.S. Pat. No. 5,320,094.
  • the intrabronchial administration of recombinant insulin is briefly described in Schlyter et al. (Abstract) (1984) Diabetes 33:75A and Kshler et al. (1987) Atemw. Lungenkrkh. 13:230-232.
  • Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer are described in U.S. Pat. No. 5,011,678 and Nagai et al. (1984) J. Contr. Rel. 1:15-22.
  • U.S. Pat. Nos. 4,833,125 and 4,698,328 describe the administration of active parathyroid hormone fragments in combination with vitamin D or a dietary calcium supplement. Suggested administration routes include parenteral by injection, rapid infusion, nasopharyngeal absorption, dermal absorption, or oral. See also, Neer et al. (1987) Osteoporosis 53:829-835.
  • U.S. Pat. No. 5,011,678 describes the use of amphophilic steroids as a penetration enhancer for nasal or bronchopulmonary delivery of proteins and polypeptides, listing parathyroid hormone as one of a “veritable host” of proteins which could be delivered with the enhancer.
  • Parathyroid hormone (full length) is secreted naturally from the parathyroid gland as a series of spikes in a pulsatile fashion which is analogous to pituitary hormones (Harms et al. (1987) Int. Symp. on Osteoporosis, Aalborg, Abstract 232). The full length hormone is rapidly broken down in the circulation into several fragments which are the dominant serum forms. It is hypothesized that an intermittent or pulsatile secretion pattern for parathyroid hormone is necessary to maintain its bone restoring properties (Hesch et al. (1988) Calcif. Tissue Int. 42:341-344 and Habener et al. (1971). Proc. Natl. Acad. Sci USA 68:2986-2991). Patton and Platz (1992) Adv. Drug Deliver. Rev. 8:179-196, describe methods for delivering proteins and polypeptides by inhalation through the deep lung.
  • Interleukin-1 receptor compositions are disclosed in U.S. Pat. Nos. 4,968,607, 5,081,228 and 5,180,812.
  • Aerosol formulations of interferons have been produced for pulmonary delivery as described in International Patent Publication No. WO 91/16038.
  • International Patent Publication No. WO 91/16038 teaches adding a surfactant or the like to improve the dispersibility of a human interferon from a CFC delivery system.
  • Methods and compositions for the preparation of solid polypeptide microparticles as a pharmaceutical aerosol formulation are disclosed in International Patent Publication No. WO 91/16038.
  • the purification of proteins of molecular weight in excess of 12,000, including human IFN is disclosed in U.S. Pat. No. 4,503,035.
  • Low pH pharmaceutical compositions of recombinant IFN-beta are disclosed in International Patent Publication No. WO 89/05158.
  • An object of the present invention is to provide a pharmaceutical composition suitable for long-term pulmonary administration to a patient in need thereof.
  • Another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that is administered by inhalation in a manner that is free of a liquid propellant such as a CFC, HFC or carbon dioxide.
  • Another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that can be easily manufactured by a method that maintains a high percentage of pharmaceutical activity.
  • Another object of this invention is to provide a manufacturable method for the production of a pharmaceutical composition of sufficient purity.
  • Still another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that exhibits a high level of stability.
  • a dispersible dry powder pharmaceutical-based composition is one having a moisture content of less than about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w; a particle size of about 1.0-5.0 (m mass median diameter (MMD), usually 1.0-4.0 (m MMD, and preferably 1.0-3.0 (m MMD; a delivered dose of about (30%, usually (40%, preferably (50%, and most preferred (60%; and an aerosol particle size distribution of about 1.0-5.0 (m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 (m MMAD, and preferably 1.5-4.0 MMAD.
  • Such compositions are of pharmaceutical grade purity.
  • the present invention is based at least in part on the dispersibility characteristics of the pharmaceutical-based dry powder compositions produced according to the present invention.
  • the dispersibility characteristics of the subject pharmaceutical-based compositions means that they are more suitable for use in pulmonary delivery devices than compositions prepared by other methods.
  • the compositions of the invention are readily aerosolized and rapidly absorbed through the lungs of a host when delivered by a dry powder inhaler.
  • the term “dispersibility” or “dispersible” means a dry powder having a moisture content of less than about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w; a particle size of about 1.0-5.0 (m mass median diameter (MMD), usually 1.0-4.0 (m MMD, and preferably 1.0-3.0 (m MMD; a delivered dose of about (30%, usually (40%, preferably (50%, and most preferred (60%; and an aerosol particle size distribution of about 1.0-5.0 (m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 (m MMAD, and preferably 1.5-4.0 (m MMAD.
  • Methods and compositions for improving dispersibility are disclosed in U.S. application Ser. No. 08/423,568, filed Apr. 14, 1995, the disclosure of which is hereby incorporated by reference.
  • the term “powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli.
  • the powder is said to be “respirable.”
  • the average particle size is less than about 10 microns ( ⁇ m) in diameter with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 ⁇ m and most preferably less than about 5.0 ⁇ m.
  • the particle size distribution is between about 0.1 ⁇ m and about 5 ⁇ m in diameter, particularly about 0.3 ⁇ m to about 5 ⁇ m.
  • dry means that the composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol.
  • This moisture content is generally below about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w.
  • terapéuticaally effective amount is the amount present in the composition that is needed to provide the desired level of drug in the subject to be treated to give the anticipated physiological response. This amount is determined for each drug on a case-by-case basis. Guidelines are given hereafter.
  • physiologically effective amount is that amount delivered to a subject to give the desired palliative or curative effect. This amount is specific for each drug and its ultimate approved dosage level. Guidelines are given hereafter.
  • pharmaceutically acceptable carrier means that the carrier can be taken into the lungs with no significant adverse toxicological effects on the lungs.
  • One aspect of this invention is a dispersible pharmaceutical-based dry powder composition for pulmonary delivery, the composition comprising a therapeutically effective amount of a pharmaceutical in combination with a pharmaceutically acceptable carrier.
  • compositions of this invention have a suitable for pulmonary delivery because of their dispersibility characteristics. Such compositions were not previously known in the art.
  • the pharmaceutical In the dry state, the pharmaceutical may be in crystalline or amorphous form.
  • Pharmaceutical compositions suitable for formulation into dispersible dry powders are listed in Table 1. These include macromolecule and non-macromolecule-based pharmaceuticals, usually macromolecules, with insulin, interleukin-1 receptor, parathyroid hormone (PTH-34), alpha-1 antitrypsin, calcitonin, low molecular weight heparin, heparin, interferon, and nucleic acids being preferred.
  • a therapeutically effective amount of active pharmaceutical will vary in the composition depending on the biological activity of the drug employed and the amount needed in a unit dosage form. Because the subject compounds are dispersible, it is highly preferred that they be manufactured in a unit dosage form in a manner that allows for ready manipulation by the formulator and by the consumer. This generally means that a unit dosage will be between about 0.5 mg and 15 mg of total material in the dry powder composition, preferably between about 2 mg and 10 mg. Generally, the amount of drug in the composition will vary from about 0.05%w to about 99.0%w. Most preferably the composition will be about 0.2% to about 97.0%w drug.
  • the amount of the pharmaceutically acceptable carrier is that amount needed to provide the necessary stability, dispersibility, consistency and bulking characteristics to ensure a uniform pulmonary delivery of the composition to a subject in need thereof. Numerically the amount may be from about 0.05%w to about 99.95%w, depending on the activity of the drug being employed. Preferably about 5%w to about 95%w will be used.
  • the carrier may be one or a combination of two or more pharmaceutical excipients, but will generally be substantially free of any “penetration enhancers.”
  • Penetration enhancers are surface active compounds which promote penetration of a drug through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations.
  • Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like.
  • penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds.
  • the dry powder compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
  • the types of pharmaceutical excipients that are useful as carriers in this invention include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two.
  • HSA human serum albumin
  • bulking agents such as carbohydrates, amino acids and polypeptides
  • pH adjusters or buffers such as sodium chloride
  • salts such as sodium chloride
  • HSA is particularly valuable as a carrier in that it provides improved dispersibility.
  • Bulking agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids or combinations thereof.
  • Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like.
  • a preferred group of carbohydrates includes lactose, threhalose, raffinose, maltodextrins, and mannitol.
  • Suitable polypeptides include aspartame.
  • Amino acids include alanine and glycine, with glycine being preferred.
  • Additives which are minor components of the composition of this invention, may be included for conformational stability during spray drying and for improving dispersibility of the powder.
  • additives include hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine, and the like.
  • Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.
  • Another aspect of this invention is a unit dosage form for pulmonary delivery of dispersible dry powder pharmaceutical-based compositions, which dosage form comprises a unit dosage receptacle containing a pharmaceutical-based dry powder composition, which composition comprises a therapeutically effective amount of a pharmaceutical in combination with a pharmaceutically acceptable carrier.
  • the composition of this invention (as discussed hereinbefore) is placed within a suitable dosage receptacle in an amount sufficient to provide a subject with drug for a unit dosage treatment.
  • the dosage receptacle is one that fits within a suitable inhalation device to allow for the aerosolization of the interferon-based dry powder composition by dispersion into a gas stream to form an aerosol and then capturing the aerosol so produced in a chamber having a mouthpiece attached for subsequent inhalation by a subject in need of treatment.
  • Such a dosage receptacle includes any container enclosing the composition known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the container to disperse the dry powder composition.
  • a stream of gas e.g., air
  • Such containers are exemplified by those shown in U.S. Pat. No. 4,227,522 issued Oct. 14, 1980; U.S. Pat. No. 4,192,309 issued Mar. 11, 1980; and U.S. Pat. No. 4,105,027 issued Aug. 8, 1978.
  • Suitable containers also include those used in conjunction with Glaxo's Ventolin® Rotohaler brand powder inhaler or Fison's Spinhaler® brand powder inhaler.
  • Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate.
  • the pharmaceutical-based powder is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate.
  • Such a container for use with a powder inhalation device is described in U.S. Pat. No. 4,778,054 and is used with Glaxo's Diskhaler (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237). All of these references are incorporated herein by reference.
  • Another aspect of this invention is a method of treating a condition responsive to treatment by a pharmaceutical of interest, which method comprises pulmonarily administering to a subject in need thereof a physiologically effective amount of a dispersible pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier.
  • the physiologically effective amount needed to treat a particular condition or disease state will depend on the individual, the condition, length of treatment, the regularity of treatment, the type of drug, and other factors, but can be determined by one of ordinary skill in the medicinal arts.
  • the effective absorption by a host of dry powder composition according to the present invention results from a rapid dissolution in the ultra-thin ( ⁇ 0.1 (m) fluid layer of the alveolar lining of the lung.
  • the particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the interferon systemically absorbed in a rapid manner for either local lung or systemic treatment.
  • An understanding of the precise mechanism, however, is not necessary for practicing the present invention as described herein.
  • the aerosolized pharmaceutical-based dry powders of this invention are particularly useful in place of parenteral delivery.
  • the methods and compositions of the present invention will be particularly valuable in chronic treatment protocols where a patient can self-medicate.
  • the patient can achieve a desired dosage by inhaling an appropriate amount of drug, as just described.
  • the efficiency of systemic delivery via the method as just described will typically be in the range from about 15% to 50%.
  • Still another aspect of this invention is a device and method for aerosolizing a pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier, which method comprises dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient.
  • Still another aspect of this invention is a method for preparing a dispersible pharmaceutical-based dry powder composition of this invention that comprises spray drying an aqueous mixture of the drug and a pharmaceutically acceptable carrier under conditions to provide a respirable dry powder composition.
  • Spray drying is a process in which a homogeneous aqueous mixture of drug and the carrier is introduced via a nozzle (e.g., a two fluid nozzle), spinning disc or an equivalent device into a hot gas stream to atomize the solution to form fine droplets.
  • the aqueous mixture may be a solution, suspension, slurry, or the like, but needs to be homogeneous to ensure uniform distribution of the components in the mixture and ultimately the powdered composition.
  • the aqueous mixture is a solution.
  • the solvent generally water, rapidly evaporates from the droplets producing a fine dry powder having particles 1 to 5 ⁇ m in diameter.
  • the drug is not degraded when it is exposed to the hot drying gas, and the interferon powders can be prepared having sufficient purity for pharmaceutical use.
  • An acceptable purity is defined as less than 5% degradation products and contaminates, preferably less than 3% and most preferably less than 1%.
  • the spray drying is done under conditions that result in a substantially amorphous powder of homogeneous constitution having a particle size that is respirable, a low moisture content and flow characteristics that allow for ready aerosolization.
  • the particle size of the resulting powder is such that more than about 98% of the mass is in particles having a diameter of about 10 ⁇ m or less with about 90% of the mass being in particles having a diameter less than 5 ⁇ m.
  • about 95% of the mass will have particles with a diameter of less than 10 ⁇ m with about 80% of the mass of the particles having a diameter of less than 5 ⁇ m.
  • the solutions may then be sprayed dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, Yamato Chemical Co., Okawara Kakoki Co., and the like, resulting in a substantially amorphous particulate product.
  • spraying methods such as rotary atomization, pressure atomization and two-fluid atomization can be used.
  • the devices used in these processes include “Parubisu [phonetic rendering] Mini-Spray GA-32” and “Parubisu Spray Drier DL-41 ”, manufactured by Yamato Chemical Co., or “Spray Drier CL-8,” “Spray Drier L-8,” “Spray Drier FL-12,” “Spray Drier FL-16” or “Spray Drier FL-20,” manufactured by Okawara Kakoki Co., can be used for the method of spraying using a rotary-disk atomizer.
  • nozzle types “1A,” “1,” “2A,” “2,” “3” and the like, manufactured by Yamato Chemical Co. can be used for the above-mentioned spray-drier, manufactured by the same company.
  • disks type “MC-50,” “MC-65” or “MC-85,” manufactured by Okawara Kakoki Co. can be used as rotary disks of the spray-drier atomizer, manufactured by the same company.
  • the temperature of the inlet of the gas used to dry the sprayed materials is such that it does not cause heat deactivation of the sprayed material.
  • the range of temperatures may vary between about 50° C. to about 200° C., preferably between about 50° C. and 100° C.
  • the temperature of the outlet gas used to dry the sprayed material may vary between about 0° C. and about 150°, preferably between 0° C. and 90° C., and even more preferably between 0° C. and 60° C.
  • inlet and outlet temperatures above about 55° C. can be used is surprising in view of the fact that most macromolecule-based drugs deactivate at that temperature, with nearly complete deactivation occurring at about 70° C.
  • the dispersible pharmaceutical-based dry powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration.
  • Such carriers may serve simply as bulking agents when it is desired to reduce the pharmaceutical concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the compositions and to improve the dispersibility of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the powder and to improve handling characteristics flowability and consistency to facilitate manufacturing and powder filling.
  • Such carrier materials may be combined with the drug prior to spray drying, i.e., by adding the carrier material to the purified bulk solution. In that way, the carrier particles will be formed simultaneously with the drug particles to produce a homogeneous powder.
  • the carriers may be separately prepared in a dry powder form and combined with the dry powder drug by blending.
  • the powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous.
  • the size of the carrier particles may be selected to improve the flowability of the drug powder, typically being in the range from 25 ⁇ m to 100 ⁇ m.
  • a preferred carrier material is crystalline lactose having a size in the above-stated range.
  • dry powder compositions may be prepared by other processes such as lyophilization and jet milling as disclosed in International Patent Publication No. WO 91/16038, the disclosure of which is hereby incorporated by reference.
  • EPO Anemia Factor IX Hemophilia B Granulocyte Colony Stimulating Netropenia Factor (G-CSF) Granulocyte Marcrophage Colony Bone Marrow Engraftment/Trans- Stimulating Factor (GM-CSF) plant Failure Short Stature Renal Failure Heparin Blood Clotting Heparin (Low Molecular Weight) Blood Clotting Insulin Type I and Type II Diabetes Interferon Alpha Hepatitis B and C Kaposi's Sarcoma Interferon Beta Multiple Sclerosis Interfer
  • a dry powder of the 20% insulin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 120-122° C. Feed rate 5.3 mL/min Outlet temperature 80-81° C.
  • the outlet temperature was maintained at ⁇ 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 20% insulin dry powder composition contained 66.1% mannitol and 13.9% citrate.
  • the composition was found to contain 1.1 to 2.0% moisture as measured by a coulombic Karl Fischer method using a Mitsubishi CA-06 Moisture Meter.
  • the particle size distribution of the composition was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powder on Sedisperse A-11 (Micrometrics, Norcross, Ga.) and was determined to be 1.3 ⁇ m to 1.5 ⁇ m MMD.
  • the delivered dose of the insulin powder composition was measured by collecting the aerosol powder produced by a dry powder dispersion device, similar to devices described in co-pending U.S. application Ser. Nos. 07/910,048; 08/313,707; 08/309,691 and PCT/US92/05621, the disclosures of which are hereby incorporated by reference, on a filter placed over the device mouthpiece.
  • the delivered dose of the insulin powder composition was determined to be 563 ⁇ 16 ⁇ g or 60 to 64% of the total powder (5.0 mg) loaded into the device.
  • the aerosol particle size distribution measured using a cascade impactor (California Measurements IMPAQ-6), was determined to be 2.0 ⁇ m MMAD, with 86% to 90% of the particles ⁇ 5.0 ⁇ m in diameter.
  • the insulin content of the powder measured by reverse phase HPLC (rpHPLC) was determined to be 197 ⁇ g/mg powder, accounting for 99% of the expected insulin. No degradation peaks were detected in the chromatogram.
  • PTH parathyroid hormone
  • a dry powder of the 5.0% PTH (1-34) formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 122-124° C. Feed rate 5.2 mL/min Outlet temperature 73-74° C.
  • the outlet temperature was maintained at ⁇ 80° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the particle size distribution of the composition was determined to be 2.4 ⁇ m and 2.7 ⁇ m MMD in separate measurements.
  • the delivered dose of the PTH (1-34) powder was determined to be 161 ⁇ g or 64.5% and 175 ⁇ g or 69.2% in separate measurements.
  • the PTH (1-34) content of the powder, measured by rpHPLC was determined to be 48.5 ⁇ g/mg powder, accounting for 97% of the expected value. No degradation peaks were detected in the chromatogram.
  • IL-1 receptor Bulk interleukin-1 receptor, IL-1 receptor, was obtained from Immunex Corporation, Seattle, Wash. A 0.7% IL-1 receptor formulation was achieved by combining 0.053 mg 1L-1 receptor per 1.0 mL deionized water with 7.07 mg/mL raffinose (Pfanstiehl, Waukegan, Ill.) and 0.373 mg/mL Tris buffer at pH 7.18.
  • a dry powder of the 0.7% IL-1 receptor formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 135-137° C. Feed rate 4.9 mL/min Outlet temperature 92-93° C.
  • the outlet temperature was maintained at 90° C. for about 15 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 0.7% IL-1 receptor dry powder composition contained 94.3% raffinose and 5.0% Tris.
  • the formulation contained 1.84 ⁇ 0.25% moisture.
  • the particle size distribution of the composition was determined to be 1.95 ⁇ m MMD with 100% of the particles ⁇ 5.0 ⁇ m.
  • the delivered dose of the IL-1 receptor powder was determined to be 22.3 ⁇ 2.0 ⁇ g or 53.4 ⁇ 4.7%.
  • the aerosol particle size distribution was determined to be 3.2 ⁇ m MMAD, with 77% of the particles ⁇ 5.0 ⁇ m in diameter.
  • the IL-1 receptor content of the powder as measured by rpHPLC was determined to be 8.4 ⁇ g/mg, accounting for 120% of the expected IL-1 receptor. No degradation peaks were detected in the chromatogram.
  • IL-1 receptor Bulk interleukin-1 receptor, IL-1 receptor, was obtained from Immunex Corporation, Seattle, Wash. A 5.0% IL-1 receptor formulation was achieved by combining 0.375 mg IL-1 receptor per 1.0 mL deionized water with 6.77 mg/mL raffinose and 0.351 mg/mL Tris buffer at pH 7.35.
  • a dry powder of the 5.0% IL-1 receptor formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 138° C. Feed rate 4.9 mL/min Outlet temperature 91° C.
  • the outlet temperature was maintained at 90° C. for about 15 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 5.0% IL-I receptor dry powder composition contained 90.3% raffinose and 4.7% Tris.
  • the formulation contained 1.75 ⁇ 0.26% moisture.
  • the particle size distribution of the composition was determined to be 2.74 ⁇ m MMD with 97% of the particles ⁇ 5.0 ⁇ m.
  • the delivered dose of the IL-1 receptor powder was determined to be 123.4+24.5 ⁇ g or 49.3 ⁇ 9.8%.
  • the aerosol particle size distribution was determined to be 4.1 ⁇ m MMAD, with 64% of the particles ⁇ 5.0 ⁇ m in diameter.
  • the IL-1 receptor content of the powder as measured by rpHPLC was determined to be 52.7 ⁇ 1.8 ⁇ g/mg, accounting for 105% of the expected IL-1 receptor. No degradation peaks were detected in the chromatogram.
  • a dry powder of the 26.7% human calcitonin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 4° C. Inlet temperature 119° C. Feed rate 5.5 mL/min Outlet temperature 78° C. Atomizer coolant temperature 0-5° C. Cyclone coolant temperature 25-30° C.
  • the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 26.7% human calcitonin dry powder composition contained 60% mannitol and 13.3% citrate. The formulation contained 0.71% moisture.
  • the particle size distribution of the composition was determined to be 1.33 ⁇ 0.63 ⁇ m MMD.
  • the delivered dose of the human calcitonin powder was determined to be 76.8 ⁇ 6.7%.
  • the human calcitonin content of the powder as measured by rpHPLC was determined to be 272.0 ⁇ g/mg, accounting for 102 ⁇ 1.7% of the expected human calcitonin. No degradation peaks were detected in the chromatogram.
  • A1A Bulk alpha-I antitrypsin, A1A, was obtained from Armour Pharmaceutical Company, Kankakee, 1L. A 90% A1A formulation was achieved by combining 4.89 mg A1A per 1.0 mL deionized water with 0.54 mg/mL citrate buffer at pH 6.0.
  • a dry powder of the 90% A1A formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 4° C. Inlet temperature 98-101° C. Feed rate 5.0 mL/min Outlet temperature 65° C. Atomizer coolant temperature 2-8° C. Cyclone coolant temperature 30° C.
  • the outlet temperature was maintained at 69° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 90% A1A dry powder composition contained 10.0% citrate.
  • the formulation contained 4.79% moisture.
  • the particle size distribution of the composition was determined to be 1.71 ⁇ 0.87 ⁇ m MMD.
  • the delivered dose of the 90% A1A powder was determined to be 67.0 ⁇ 5.0%.
  • the aerosol particle size distribution was determined to be 1.0 ⁇ m MMAD, with 90% of the particles ⁇ 5.0 ⁇ m in diameter.
  • the A1A content of the powder as measured by rpHPLC was determined to be 80% of the expected value. No degradation peaks were detected in the chromatogram. The activity after spray drying was determined to be 74 ⁇ 1%
  • IFN- ⁇ Bulk beta interferon, IFN- ⁇ , was obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN- ⁇ formulation was achieved by combining 0.025 mg IFN- ⁇ per 1.0 mL deionized water with 5.54 mg/mL human serum albuman (HSA), 2.3 mg/L citrate buffer and 0.345 mg/mL of NaCl at pH 4.5.
  • HSA human serum albuman
  • a dry powder of the 0.3% IFN- ⁇ formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 93° C. Feed rate 2.7 mL/min Outlet temperature 62° C.
  • the above 0.3% IFN- ⁇ dry powder composition contained 66.0% HSA, 27.4% citrate, 4.1% NaCl.
  • the formulation contained 4.22% moisture.
  • the particle size distribution of the composition was determined to be 1.62 ⁇ m MMD with 94.8% of the particles ⁇ 5 ⁇ m.
  • the delivered dose of the 0.3% IFN- ⁇ powder was determined to be 9.9 ⁇ g/mg or 66.0 ⁇ 4.0%.
  • the aerosol particle size distribution was determined to be 2.0 ⁇ m MMAD, with 85% of the particles ⁇ 5.0 ⁇ m in diameter.
  • IFN-1 activity of the powder as measured by IFN- ⁇ enzyme immunoassay (Toray-Fuji Bionics) and was determined to be 109 ⁇ 8% of the expected activity.
  • IFN- ⁇ Bulk beta interferon, IFN- ⁇ , was obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN- ⁇ formulation was achieved by combining 0.025 mg IFN- ⁇ per 1.0 mL deionized water with 4.7 mg/mL raffinose, 1.0 mg/mL human serum albuman (HSA), 2.3 mg/mL citrate buffer and 0.3 mg/mL of NaCl at pH 4.5.
  • HSA human serum albuman
  • a dry powder of the 0.3% IFN- ⁇ formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 145° C. Feed rate 5.0 mL/min Outlet temperature 87° C.
  • the outlet temperature was maintained at 97° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 0.3% IFN- ⁇ dry powder composition contained 56.4% raffinose, 11.9% HSA, 27.4% citrate, 3.5% NaCl.
  • the formulation contained 0.69% moisture.
  • the particle size distribution of the composition was determined to be 2.06 ⁇ m MMD with 88.9% of the particles ⁇ 5 ⁇ m.
  • the delivered dose of the 0.3% IFN- ⁇ powder was determined to be 10.2 ⁇ g/mg or 68.0 ⁇ 2.0%.
  • the aerosol particle size distribution was determined to be 2.5 ⁇ m MMAD, with 84% of the particles ⁇ 5.0 Am in diameter.
  • IFN- ⁇ activity of the powder as measured by IFN- ⁇ enzyme immunoassay (Toray-Fuji Bionics) and was determined to be 109 ⁇ 8% of the expected activity.
  • heparin sodium salt (Av. Mol. Wt.: Approx. 6000) from porcine intestinal mucosa, heparin (LMW), was obtained from Sigma Chemical, St. Louis, Mo.
  • a 93% heparin (LMW) formulation was achieved by combining 6.9 mg heparin (LMW) per 1.0 mL deionized water with 0.5 mg/mL HSA at pH 6.9.
  • a dry powder of the 93% heparin (LMW) formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 140° C. Feed rate 3.8 mL/min Outlet temperature 85° C. Atomizer coolant temperature 2-8° C. Cyclone coolant temperature 20° C.
  • the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 93% heparin (LMW) dry powder composition contained 7.0% HSA.
  • the delivered dose of the 93% heparin (LMW) powder was determined to be 60.0 ⁇ 1.0%.
  • the aerosol particle size distribution was determined to be 3.5 ⁇ m MMAD, with 70% of the particles ⁇ 5.0 ⁇ m in diameter.
  • a dry powder of the 97% heparin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 150° C. Feed rate 4.0 mL/min Outlet temperature 85° C. Atomizer coolant temperature 2-8° C. Cyclone coolant temperature 20° C.
  • the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above 97% heparin dry powder composition contained 3.0% HSA.
  • the formulation contained 5.11% moisture.
  • the particle size distribution of the composition was determined to be 2.0 to 2.5 ⁇ m MMD.
  • the delivered dose of the 97% heparin powder was determined to be 79.0 ⁇ 6.0%.
  • the aerosol particle size distribution was determined to be 3.2 ⁇ m MMAD, with 70% of the particles ⁇ 5.0 ⁇ m in diameter.
  • a dry powder of the DNA:Lipid vector formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 120° C. Feed rate 3.8 mL/min Outlet temperature 71° C. Atomizer coolant temperature 2-8° C. Cyclone coolant temperature 2-8° C.
  • the outlet temperature was maintained at 65° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • DNA:Lipid vector dry powder composition contained 93.97% glycine, and 5.32% HSA.
  • the particle size distribution of the composition was determined to be 2.0 ⁇ m MMD.
  • the delivered dose of the powder was determined to be 64.0 ⁇ 1.0%.
  • the aerosol particle size distribution was determined to be 2.4 ⁇ m MMAD, with 75% of the particles ⁇ 5.0 ⁇ m in diameter.
  • a dry powder of the DNA:Lipid vector formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: Temperature of aqueous mixture 2-8° C. Inlet temperature 105° C. Feed rate 2.9 mL/min Outlet temperature 72° C. Atomizer coolant temperature 2-8° C. Cyclone coolant temperature 20° C.
  • the outlet temperature was maintained at 70° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
  • the above DNA:adenovirous vector dry powder composition contained 58% glycine, and 24% HSA and 18% phosphate buffer.
  • the particle size distribution of the composition was determined to be 2.3 ⁇ m MMD.
  • the delivered dose of the powder was determined to be 51.0 ⁇ 1.0%.
  • the aerosol particle size distribution was determined to be 1.8 Am MMAD, with 80% of the particles ⁇ 5.0 ⁇ m in diameter.

Abstract

According to the subject invention, dispersible dry powder pharmaceutical-based compositions are provided, including methods for their manufacture and dry powder dispersion devices. A dispersible dry powder pharmaceutical-based composition is one having a moisture content of less than about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w; a particle size of about 1.0-5.0 (m mass median diameter (MMD), usually 1.0-4.0 (m MMD, and preferably 1.0-3.0 (m MMD; a delivered dose of about (30%, usually (40%, preferably (50%, and most preferred (60%; and an aerosol particle size distribution of about 1.0-5.0 (m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 (m MMAD, and preferably 1.5-4.0 MMAD. Such composition are of pharmaceutical grade purity.

Description

    BACKGROUND OF THE INVENTION
  • This application is a Continuation of U.S. patent application Ser. No. 08/423,515, filed on Apr. 14, 1995 and is a Continuation-In-Part of the following U.S. patent application Ser. No. 08/737,724, filed on Jul. 14, 1997, which is a 371 of PCT/US95/06008 filed May 15, 1995 and having a priority date of May 18, 1994; Ser. No. 07/910,048, filed Jul. 8, 1992 now U.S. Pat. No. 4,458,135; Ser. No. 08/417,507, filed Apr. 4, 1995, which is a file wrapper continuation of Ser. No. 08/044,358, filed Apr. 7, 1993 now abandoned; Ser. No. 08/232,849, filed Apr. 25, 1994 now U.S. Pat. No. 5,607,915; Ser. No. 08/309,691, filed Sep. 21, 1994 now U.S. Pat. No. 5,785,049; Ser. No. 08/246,034, filed May 18, 1994 now abandoned; Ser. No. 08/313,707, filed Sep. 27, 1994 now abandoned; and, Ser. No. 08/383,475, filed Feb. 1, 1995, the full disclosures of which are incorporated herein by reference. [0001]
  • 1. Field of the Invention [0002]
  • The present invention relates generally to methods and compositions for the dry powder formulation of pharmaceuticals, including macromolecules, for pulmonary delivery. [0003]
  • Over the years, certain drugs have been sold in compositions suitable for forming a drug dispersion for oral inhalation (pulmonary delivery) to treat various conditions in humans. Such pulmonary drug delivery compositions are designed to be delivered by inhalation by the patient of a drug dispersion so that the active drug within the dispersion can reach the lung. It has been found that certain drugs delivered to the lung are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of macromolecules (proteins, polypeptides and nucleic acids) which are difficult to deliver by other routes of administration. Such pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs. [0004]
  • Pulmonary drug delivery can itself be achieved by different approaches, including liquid nebulizers, aerosol-based metered dose inhalers (MDI's), and dry powder dispersion devices. Aerosol-based MDI's are losing favor because they rely on the use of chlorofluorocarbons (CFC's), which are being banned because of their adverse effect on the ozone layer. Dry powder dispersion devices, which do not rely on CFC aerosol technology, are promising for delivering drugs that may be readily formulated as dry powders. Many otherwise labile macromolecules may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers. The ability to deliver pharmaceutical compositions as dry powders, however, is problematic in certain respects. The dosage of many pharmaceutical compositions is often critical so it is necessary that any dry powder delivery system be able to accurately, precisely, and reliably deliver the intended amount of drug. Moreover, many pharmaceutical compositions are quite expensive. Thus, the ability to efficiently deliver the dry powders with a minimal loss of drug is critical. It is also essential that the powder be readily dispersible prior to inhalation by the patient in order to assure adequate distribution and systemic absorption. [0005]
  • A particularly promising approach for the pulmonary delivery of dry powder drugs utilizes a hand-held device with a hand pump for providing a source of pressurized gas. The pressurized gas is abruptly released through a powder dispersion device, such as a venturi nozzle, and the dispersed powder made available for patient inhalation. While advantageous in many respects, such hand-held devices are problematic in a number of other respects. The particles being delivered are less than 10 μm in size, usually in the range from 1 μm to 5 μm, making powder handling and dispersion more difficult than with larger particles. The problems are exacerbated by the relatively small volumes of pressurized gas, which are available using hand-actuated pumps. In particular, venturi dispersion devices are unsuitable for difficult-to-disperse powders when only small volumes of pressurized gas are available. Another requirement for hand-held and other powder delivery devices is efficiency. It is important that the concentration of drug in the bolus of gas be relatively high to reduce the number of breaths required to achieve a total dosage. The ability to achieve both adequate dispersion and small dispersed volumes is a significant technical challenge that requires in part that each unit dosage of the powdered composition be readily and reliably dispersible. [0006]
  • 2. Description of the Relevant Literature [0007]
  • Dry powder dispersion devices for medicaments are described in a number of patent documents. U.S. Pat. No. 3,921,637 describes a manual pump with needles for piercing through a single capsule of powdered medicine. The use of multiple receptacle disks or strips of medication is described in European Patent Application No. EP467172 (where a reciprocatable punch is used to open a blister pack); International Patent Publication Nos. WO91/02558; WO93/09832; U.S. Pat. Nos. 4,627,432; 4,811,731; 5,035,237; 5,048,514; 4,446,862; 5,048,514; and 4,446,862. Other patents which show puncturing of single medication capsules include U.S. Pat. Nos. 4,338,931; 3,991,761; 4,249,526; 4,069,819; 4,995,385; 4,889,114; and 4,884,565; and European Patent Application No. EP469814. International Patent Publication No. WO90/07351 describes a hand-held pump device with a loose powder reservoir. [0008]
  • A dry powder sonic velocity disperser is described in Witham and Gates, Dry Dispersion with Sonic Velocity Nozzles, presented at the workshop on Dissemination Techniques for Smoke and Obscurants, Chemical Systems Laboratory, Aberdeen Proving Ground, Md., Mar. 14-16, 1983. [0009]
  • U.S. Pat. Nos. 4,926,852 and 4,790,305, describe a type of “spacer” for use with a metered dose inhaler. The spacer defines a large cylindrical volume which receives an axially directed burst of drug from a propellant-driven drug supply. U.S. Pat. No. 5,027,806, is an improvement over the '852 and '305 patents, having a conical holding chamber which receives an axial burst of drug. U.S. Pat. No. 4,624,251, describes a nebulizer connected to a mixing chamber to permit a continuous recycling of gas through the nebulizer. U.S. Pat. No. 4,677,975, is described above. European Patent Application 347,779 describes an expandable spacer for a metered dose inhaler having a one-way valve on the mouthpiece. International Patent Publication No. WO 90/07351 describes a dry powder oral inhaler having a pressurized gas source (a piston pump) which draws a measured amount of powder into a venturi arrangement. [0010]
  • The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with GSnsslen (1925) Klin. Wochenschr. 4:71 and including Laube et al. (1993) JAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. 23:293-297; Wigley et al. (1971) Diabetes 20:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167; Hastings et al. (1992) J. Appl. Physiol. 73:1310-1316; Liu et al. (1993) JAMA 269:2106-2109; Nagano et al. (1985) Jikeikai Med. J. 32:503-506; Sakr (1992) Int. J. Phar. 86:1-7; and Yoshida et al. (1987) Clin. Res. 35:160-166. Pulmonary delivery of dry powder medicaments, such as insulin, in a large particle carrier vehicle is described in U.S. Pat. No. 5,254,330. A metered dose inhaler (MDI) for delivering crystalline insulin suspended in a propellant is described in Lee and Sciara (1976) J. Pharm. Sci. 65:567-572. A MDI for delivering insulin into a spacer for regulating inhalation flow rate is described in U.S. Pat. No. 5,320,094. The intrabronchial administration of recombinant insulin is briefly described in Schlyter et al. (Abstract) (1984) Diabetes 33:75A and Kshler et al. (1987) Atemw. Lungenkrkh. 13:230-232. Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer, are described in U.S. Pat. No. 5,011,678 and Nagai et al. (1984) J. Contr. Rel. 1:15-22. Intranasal delivery of insulin in the presence of enhancers and/or contained in controlled release formulations are described in U.S. Pat. Nos. 5,204,108; 4,294,829; and 4,153,689; PCT Applications WO 93/02712, WO 91/02545, WO 90/09780, and WO 88/04556; British Patent 1,527,605; Ryd□n and Edman (1992) Int. J. Pharm. 83:1-10; and Bj[0011]
    Figure US20030198601A1-20031023-P00900
    srk and Edman (1988) nt. J. Pharm. 47:233-238. The preparation and stability of amorphous insulin were described by Rigsbee and Pikal at the American Association of Pharmaceutical Sciences (AAPS), Nov. 14-18, 1993, Lake Buena Vista, Florida. Methods for spray drying polypeptide, polynucleotide and other labile drugs in a carrier which forms an amorphous structure which stabilizes the drug are described in European Patent Application No. 520 748. (AAPS), Nov. 14-18, 1993, Lake Buena Vista, Florida.
  • Stribling et al. (1992) J. Biopharm. Sci. 3:255-263, describes the aerosol delivery of plasmids carrying a chloramphenicol acetyltransferase (CAT) reporter gene to mice. The plasmids were incorporated in DOTMA or cholesterol liposomes, and aqueous suspensions of the liposomes were nebulized into a small animal aerosol delivery chamber. Mice breathing the aerosol were found to at least transiently express CAT activity in their lung cells. Rosenfeld et al. (1991) Science: 252:431-434, describes the in vivo delivery of an alpha-I antitrypsin gene to rats, with secretion of the gene product being observable for at least one week. The gene was diluted in saline and instilled directly into the rat trachea. Friedman (1989) Science 244:1275-1281 is a review article describing human gene therapy strategies. [0012]
  • U.S. Pat. Nos. 4,833,125 and 4,698,328, describe the administration of active parathyroid hormone fragments in combination with vitamin D or a dietary calcium supplement. Suggested administration routes include parenteral by injection, rapid infusion, nasopharyngeal absorption, dermal absorption, or oral. See also, Neer et al. (1987) Osteoporosis 53:829-835. U.S. Pat. No. 5,011,678, describes the use of amphophilic steroids as a penetration enhancer for nasal or bronchopulmonary delivery of proteins and polypeptides, listing parathyroid hormone as one of a “veritable host” of proteins which could be delivered with the enhancer. Parathyroid hormone (full length) is secreted naturally from the parathyroid gland as a series of spikes in a pulsatile fashion which is analogous to pituitary hormones (Harms et al. (1987) Int. Symp. on Osteoporosis, Aalborg, Abstract 232). The full length hormone is rapidly broken down in the circulation into several fragments which are the dominant serum forms. It is hypothesized that an intermittent or pulsatile secretion pattern for parathyroid hormone is necessary to maintain its bone restoring properties (Hesch et al. (1988) Calcif. Tissue Int. 42:341-344 and Habener et al. (1971). Proc. Natl. Acad. Sci USA 68:2986-2991). Patton and Platz (1992) Adv. Drug Deliver. Rev. 8:179-196, describe methods for delivering proteins and polypeptides by inhalation through the deep lung. [0013]
  • The aerosolization of protein therapeutic agents, including alpha-i antitrypsin, is disclosed in European Patent Application No. EP0289336. The use of alpha-I antityrpsin for treating pulmonary inflammation is disclosed in U.S. Pat. No. 5,093,316. [0014]
  • Therapeutic aerosol formulations, including calcitonin, are disclosed in International Patent Publication No. WO 90/09781. [0015]
  • Methods and compositions for inhibiting neutrophil elastase and cathespin G employing aerosolized 2-0-desulfated heparin are disclosed in International Patent Publication No. WO94/02107. [0016]
  • Interleukin-1 receptor compositions are disclosed in U.S. Pat. Nos. 4,968,607, 5,081,228 and 5,180,812. [0017]
  • Aerosol formulations of interferons have been produced for pulmonary delivery as described in International Patent Publication No. WO 91/16038. International Patent Publication No. WO 91/16038 teaches adding a surfactant or the like to improve the dispersibility of a human interferon from a CFC delivery system. Methods and compositions for the preparation of solid polypeptide microparticles as a pharmaceutical aerosol formulation are disclosed in International Patent Publication No. WO 91/16038. The purification of proteins of molecular weight in excess of 12,000, including human IFN is disclosed in U.S. Pat. No. 4,503,035. Low pH pharmaceutical compositions of recombinant IFN-beta are disclosed in International Patent Publication No. WO 89/05158. [0018]
  • 3. Objects of the Invention [0019]
  • An object of the present invention is to provide a pharmaceutical composition suitable for long-term pulmonary administration to a patient in need thereof. [0020]
  • Another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that is administered by inhalation in a manner that is free of a liquid propellant such as a CFC, HFC or carbon dioxide. [0021]
  • Another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that can be easily manufactured by a method that maintains a high percentage of pharmaceutical activity. [0022]
  • Another object of this invention is to provide a manufacturable method for the production of a pharmaceutical composition of sufficient purity. [0023]
  • Still another object of this invention is to provide a pharmaceutical-containing dispersible dry powdered composition that exhibits a high level of stability. [0024]
  • Other objects may be apparent to one of ordinary skill upon reviewing the following specification and claims. [0025]
  • SUMMARY OF THE INVENTION
  • According to the subject invention, dispersible dry powder pharmaceutical-based compositions are provided, including methods for their manufacture and dry powder dispersion devices. A dispersible dry powder pharmaceutical-based composition is one having a moisture content of less than about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w; a particle size of about 1.0-5.0 (m mass median diameter (MMD), usually 1.0-4.0 (m MMD, and preferably 1.0-3.0 (m MMD; a delivered dose of about (30%, usually (40%, preferably (50%, and most preferred (60%; and an aerosol particle size distribution of about 1.0-5.0 (m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 (m MMAD, and preferably 1.5-4.0 MMAD. Such compositions are of pharmaceutical grade purity. [0026]
  • DESCRIPTION OF SPECIFIC EMBODIMENTS
  • The present invention is based at least in part on the dispersibility characteristics of the pharmaceutical-based dry powder compositions produced according to the present invention. The dispersibility characteristics of the subject pharmaceutical-based compositions means that they are more suitable for use in pulmonary delivery devices than compositions prepared by other methods. The compositions of the invention are readily aerosolized and rapidly absorbed through the lungs of a host when delivered by a dry powder inhaler. [0027]
  • DEFINITIONS [0028]
  • In interpreting the claims to the various aspects of this invention, there are several important definitions that should be considered. [0029]
  • The term “dispersibility” or “dispersible” means a dry powder having a moisture content of less than about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w; a particle size of about 1.0-5.0 (m mass median diameter (MMD), usually 1.0-4.0 (m MMD, and preferably 1.0-3.0 (m MMD; a delivered dose of about (30%, usually (40%, preferably (50%, and most preferred (60%; and an aerosol particle size distribution of about 1.0-5.0 (m mass median aerodynamic diameter (MMAD), usually 1.5-4.5 (m MMAD, and preferably 1.5-4.0 (m MMAD. Methods and compositions for improving dispersibility are disclosed in U.S. application Ser. No. 08/423,568, filed Apr. 14, 1995, the disclosure of which is hereby incorporated by reference. [0030]
  • The term “powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli. Thus, the powder is said to be “respirable.” Preferably the average particle size is less than about 10 microns (μm) in diameter with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 μm and most preferably less than about 5.0 μm. Usually the particle size distribution is between about 0.1 μm and about 5 μm in diameter, particularly about 0.3 μm to about 5 μm. [0031]
  • The term “dry” means that the composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w. [0032]
  • The term “therapeutically effective amount” is the amount present in the composition that is needed to provide the desired level of drug in the subject to be treated to give the anticipated physiological response. This amount is determined for each drug on a case-by-case basis. Guidelines are given hereafter. [0033]
  • The term “physiologically effective amount” is that amount delivered to a subject to give the desired palliative or curative effect. This amount is specific for each drug and its ultimate approved dosage level. Guidelines are given hereafter. [0034]
  • The term “pharmaceutically acceptable carrier” means that the carrier can be taken into the lungs with no significant adverse toxicological effects on the lungs. [0035]
  • COMPOSITIONS OF THE INVENTION
  • One aspect of this invention is a dispersible pharmaceutical-based dry powder composition for pulmonary delivery, the composition comprising a therapeutically effective amount of a pharmaceutical in combination with a pharmaceutically acceptable carrier. [0036]
  • In general, the compositions of this invention have a suitable for pulmonary delivery because of their dispersibility characteristics. Such compositions were not previously known in the art. In the dry state, the pharmaceutical may be in crystalline or amorphous form. Pharmaceutical compositions suitable for formulation into dispersible dry powders are listed in Table 1. These include macromolecule and non-macromolecule-based pharmaceuticals, usually macromolecules, with insulin, interleukin-1 receptor, parathyroid hormone (PTH-34), alpha-1 antitrypsin, calcitonin, low molecular weight heparin, heparin, interferon, and nucleic acids being preferred. [0037]
  • A therapeutically effective amount of active pharmaceutical will vary in the composition depending on the biological activity of the drug employed and the amount needed in a unit dosage form. Because the subject compounds are dispersible, it is highly preferred that they be manufactured in a unit dosage form in a manner that allows for ready manipulation by the formulator and by the consumer. This generally means that a unit dosage will be between about 0.5 mg and 15 mg of total material in the dry powder composition, preferably between about 2 mg and 10 mg. Generally, the amount of drug in the composition will vary from about 0.05%w to about 99.0%w. Most preferably the composition will be about 0.2% to about 97.0%w drug. [0038]
  • The amount of the pharmaceutically acceptable carrier is that amount needed to provide the necessary stability, dispersibility, consistency and bulking characteristics to ensure a uniform pulmonary delivery of the composition to a subject in need thereof. Numerically the amount may be from about 0.05%w to about 99.95%w, depending on the activity of the drug being employed. Preferably about 5%w to about 95%w will be used. [0039]
  • The carrier may be one or a combination of two or more pharmaceutical excipients, but will generally be substantially free of any “penetration enhancers.” Penetration enhancers are surface active compounds which promote penetration of a drug through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations. Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like. The use of penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds. The dry powder compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers. [0040]
  • The types of pharmaceutical excipients that are useful as carriers in this invention include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two. [0041]
  • It has been found that HSA is particularly valuable as a carrier in that it provides improved dispersibility. [0042]
  • Bulking agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids or combinations thereof. Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like. A preferred group of carbohydrates includes lactose, threhalose, raffinose, maltodextrins, and mannitol. Suitable polypeptides include aspartame. Amino acids include alanine and glycine, with glycine being preferred. [0043]
  • Additives, which are minor components of the composition of this invention, may be included for conformational stability during spray drying and for improving dispersibility of the powder. These additives include hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine, and the like. [0044]
  • Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred. [0045]
  • The unit dosage form, method of treatment, and process of preparation of this invention are described hereafter. [0046]
  • Unit Dosage Form. [0047]
  • Another aspect of this invention is a unit dosage form for pulmonary delivery of dispersible dry powder pharmaceutical-based compositions, which dosage form comprises a unit dosage receptacle containing a pharmaceutical-based dry powder composition, which composition comprises a therapeutically effective amount of a pharmaceutical in combination with a pharmaceutically acceptable carrier. [0048]
  • In this aspect of the invention, the composition of this invention (as discussed hereinbefore) is placed within a suitable dosage receptacle in an amount sufficient to provide a subject with drug for a unit dosage treatment. The dosage receptacle is one that fits within a suitable inhalation device to allow for the aerosolization of the interferon-based dry powder composition by dispersion into a gas stream to form an aerosol and then capturing the aerosol so produced in a chamber having a mouthpiece attached for subsequent inhalation by a subject in need of treatment. Such a dosage receptacle includes any container enclosing the composition known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the container to disperse the dry powder composition. Such containers are exemplified by those shown in U.S. Pat. No. 4,227,522 issued Oct. 14, 1980; U.S. Pat. No. 4,192,309 issued Mar. 11, 1980; and U.S. Pat. No. 4,105,027 issued Aug. 8, 1978. Suitable containers also include those used in conjunction with Glaxo's Ventolin® Rotohaler brand powder inhaler or Fison's Spinhaler® brand powder inhaler. Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The pharmaceutical-based powder is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate. Such a container for use with a powder inhalation device is described in U.S. Pat. No. 4,778,054 and is used with Glaxo's Diskhaler (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237). All of these references are incorporated herein by reference. [0049]
  • Method of Treating a Disease State. [0050]
  • Another aspect of this invention is a method of treating a condition responsive to treatment by a pharmaceutical of interest, which method comprises pulmonarily administering to a subject in need thereof a physiologically effective amount of a dispersible pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier. [0051]
  • Conditions that may be treated by the compositions of this are described in Table 1. [0052]
  • The physiologically effective amount needed to treat a particular condition or disease state will depend on the individual, the condition, length of treatment, the regularity of treatment, the type of drug, and other factors, but can be determined by one of ordinary skill in the medicinal arts. [0053]
  • It is presently believed that the effective absorption by a host of dry powder composition according to the present invention results from a rapid dissolution in the ultra-thin (<0.1 (m) fluid layer of the alveolar lining of the lung. The particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the interferon systemically absorbed in a rapid manner for either local lung or systemic treatment. An understanding of the precise mechanism, however, is not necessary for practicing the present invention as described herein. [0054]
  • The aerosolized pharmaceutical-based dry powders of this invention are particularly useful in place of parenteral delivery. Thus, the methods and compositions of the present invention will be particularly valuable in chronic treatment protocols where a patient can self-medicate. The patient can achieve a desired dosage by inhaling an appropriate amount of drug, as just described. The efficiency of systemic delivery via the method as just described will typically be in the range from about 15% to 50%. [0055]
  • Method for Aerosolizing the Powder. [0056]
  • Still another aspect of this invention is a device and method for aerosolizing a pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier, which method comprises dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient. [0057]
  • A further detailed description of this method is found in pending U.S. patent application Serial Nos. 07/910,048 and 08/207,472, both of which are incorporated herein by reference. [0058]
  • Preparing the Compositions. [0059]
  • Still another aspect of this invention is a method for preparing a dispersible pharmaceutical-based dry powder composition of this invention that comprises spray drying an aqueous mixture of the drug and a pharmaceutically acceptable carrier under conditions to provide a respirable dry powder composition. [0060]
  • Spray drying is a process in which a homogeneous aqueous mixture of drug and the carrier is introduced via a nozzle (e.g., a two fluid nozzle), spinning disc or an equivalent device into a hot gas stream to atomize the solution to form fine droplets. The aqueous mixture may be a solution, suspension, slurry, or the like, but needs to be homogeneous to ensure uniform distribution of the components in the mixture and ultimately the powdered composition. Preferably the aqueous mixture is a solution. The solvent, generally water, rapidly evaporates from the droplets producing a fine dry powder having particles 1 to 5 μm in diameter. Surprisingly, the drug is not degraded when it is exposed to the hot drying gas, and the interferon powders can be prepared having sufficient purity for pharmaceutical use. An acceptable purity is defined as less than 5% degradation products and contaminates, preferably less than 3% and most preferably less than 1%. [0061]
  • The spray drying is done under conditions that result in a substantially amorphous powder of homogeneous constitution having a particle size that is respirable, a low moisture content and flow characteristics that allow for ready aerosolization. Preferably the particle size of the resulting powder is such that more than about 98% of the mass is in particles having a diameter of about 10 μm or less with about 90% of the mass being in particles having a diameter less than 5 μm. Alternatively, about 95% of the mass will have particles with a diameter of less than 10 μm with about 80% of the mass of the particles having a diameter of less than 5 μm. [0062]
  • The solutions may then be sprayed dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, Yamato Chemical Co., Okawara Kakoki Co., and the like, resulting in a substantially amorphous particulate product. [0063]
  • For the spraying process, spraying methods such as rotary atomization, pressure atomization and two-fluid atomization can be used. Examples of the devices used in these processes include “Parubisu [phonetic rendering] Mini-Spray GA-32” and “Parubisu Spray Drier DL-41 ”, manufactured by Yamato Chemical Co., or “Spray Drier CL-8,” “Spray Drier L-8,” “Spray Drier FL-12,” “Spray Drier FL-16” or “Spray Drier FL-20,” manufactured by Okawara Kakoki Co., can be used for the method of spraying using a rotary-disk atomizer. [0064]
  • While no special restrictions are placed on the nozzle of the atomizer used in the process of spraying, it is recommended to use a nozzle which can produce a spray-dried composition with a grain diameter suitable for nasal, pharyngeal or pulmonary administration. For example, nozzle types “1A,” “1,” “2A,” “2,” “3” and the like, manufactured by Yamato Chemical Co., can be used for the above-mentioned spray-drier, manufactured by the same company. In addition, disks type “MC-50,” “MC-65” or “MC-85,” manufactured by Okawara Kakoki Co., can be used as rotary disks of the spray-drier atomizer, manufactured by the same company. [0065]
  • While no particular restrictions are placed on the gas used to dry the sprayed material, it is recommended to use air, nitrogen gas or an inert gas. The temperature of the inlet of the gas used to dry the sprayed materials is such that it does not cause heat deactivation of the sprayed material. The range of temperatures may vary between about 50° C. to about 200° C., preferably between about 50° C. and 100° C. The temperature of the outlet gas used to dry the sprayed material may vary between about 0° C. and about 150°, preferably between 0° C. and 90° C., and even more preferably between 0° C. and 60° C. The fact that inlet and outlet temperatures above about 55° C. can be used is surprising in view of the fact that most macromolecule-based drugs deactivate at that temperature, with nearly complete deactivation occurring at about 70° C. [0066]
  • The dispersible pharmaceutical-based dry powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the pharmaceutical concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the compositions and to improve the dispersibility of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the powder and to improve handling characteristics flowability and consistency to facilitate manufacturing and powder filling. [0067]
  • Such carrier materials may be combined with the drug prior to spray drying, i.e., by adding the carrier material to the purified bulk solution. In that way, the carrier particles will be formed simultaneously with the drug particles to produce a homogeneous powder. Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder drug by blending. The powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the drug powder, typically being in the range from 25 μm to 100 μm. A preferred carrier material is crystalline lactose having a size in the above-stated range. [0068]
  • Alternatively, dry powder compositions may be prepared by other processes such as lyophilization and jet milling as disclosed in International Patent Publication No. WO 91/16038, the disclosure of which is hereby incorporated by reference. [0069]
    TABLE 1
    DRUG INDICATIONS
    SELECTED MACROMOLOCULE DRUGS
    FOR SYSTEMIC APPLICATIONS
    Calcitonin Osteoporosis Prophylaxis
    Paget's Disease
    Hypercalcemia
    Erythropoietin (EPO) Anemia
    Factor IX Hemophilia B
    Granulocyte Colony Stimulating Netropenia
    Factor (G-CSF)
    Granulocyte Marcrophage Colony Bone Marrow Engraftment/Trans-
    Stimulating Factor (GM-CSF) plant Failure Short Stature
    Renal Failure
    Heparin Blood Clotting
    Heparin (Low Molecular Weight) Blood Clotting
    Insulin Type I and Type II Diabetes
    Interferon Alpha Hepatitis B and C
    Kaposi's Sarcoma
    Interferon Beta Multiple Sclerosis
    Interferon Gamma Chronic Granulomatous Disease
    Luteinizing Hormone Releasing Prostate Cancer
    Hormone (LHRH) Endometriosis
    Somatostatin Analog Gastrointestinal Cancers
    Vasopressin Analog Diabetes Insipidus
    Bed Wetting
    Amylin Type 1 Diabetes
    Ciliary Neurotrophic Factor Lou Gehrig's Disease
    Growth Hormone Releasing Factor Short Stature
    (GRF)
    Insulin-Like Growth Factor Osteoporosis
    Nutritional Support
    Insulinotropin Type II Diabetes
    Interferon Beta Hepatitis B and C
    Interferon Gamma Rheumatoid Arthirits
    Interleukin-3 Adjuvant to Chemotherapy
    Interleukin-4 Immunodeficiency Disease
    Interleukin-6 Thrombocytopenia
    Macrophage Colony Stimulating Fungal Disease
    Factor (M-CSF) Cancer
    Hypercholesterolemia
    Nerve Growth Factor Peripheral Neuropathies
    Parathyroid Hormone Osteoporosis
    Somatostatin Analog Refractory Diarrheas
    Thymosin Alpha 1 Hepatitis B and C
    Iib/IIIa Inhibitor Unstable Angina
    Alpha-1 Antitrypsin Cycstic Fibrosis
    Anti-RSV Antibody Respiratory Syncytial Virus
    Regulator CFTR) Gene
    Deoxyribonuclase (DNase) Chronic Bronchitis
    Heparin Asthma
    Bactericidal/Permeability Adult Respiratory Distress Syndrom
    Increasing Protein (BPI) (ARDS)
    Anti-CMV Antibody Cytomegalovirus
    Interleukin-1 Receptor Asthma
    SELECTED NON-MACROMOLECULE DRUGS FOR
    SYSTEMIC AND LOCAL LUNG APPLICATIONS
    Pentamiding isethiouate Pneumocystis carini peneumonia
    Albuterol sulfate Broncospasm
    Metaproterenol sulfate Bronchial asthma
    Beclomethasone diprepionate
    Trimcinoline acetomide
    Budesonide acetonide
    Ipratropium bromide
    Flunisolide
    Cromolyn sodium
    Ergotamine Tartrate Migraines
  • The following examples are offered by way of illustration and not limitation. [0070]
  • EXPERIMENTAL
  • According to the subject invention, the following dispersible dry powder formulations were prepared as described. All compositions produced according to the present invention meet the strict specifications for content and purity required of pharmaceutical products. [0071]
  • Example I 20.0% Insulin Formulation for Pulmonary Delivery
  • A. Formulation. [0072]
  • Bulk crystalline human zinc insulin was obtained from Eli Lilly and Company, Indianapolis, Ind. A 20% insulin formulation was achieved by combining 1.5 mg insulin per 1.0 mL deionized water with 4.96 mg/mL USP mannitol and 1.04 mg/niL citrate buffer (sodium citrate dihydrate USP and citric acid monohydrate USP) for a total solids concentration of 7.5 mg/mL at pH 6.7±0.3. [0073]
  • B. Spray Drying. [0074]
  • A dry powder of the 20% insulin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0075]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 120-122° C.
    Feed rate 5.3 mL/min
    Outlet temperature 80-81° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at <80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0076]
  • C. Characterization. [0077]
  • The above 20% insulin dry powder composition contained 66.1% mannitol and 13.9% citrate. The composition was found to contain 1.1 to 2.0% moisture as measured by a coulombic Karl Fischer method using a Mitsubishi CA-06 Moisture Meter. [0078]
  • The particle size distribution of the composition was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powder on Sedisperse A-11 (Micrometrics, Norcross, Ga.) and was determined to be 1.3 μm to 1.5 μm MMD. [0079]
  • The delivered dose of the insulin powder composition was measured by collecting the aerosol powder produced by a dry powder dispersion device, similar to devices described in co-pending U.S. application Ser. Nos. 07/910,048; 08/313,707; 08/309,691 and PCT/US92/05621, the disclosures of which are hereby incorporated by reference, on a filter placed over the device mouthpiece. The delivered dose of the insulin powder composition was determined to be 563±16 μg or 60 to 64% of the total powder (5.0 mg) loaded into the device. [0080]
  • The aerosol particle size distribution, measured using a cascade impactor (California Measurements IMPAQ-6), was determined to be 2.0 μm MMAD, with 86% to 90% of the particles <5.0 μm in diameter. [0081]
  • The insulin content of the powder, measured by reverse phase HPLC (rpHPLC) was determined to be 197 μg/mg powder, accounting for 99% of the expected insulin. No degradation peaks were detected in the chromatogram. [0082]
  • Example II 5.0% Parathyroid Hormone Formulation for Pulmonary Delivery
  • A. Formulation. [0083]
  • Bulk 34 amino acid active fragment of parathyroid hormone, PTH (1-34), was obtained from BACHEM CALIFORNIA, Torrance, Calif. A 5.0% PTH (1-34) formulation was achieved by combining 0.375 mg PTH (1-34) per 1.0 mL deionized water with 6.06 mg/mL mannitol USP and 1.04 mg/mL citrate buffer (sodium citrate dihydrate USP and citric acid monohydrate USP) for a total solids concentration of 7.48 mg/mL at pH 6.3. [0084]
  • B. Spray Drying. [0085]
  • A dry powder of the 5.0% PTH (1-34) formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0086]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 122-124° C.
    Feed rate 5.2 mL/min
    Outlet temperature 73-74° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at <80° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0087]
  • C. Characterization. [0088]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0089]
  • The above 5.0% PTH (1-34) dry powder composition contained 81.0% mannitol and 13.9% citrate. The formulation contained 0.5% moisture. [0090]
  • The particle size distribution of the composition was determined to be 2.4 μm and 2.7 μm MMD in separate measurements. [0091]
  • The delivered dose of the PTH (1-34) powder was determined to be 161 μg or 64.5% and 175 μg or 69.2% in separate measurements. [0092]
  • The PTH (1-34) content of the powder, measured by rpHPLC was determined to be 48.5 μg/mg powder, accounting for 97% of the expected value. No degradation peaks were detected in the chromatogram. [0093]
  • Example III 0.7% Interleukin-1 Receptor Formulation for Pulmonary Delivery
  • A. Formulation. [0094]
  • Bulk interleukin-1 receptor, IL-1 receptor, was obtained from Immunex Corporation, Seattle, Wash. A 0.7% IL-1 receptor formulation was achieved by combining 0.053 mg 1L-1 receptor per 1.0 mL deionized water with 7.07 mg/mL raffinose (Pfanstiehl, Waukegan, Ill.) and 0.373 mg/mL Tris buffer at pH 7.18. [0095]
  • B. Spray Drying. [0096]
  • A dry powder of the 0.7% IL-1 receptor formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0097]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 135-137° C.
    Feed rate 4.9 mL/min
    Outlet temperature 92-93° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 90° C. for about 15 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0098]
  • C. Characterization. [0099]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0100]
  • The above 0.7% IL-1 receptor dry powder composition contained 94.3% raffinose and 5.0% Tris. The formulation contained 1.84±0.25% moisture. [0101]
  • The particle size distribution of the composition was determined to be 1.95 μm MMD with 100% of the particles <5.0 μm. [0102]
  • The delivered dose of the IL-1 receptor powder was determined to be 22.3±2.0 μg or 53.4±4.7%. [0103]
  • The aerosol particle size distribution, was determined to be 3.2 μm MMAD, with 77% of the particles <5.0 μm in diameter. [0104]
  • The IL-1 receptor content of the powder as measured by rpHPLC was determined to be 8.4 μg/mg, accounting for 120% of the expected IL-1 receptor. No degradation peaks were detected in the chromatogram. [0105]
  • Example IV 5.0% Interleukin-1 Receptor Formulation for Pulmonary Delivery
  • A. Formulation. [0106]
  • Bulk interleukin-1 receptor, IL-1 receptor, was obtained from Immunex Corporation, Seattle, Wash. A 5.0% IL-1 receptor formulation was achieved by combining 0.375 mg IL-1 receptor per 1.0 mL deionized water with 6.77 mg/mL raffinose and 0.351 mg/mL Tris buffer at pH 7.35. [0107]
  • B. Spray Drying. [0108]
  • A dry powder of the 5.0% IL-1 receptor formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0109]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 138° C.
    Feed rate 4.9 mL/min
    Outlet temperature 91° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 90° C. for about 15 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0110]
  • C. Characterization. [0111]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0112]
  • The above 5.0% IL-I receptor dry powder composition contained 90.3% raffinose and 4.7% Tris. The formulation contained 1.75±0.26% moisture. [0113]
  • The particle size distribution of the composition was determined to be 2.74 μm MMD with 97% of the particles <5.0 μm. [0114]
  • The delivered dose of the IL-1 receptor powder was determined to be 123.4+24.5 μg or 49.3±9.8%. [0115]
  • The aerosol particle size distribution, was determined to be 4.1 μm MMAD, with 64% of the particles <5.0 μm in diameter. [0116]
  • The IL-1 receptor content of the powder as measured by rpHPLC was determined to be 52.7±1.8 μg/mg, accounting for 105% of the expected IL-1 receptor. No degradation peaks were detected in the chromatogram. [0117]
  • Example V 26.7% Human Calcitonin Formulation for Pulmonary Delivery
  • A. Formulation. [0118]
  • Bulk human calcitonin was obtained from Ciba-Geigy. A 26.7% human calcitonin formulation was achieved by combining 1.9 mg human calcitonin per 1.0 mL deionized water with 4.3 mg/mL mannitol and 0.9 mg/mL citrate buffer at pH 3.85. [0119]
  • B. Spray Drying. [0120]
  • A dry powder of the 26.7% human calcitonin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0121]
    Temperature of aqueous mixture C.
    Inlet temperature 119° C.
    Feed rate 5.5 mL/min
    Outlet temperature 78° C.
    Atomizer coolant temperature 0-5° C.
    Cyclone coolant temperature 25-30° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0122]
  • C. Characterization. [0123]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0124]
  • The above 26.7% human calcitonin dry powder composition contained 60% mannitol and 13.3% citrate. The formulation contained 0.71% moisture. [0125]
  • The particle size distribution of the composition was determined to be 1.33±0.63 μm MMD. [0126]
  • The delivered dose of the human calcitonin powder was determined to be 76.8±6.7%. [0127]
  • The human calcitonin content of the powder as measured by rpHPLC was determined to be 272.0 μg/mg, accounting for 102±1.7% of the expected human calcitonin. No degradation peaks were detected in the chromatogram. [0128]
  • Example VI 90% Alpha-1 Antitrypsin Formulation for Pulmonary Delivery
  • A. Formulation. [0129]
  • Bulk alpha-I antitrypsin, A1A, was obtained from Armour Pharmaceutical Company, Kankakee, 1L. A 90% A1A formulation was achieved by combining 4.89 mg A1A per 1.0 mL deionized water with 0.54 mg/mL citrate buffer at pH 6.0. [0130]
  • B. Spray Drying. [0131]
  • A dry powder of the 90% A1A formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0132]
    Temperature of aqueous mixture C.
    Inlet temperature 98-101° C.
    Feed rate 5.0 mL/min
    Outlet temperature 65° C.
    Atomizer coolant temperature 2-8° C.
    Cyclone coolant temperature 30° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 69° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0133]
  • C. Characterization. [0134]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0135]
  • The above 90% A1A dry powder composition contained 10.0% citrate. The formulation contained 4.79% moisture. [0136]
  • The particle size distribution of the composition was determined to be 1.71±0.87 μm MMD. [0137]
  • The delivered dose of the 90% A1A powder was determined to be 67.0±5.0%. [0138]
  • The aerosol particle size distribution, was determined to be 1.0 μm MMAD, with 90% of the particles <5.0 μm in diameter. [0139]
  • The A1A content of the powder as measured by rpHPLC was determined to be 80% of the expected value. No degradation peaks were detected in the chromatogram. The activity after spray drying was determined to be 74±1% [0140]
  • Example VII 0.3% Beta Interferon Formulation for Pulmonary Delivery Containing Human Serum Albumin
  • A. Formulation. [0141]
  • Bulk beta interferon, IFN-β, was obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN-β formulation was achieved by combining 0.025 mg IFN-β per 1.0 mL deionized water with 5.54 mg/mL human serum albuman (HSA), 2.3 mg/L citrate buffer and 0.345 mg/mL of NaCl at pH 4.5. [0142]
  • B. Spray Drying. [0143]
  • A dry powder of the 0.3% IFN-β formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0144]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 93° C.
    Feed rate 2.7 mL/min
    Outlet temperature 62° C.
  • C. Characterization. [0145]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0146]
  • The above 0.3% IFN-β dry powder composition contained 66.0% HSA, 27.4% citrate, 4.1% NaCl. The formulation contained 4.22% moisture. [0147]
  • The particle size distribution of the composition was determined to be 1.62 μm MMD with 94.8% of the particles <5 μm. [0148]
  • The delivered dose of the 0.3% IFN-β powder was determined to be 9.9 μg/mg or 66.0±4.0%. [0149]
  • The aerosol particle size distribution, was determined to be 2.0 μm MMAD, with 85% of the particles <5.0 μm in diameter. [0150]
  • The IFN-1 activity of the powder as measured by IFN-β enzyme immunoassay (Toray-Fuji Bionics) and was determined to be 109±8% of the expected activity. [0151]
  • Example VII 0.3% Beta Interferon Formulation for Pulmonary Delivery Containing Raffinose
  • A. Formulation. [0152]
  • Bulk beta interferon, IFN-β, was obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN-β formulation was achieved by combining 0.025 mg IFN-β per 1.0 mL deionized water with 4.7 mg/mL raffinose, 1.0 mg/mL human serum albuman (HSA), 2.3 mg/mL citrate buffer and 0.3 mg/mL of NaCl at pH 4.5. [0153]
  • B. Spray Drying. [0154]
  • A dry powder of the 0.3% IFN-β formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0155]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 145° C.
    Feed rate 5.0 mL/min
    Outlet temperature 87° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 97° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0156]
  • C. Characterization. [0157]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0158]
  • The above 0.3% IFN-β dry powder composition contained 56.4% raffinose, 11.9% HSA, 27.4% citrate, 3.5% NaCl. The formulation contained 0.69% moisture. [0159]
  • The particle size distribution of the composition was determined to be 2.06 μm MMD with 88.9% of the particles <5 μm. [0160]
  • The delivered dose of the 0.3% IFN-β powder was determined to be 10.2 μg/mg or 68.0±2.0%. [0161]
  • The aerosol particle size distribution, was determined to be 2.5 μm MMAD, with 84% of the particles <5.0 Am in diameter. [0162]
  • The IFN-β activity of the powder as measured by IFN-β enzyme immunoassay (Toray-Fuji Bionics) and was determined to be 109±8% of the expected activity. [0163]
  • Example IX 93% Low Molecular Weight Heparin Formulation for Pulmonary Delivery
  • A. Formulation. [0164]
  • Bulk low molecular weight heparin sodium salt (Av. Mol. Wt.: Approx. 6000) from porcine intestinal mucosa, heparin (LMW), was obtained from Sigma Chemical, St. Louis, Mo. A 93% heparin (LMW) formulation was achieved by combining 6.9 mg heparin (LMW) per 1.0 mL deionized water with 0.5 mg/mL HSA at pH 6.9. [0165]
  • B. Spray Drying. [0166]
  • A dry powder of the 93% heparin (LMW) formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0167]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 140° C.
    Feed rate 3.8 mL/min
    Outlet temperature 85° C.
    Atomizer coolant temperature 2-8° C.
    Cyclone coolant temperature 20° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0168]
  • C. Characterization. [0169]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0170]
  • The above 93% heparin (LMW) dry powder composition contained 7.0% HSA. [0171]
  • The delivered dose of the 93% heparin (LMW) powder was determined to be 60.0±1.0%. [0172]
  • The aerosol particle size distribution, was determined to be 3.5 μm MMAD, with 70% of the particles <5.0 μm in diameter. [0173]
  • Example X 97% Unfractionated Heparin Formulation for Pulmonary Delivery
  • A. Formulation. [0174]
  • Bulk unfractionated heparin sodium salt from porcine intestinal mucosa, heparin, was obtained from Sigma Chemical, St. Louis, Mo. A 97% heparin formulation was achieved by combining 7.0 mg heparin per 1.0 mL deionized water with 0.25 mg/mL HSA at pH 6.55. [0175]
  • B. Spray Drying. [0176]
  • A dry powder of the 97% heparin formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0177]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 150° C.
    Feed rate 4.0 mL/min
    Outlet temperature 85° C.
    Atomizer coolant temperature 2-8° C.
    Cyclone coolant temperature 20° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 80° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0178]
  • C. Characterization. [0179]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0180]
  • The above 97% heparin dry powder composition contained 3.0% HSA. The formulation contained 5.11% moisture. [0181]
  • The particle size distribution of the composition was determined to be 2.0 to 2.5 μm MMD. [0182]
  • The delivered dose of the 97% heparin powder was determined to be 79.0±6.0%. [0183]
  • The aerosol particle size distribution, was determined to be 3.2 μm MMAD, with 70% of the particles <5.0 μm in diameter. [0184]
  • Example XI Lipid Vector Gene Formulation for Pulmonary Delivery
  • A. Formulation. [0185]
  • Bulk pCMVβ DNA:Lipid vector as described in U.S. application Ser. No. 08/417,507 filed Apr. 14, 1995 entitled, “COMPOSITIONS AND METHODS FOR NUCLEIC ACID DELIVERY TO THE LUNG”, the disclosure of which is hereby incorporated by reference, was obtained from Genzyme Corporation, Cambridge, Mass. A 0.71% DNA:Lipid vector formulation was achieved by combining 0.005:0.03 mg DNA:Lipid vector per 1.0 mL deionized water with 5.3 mg/mL glycine (J. T. Baker) 0.3 mg/mL HSA at pH 6.4. [0186]
  • B. Spray Drying. [0187]
  • A dry powder of the DNA:Lipid vector formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0188]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 120° C.
    Feed rate 3.8 mL/min
    Outlet temperature 71° C.
    Atomizer coolant temperature 2-8° C.
    Cyclone coolant temperature 2-8° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 65° C. for about 5 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0189]
  • C. Characterization. [0190]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0191]
  • The above 0.71% DNA:Lipid vector dry powder composition contained 93.97% glycine, and 5.32% HSA. [0192]
  • The particle size distribution of the composition was determined to be 2.0 μm MMD. [0193]
  • The delivered dose of the powder was determined to be 64.0±1.0%. [0194]
  • The aerosol particle size distribution, was determined to be 2.4 μm MMAD, with 75% of the particles <5.0 μm in diameter. [0195]
  • Activity after spray drying was determined to be 160% of the expected value. [0196]
  • Example XII Adenoviral Vector Gene Formulation for Pulmonary Delivery
  • A. Formulation. [0197]
  • Bulk pCMVβ DNA:Adenovirous vector as described in U.S. application Ser. No. 08/417,507 filed Apr. 14, 1995, entitled “COMPOSITIONS AND METHODS FOR NUCLEIC ACID DELIVERY TO THE LUNG”, the disclosure of which is hereby incorporated by reference, was obtained from Genzyme Corporation, Cambridge, Mass. A DNA:adenovirous vector formulation was achieved by combining 108 PFU/mL DNA:Lipid vector per 1.0 mL deionized water with 6.1 mg/mL glycine J. T. Baker) 2.5 mg/mL HSA, 1.9 mg/mL phosphate buffer at pH 7.4. [0198]
  • B. Spray Drying. [0199]
  • A dry powder of the DNA:Lipid vector formulation described above was produced by spray drying the aqueous mixture using a Buchi Laboratory Spray Dryer under the following conditions: [0200]
    Temperature of aqueous mixture 2-8° C.
    Inlet temperature 105° C.
    Feed rate 2.9 mL/min
    Outlet temperature 72° C.
    Atomizer coolant temperature 2-8° C.
    Cyclone coolant temperature 20° C.
  • Once the aqueous mixture was consumed, the outlet temperature was maintained at 70° C. for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying. [0201]
  • C. Characterization. [0202]
  • The following characterization of the dry powder formulation described above was carried out using the methods described in Example I unless indicated otherwise. [0203]
  • The above DNA:adenovirous vector dry powder composition contained 58% glycine, and 24% HSA and 18% phosphate buffer. [0204]
  • The particle size distribution of the composition was determined to be 2.3 μm MMD. [0205]
  • The delivered dose of the powder was determined to be 51.0±1.0%. [0206]
  • The aerosol particle size distribution, was determined to be 1.8 Am MMAD, with 80% of the particles <5.0 μm in diameter. [0207]
  • Activity after spray drying was determined to be 76% of the expected value. [0208]
  • All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. [0209]
  • The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims. [0210]

Claims (21)

The subject matter claimed is:
1. A dispersible pharmaceutical-based dry powder composition for pulmonary delivery, said composition comprising a therapeutically effective amount of the pharmaceutical in combination with a pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the composition is substantially free from penetration enhancers.
3. The composition of claim 2, wherein the carrier comprises HSA.
4. The composition of claim 3, wherein the carrier further comprises a carbohydrate bulking agent.
5. The composition of claim 1, wherein about 95% of the mass of the dry powder composition has a particle size of less than 10 μm.
6. The composition of claim 5, wherein about 80% of the mass of the dry powder composition has a particle size of less than 5 μm.
7. A unit dosage form for pulmonary delivery of a pharmaceutical, which dosage form comprises a unit dosage receptacle containing a dispersible pharmaceutical-based dry powder composition, which composition comprises a therapeutically effective amount of the pharmaceutical in combination with a pharmaceutically acceptable carrier.
8. The unit dosage form of claim 7 wherein the carrier comprises HSA and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than about 10 μm.
9. A method of treating a disease state responsive to treatment by a pharmaceutical, which method comprises pulmonarily administering to a subject in need thereof a physiologically effective amount of a dispersible pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of the macromolecule in combination with a pharmaceutically acceptable carrier.
10. The method of claim 9 wherein the carrier comprises HSA and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than about 10Am.
11. A method for aerosolizing a pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of the pharmaceutical in combination with a pharmaceutically acceptable carrier, which method comprises:
dispersing an amount of the dry powder composition in a gas stream to form an aerosol and
capturing the aerosol in a chamber suitable for subsequent inhalation by a patient.
12. The method of claim 11, wherein the carrier comprises HSA and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than about 10 μm.
13. A method for preparing a spray-dried, pharmaceutical-based dry powder composition that comprises a therapeutically effective amount of the macromolecule and a pharmaceutically acceptable carrier, which method comprises spray-drying an aqueous mixture of the macromolecule and the carrier under conditions to provide a respirable dry powder.
14. The method of claim 13 wherein the composition is substantially free from penetration enhancers.
15. The method of claim 14, wherein the carrier comprises HSA.
16. The method of claim 15, wherein the carrier further comprises a carbohydrate bulking agent.
17. The method of claim 16, wherein the bulking agent is mannitol.
18. The method of claim 13, wherein 95% of the mass of the spray-dry composition has a particle size less than 10 μm.
19. A spray-dried, macromolecule-based dry powder composition for pulmonary delivery, said composition comprising a therapeutically effective amount of the macromolecule in combination with a pharmaceutically acceptable carrier that comprises HSA and a carbohydrate bulking agent, wherein the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than 10 μm.
20. The composition of claim 19, wherein the bulking agent is mannitol.
21. The composition according to any of claims 1, 7, 9, 13, and 19 wherein the macromolecule is selected from the group comprising insulin, interlukin 1 receptor, parathyroid hormone (PTH-34), alpha-I antitrypsin, calcitonin, low molecular weight heparin, heparin, interferon, and nucleic acids.
US10/313,961 1992-07-08 2002-12-06 Compositions and methods for the pulmonary delivery of aerosolized medicaments Abandoned US20030198601A1 (en)

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US10/313,961 US20030198601A1 (en) 1992-07-08 2002-12-06 Compositions and methods for the pulmonary delivery of aerosolized medicaments
US11/627,884 US20070122418A1 (en) 1992-07-08 2007-01-26 Compositions and methods for the pulmonary delivery of aerosolized medicaments

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US07/910,048 US5458135A (en) 1991-07-02 1992-07-08 Method and device for delivering aerosolized medicaments
US4435893A 1993-04-07 1993-04-07
US24603494A 1994-05-18 1994-05-18
US08/309,691 US5785049A (en) 1994-09-21 1994-09-21 Method and apparatus for dispersion of dry powder medicaments
US31370794A 1994-09-27 1994-09-27
US38347595A 1995-02-01 1995-02-01
US41750795A 1995-04-04 1995-04-04
US08/423,515 US6582728B1 (en) 1992-07-08 1995-04-14 Spray drying of macromolecules to produce inhaleable dry powders
US10/313,961 US20030198601A1 (en) 1992-07-08 2002-12-06 Compositions and methods for the pulmonary delivery of aerosolized medicaments

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US10/066,106 Abandoned US20020127188A1 (en) 1992-07-08 2002-02-01 Composition for pulmonary administration comprising a drug and a hydrophobic amino acid
US10/072,430 Expired - Fee Related US6797258B2 (en) 1992-07-08 2002-02-08 Compositions and methods for the pulmonary delivery of aerosolized macromolecules
US10/242,714 Expired - Lifetime US7097827B2 (en) 1995-04-14 2002-09-13 Devices, compositions and methods for the pulmonary delivery of aerosolized medicaments
US10/313,961 Abandoned US20030198601A1 (en) 1992-07-08 2002-12-06 Compositions and methods for the pulmonary delivery of aerosolized medicaments
US10/355,578 Expired - Fee Related US6921527B2 (en) 1992-07-08 2003-01-31 Composition for pulmonary administration comprising a drug and a hydrophobic amino acid
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US11/426,927 Abandoned US20070042048A1 (en) 1995-04-14 2006-06-27 Devices, Compositions and Methods for the Pulmonary Delivery of Aerosolized Medicaments
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040087543A1 (en) * 2002-04-25 2004-05-06 Zachary Shriver Methods and products for mucosal delivery
US20050207988A1 (en) * 2003-10-01 2005-09-22 Thomas Richardson Polysaccharides for pulmonary delivery of active agents
US20050276846A1 (en) * 1994-12-02 2005-12-15 Roser Bruce J Solid dose delivery vehicle and methods of making same
US20070037776A1 (en) * 2005-08-08 2007-02-15 Tom Richardson Polysaccharides for delivery of active agents
US7709461B2 (en) 2000-10-18 2010-05-04 Massachusetts Institute Of Technology Methods and products related to pulmonary delivery of polysaccharides
US7928089B2 (en) 2003-09-15 2011-04-19 Vectura Limited Mucoactive agents for treating a pulmonary disease
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US8322046B2 (en) * 2003-12-22 2012-12-04 Zhaolin Wang Powder formation by atmospheric spray-freeze drying
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery

Families Citing this family (398)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
ATE220327T1 (en) * 1992-09-29 2002-07-15 Inhale Therapeutic Syst PULMONARY RELEASE OF ACTIVE FRAGMENTS OF THE PARATHORMONE
WO1995024183A1 (en) * 1994-03-07 1995-09-14 Inhale Therapeutic Systems Methods and compositions for pulmonary delivery of insulin
US20030113273A1 (en) * 1996-06-17 2003-06-19 Patton John S. Methods and compositions for pulmonary delivery of insulin
US6051256A (en) * 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
JPH10500672A (en) * 1994-05-18 1998-01-20 インヘイル セラピューティック システムズ,インコーポレイティド Methods and compositions relating to dry powder formulations of interferon
US6309671B1 (en) * 1995-04-14 2001-10-30 Inhale Therapeutic Systems Stable glassy state powder formulations
US6258341B1 (en) * 1995-04-14 2001-07-10 Inhale Therapeutic Systems, Inc. Stable glassy state powder formulations
US6428771B1 (en) * 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
GB9515182D0 (en) * 1995-07-24 1995-09-20 Co Ordinated Drug Dev Improvements in and relating to powders for use in dry powder inhalers
DE19539574A1 (en) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Preparations and processes for stabilizing biological materials by means of drying processes without freezing
TW403653B (en) * 1995-12-25 2000-09-01 Otsuka Pharma Co Ltd Dry compositions
KR100449789B1 (en) * 1996-01-24 2005-02-03 알타나 파마 아게 Manufacturing Method of Powdered Lung Surfactant
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US20020052310A1 (en) * 1997-09-15 2002-05-02 Massachusetts Institute Of Technology The Penn State Research Foundation Particles for inhalation having sustained release properties
US6254854B1 (en) * 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US20030203036A1 (en) 2000-03-17 2003-10-30 Gordon Marc S. Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
US7779020B2 (en) * 2002-03-01 2010-08-17 International Business Machines Corporation Small-footprint applicative query interpreter method, system and program product
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
AU748756B2 (en) 1997-07-18 2002-06-13 Infimed Therapeutics, Inc. Biodegradable macromers for the controlled release of biologically active substances
US7052678B2 (en) * 1997-09-15 2006-05-30 Massachusetts Institute Of Technology Particles for inhalation having sustained release properties
US6345617B1 (en) 1997-09-26 2002-02-12 1263152 Ontario Inc. Aerosol medication delivery apparatus and system
US6293279B1 (en) 1997-09-26 2001-09-25 Trudell Medical International Aerosol medication delivery apparatus and system
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US6565885B1 (en) 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
EE04628B1 (en) * 1997-09-29 2006-06-15 Inhale Therapeutic Systems, Inc. Powder with Perforated Microstructures and Method for Preparing a Microparticle Composition and Powder with Perforated Microstructures
ZA989744B (en) * 1997-10-31 2000-04-26 Lilly Co Eli Method for administering acylated insulin.
US6770623B1 (en) * 1997-12-09 2004-08-03 Eli Lilly And Company Stabilized teriparatide solutions
WO1999055362A1 (en) * 1998-04-29 1999-11-04 Genentech, Inc. Spray dried formulations of igf-i
US7022683B1 (en) 1998-05-13 2006-04-04 Carrington Laboratories, Inc. Pharmacological compositions comprising pectins having high molecular weights and low degrees of methoxylation
GB9814172D0 (en) * 1998-06-30 1998-08-26 Andaris Ltd Formulation for inhalation
US6451349B1 (en) 1998-08-19 2002-09-17 Quadrant Healthcare (Uk) Limited Spray-drying process for the preparation of microparticles
US6956021B1 (en) * 1998-08-25 2005-10-18 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
US7056504B1 (en) 1998-08-27 2006-06-06 Massachusetts Institute Of Technology Rationally designed heparinases derived from heparinase I and II
UA73924C2 (en) 1998-10-09 2005-10-17 Nektar Therapeutics Device for delivering active agent formulation to lungs of human patient
US8933032B2 (en) 1998-10-20 2015-01-13 Children's Hospital Medical Center Surfactant protein D for the treatment of disorders associated with lung injury
US20060171899A1 (en) * 1998-12-10 2006-08-03 Akwete Adjei Water-stabilized aerosol formulation system and method of making
AU779869B2 (en) * 1999-04-13 2005-02-17 Nektar Therapeutics Pulmonary administration of dry powder formulations for treating infertility
WO2000075281A2 (en) 1999-06-09 2000-12-14 University Technology Corporation Supercritical fluid-assisted nebulization and bubble drying
US6858199B1 (en) * 2000-06-09 2005-02-22 Advanced Inhalation Research, Inc. High efficient delivery of a large therapeutic mass aerosol
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
ES2569916T3 (en) * 1999-06-29 2016-05-13 Mannkind Corporation Pharmaceutical formulations comprising insulin complexed with a diketopiperazine
US7678364B2 (en) * 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
WO2001013891A2 (en) * 1999-08-25 2001-03-01 Advanced Inhalation Research, Inc. Modulation of release from dry powder formulations
US7252840B1 (en) 1999-08-25 2007-08-07 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles
ATE285755T1 (en) * 1999-08-25 2005-01-15 Advanced Inhalation Res Inc LARGE POROUS PARTICLES AVAILABLE BY SPRAY DRYING AND SUITABLE FOR PULMONARY USE
US6749835B1 (en) 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
US6586008B1 (en) * 1999-08-25 2003-07-01 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles during spray drying
US20010036481A1 (en) * 1999-08-25 2001-11-01 Advanced Inhalation Research, Inc. Modulation of release from dry powder formulations
DE19962221A1 (en) * 1999-10-01 2001-05-23 Glatt Process Technology Gmbh Sustained-release medicament formulation, e.g. for parenteral or transdermal use, comprising drug and carrier system consisting of solid biodegradable blood plasma proteins obtained by fluidized bed drying
NZ518401A (en) 1999-10-29 2004-01-30 Nektar Therapeutics Dry powder compositions having improved dispersivity
US6669960B2 (en) 1999-12-21 2003-12-30 Rxkinetix, Inc. Particulate drug-containing products and method of manufacture
US6761909B1 (en) 1999-12-21 2004-07-13 Rxkinetix, Inc. Particulate insulin-containing products and method of manufacture
AU784885B2 (en) * 1999-12-24 2006-07-20 Otsuka Pharmaceutical Co., Ltd. Dry compositions containing hydrophobic amino acid
FI20002217A (en) * 1999-12-30 2001-07-01 Orion Yhtymae Oyj inhalation particles
GB0003935D0 (en) * 2000-02-08 2000-04-12 King S College London Formulation for dry powder inhaler
US6645261B2 (en) 2000-03-06 2003-11-11 Cargill, Inc. Triacylglycerol-based alternative to paraffin wax
WO2001066772A2 (en) 2000-03-08 2001-09-13 Massachusetts Institute Of Technology Heparinase iii and uses thereof
JP4711520B2 (en) * 2000-03-21 2011-06-29 日本ケミカルリサーチ株式会社 Bioactive peptide-containing powder
WO2001076671A2 (en) 2000-04-11 2001-10-18 Trudell Medical International Aerosol delivery apparatus with positive expiratory pressure capacity
GB0010709D0 (en) * 2000-05-03 2000-06-28 Vectura Ltd Powders for use a in dry powder inhaler
US20040176391A1 (en) * 2002-12-31 2004-09-09 Nektar Therapeutics Aerosolizable pharmaceutical formulation for fungal infection therapy
US7575761B2 (en) * 2000-06-30 2009-08-18 Novartis Pharma Ag Spray drying process control of drying kinetics
EP2060253A1 (en) 2007-11-14 2009-05-20 Laboratorios Farmaceuticos Rovi, S.A. Pharmaceutical forms for the release of active compounds
CN1446077A (en) * 2000-08-07 2003-10-01 耐科塔医药公司 Inhaleable spray dried 4-holix bundle protein powders having minimized aggregation
ES2324701T3 (en) 2000-09-12 2009-08-13 Massachusetts Institute Of Technology METHODS AND PRODUCTS RELATED TO MOLECULAR WEIGHT HEPARINE.
EP1343372A2 (en) * 2000-12-21 2003-09-17 Nektar Therapeutics Pulmonary delivery of polyene antifungal agents
JP2004521103A (en) * 2000-12-21 2004-07-15 ネクター セラピューティックス Storage stable powder composition of interleukin 4 receptor
EP1797902A3 (en) * 2000-12-29 2007-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
EP1345629A2 (en) * 2000-12-29 2003-09-24 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
US7494669B2 (en) * 2001-02-28 2009-02-24 Carrington Laboratories, Inc. Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
US6777000B2 (en) * 2001-02-28 2004-08-17 Carrington Laboratories, Inc. In-situ gel formation of pectin
US6824572B2 (en) 2001-03-06 2004-11-30 Cargill, Incorporated Vegetable oil based wax compositions
US6887462B2 (en) 2001-04-09 2005-05-03 Chiron Corporation HSA-free formulations of interferon-beta
CN1507362A (en) * 2001-05-04 2004-06-23 �Ʒ� Method of preventing type 2 diabetes with aerosolized insulin
US7905230B2 (en) 2001-05-09 2011-03-15 Novartis Ag Metered dose inhaler with lockout
US6503285B1 (en) * 2001-05-11 2003-01-07 Cargill, Inc. Triacylglycerol based candle wax
US20050159380A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA)
US20050256068A1 (en) * 2001-05-18 2005-11-17 Sirna Therapeutics, Inc. RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA)
US20070270579A1 (en) * 2001-05-18 2007-11-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050203040A1 (en) * 2001-05-18 2005-09-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA)
US20050119212A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA)
US20050148530A1 (en) * 2002-02-20 2005-07-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20060019913A1 (en) * 2001-05-18 2006-01-26 Sirna Therapeutics, Inc. RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US20050222066A1 (en) * 2001-05-18 2005-10-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050182009A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA)
US20050176664A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA)
US20050182007A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20050233344A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA)
US20060241075A1 (en) * 2001-05-18 2006-10-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA)
US20050014172A1 (en) * 2002-02-20 2005-01-20 Ivan Richards RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA)
US7517864B2 (en) * 2001-05-18 2009-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050233997A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA)
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20050054596A1 (en) * 2001-11-30 2005-03-10 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050287128A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA)
US20050187174A1 (en) * 2001-05-18 2005-08-25 Sirna Therapeutics, Inc. RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US20070042983A1 (en) * 2001-05-18 2007-02-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050164968A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA)
US20050176666A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA)
US20050267058A1 (en) * 2001-05-18 2005-12-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (sINA)
US20050227935A1 (en) * 2001-05-18 2005-10-13 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US20040198682A1 (en) * 2001-11-30 2004-10-07 Mcswiggen James RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA)
US20050288242A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA)
US20050159376A1 (en) * 2002-02-20 2005-07-21 Slrna Therapeutics, Inc. RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA)
US20050159382A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA)
US20080161256A1 (en) * 2001-05-18 2008-07-03 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050282188A1 (en) * 2001-05-18 2005-12-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050143333A1 (en) * 2001-05-18 2005-06-30 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
EP1399132A1 (en) * 2001-06-08 2004-03-24 Powderject Vaccines, Inc. Production of hard, dense particles
EG24184A (en) 2001-06-15 2008-10-08 Otsuka Pharma Co Ltd Dry powder inhalation system for transpulmonary
WO2003000326A1 (en) 2001-06-20 2003-01-03 Nektar Therapeutics Powder aerosolization apparatus and method
NZ519403A (en) * 2001-06-21 2005-03-24 Pfizer Prod Inc Use of insulin in a medicament to reduce weight gain in a diabetic patient who is using exogenous insulin to control blood sugar levels
US7128766B2 (en) * 2001-09-25 2006-10-31 Cargill, Incorporated Triacylglycerol based wax compositions
WO2003035028A1 (en) * 2001-10-19 2003-05-01 Nektar Therapeutics Modulating charge density to produce improvements in the characteristics of spray-dried proteins
WO2003035051A2 (en) * 2001-10-19 2003-05-01 Inhale Therapeutic Systems, Inc. The use of proton sequestering agents in drug formulations
DE60227691D1 (en) * 2001-11-01 2008-08-28 Nektar Therapeutics SPRAY DRYING PROCESS
US20070203333A1 (en) * 2001-11-30 2007-08-30 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050075304A1 (en) * 2001-11-30 2005-04-07 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20040138163A1 (en) * 2002-05-29 2004-07-15 Mcswiggen James RNA interference mediated inhibition of vascular edothelial growth factor and vascular edothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
WO2003057593A1 (en) 2001-12-21 2003-07-17 Nektar Therapeutics Capsule package with moisture barrier
US20050042632A1 (en) * 2002-02-13 2005-02-24 Sirna Therapeutics, Inc. Antibodies having specificity for nucleic acids
AU2003207241A1 (en) * 2002-02-18 2003-09-04 Ajinomoto Co., Inc. Dry powder holding flavor and aroma components and process for producing the same
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
CN1635853B (en) * 2002-02-20 2010-05-12 21世纪国际新技术株式会社 Fine powder drug administration apparatus
US20050137153A1 (en) * 2002-02-20 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using short interfering nucleic acid (siNA)
EP1479300B1 (en) * 2002-02-22 2009-10-21 Ajinomoto Co., Inc. Amino acid powder and process for producing the same
EP1483283A4 (en) 2002-03-13 2007-04-11 Signum Biosciences Inc Modulation of protein methylation and phosphoprotein phosphate
JP2005520847A (en) * 2002-03-20 2005-07-14 アドバンスト インハレーション リサーチ,インコーポレイテッド HGH (human growth hormone) formulation for pulmonary administration
ES2425392T3 (en) 2002-03-20 2013-10-15 Mannkind Corporation Cartridge for an inhalation device
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
US7008644B2 (en) * 2002-03-20 2006-03-07 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
US7754242B2 (en) * 2002-03-20 2010-07-13 Alkermes, Inc. Inhalable sustained therapeutic formulations
US20110123574A1 (en) * 2002-03-20 2011-05-26 Alkermes, Inc. Inhalable sustained therapeutic formulations
CA2484052C (en) 2002-04-11 2011-06-14 Medimmune Vaccines, Inc. Preservation of bioactive materials by spray drying
EP1503754B1 (en) 2002-04-19 2005-11-23 Yissum Research Development Company, of The Hebrew University of Jerusalem Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
GB0216562D0 (en) 2002-04-25 2002-08-28 Bradford Particle Design Ltd Particulate materials
US20030205226A1 (en) 2002-05-02 2003-11-06 Pre Holding, Inc. Aerosol medication inhalation system
GB0219815D0 (en) 2002-08-24 2002-10-02 Accentus Plc Preparation of small crystals
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
US6904908B2 (en) 2002-05-21 2005-06-14 Trudell Medical International Visual indicator for an aerosol medication delivery apparatus and system
US6941980B2 (en) 2002-06-27 2005-09-13 Nektar Therapeutics Apparatus and method for filling a receptacle with powder
DE10234165B4 (en) * 2002-07-26 2008-01-03 Advanced Micro Devices, Inc., Sunnyvale A method of filling a trench formed in a substrate with an insulating material
EP1556018A1 (en) * 2002-09-30 2005-07-27 Acusphere, Inc. Sustained release porous microparticles for inhalation
US6773469B2 (en) * 2002-11-12 2004-08-10 Cargill, Incorporated Triacylglycerol based wax for use in candles
US6797020B2 (en) * 2002-11-12 2004-09-28 Cargill, Incorporated Triacylglycerol based wax for use in container candles
US7516741B2 (en) 2002-12-06 2009-04-14 Novartis Ag Aerosolization apparatus with feedback mechanism
US20060002862A1 (en) * 2002-12-17 2006-01-05 Medimmune Vaccines, Inc. High pressure spray-dry of bioactive materials
EP1581639A4 (en) * 2002-12-17 2006-03-08 Medimmune Vaccines Inc High pressure spray-dry of bioactive materials
US7967221B2 (en) * 2002-12-30 2011-06-28 Novartis Ag Prefilming atomizer
US7669596B2 (en) 2002-12-31 2010-03-02 Novartis Pharma Ag Aerosolization apparatus with rotating capsule
AU2003300137A1 (en) * 2002-12-31 2004-07-29 Novartis Ag Pharmaceutical formulation with an insoluble active agent for pulmonary administration
WO2004060343A1 (en) * 2002-12-31 2004-07-22 Nektar Therapeutics Antibody-containing particles and compositions
WO2004091705A1 (en) 2003-04-09 2004-10-28 Nektar Therapeutics Aerosolization apparatus with air inlet shield
US20050008580A1 (en) * 2003-04-09 2005-01-13 Wyeth Hemophilia treatment by inhalation of coagulation factors
EP1615689B1 (en) 2003-04-09 2016-02-03 Novartis AG Aerosolization apparatus with capsule puncture alignment guide
US8869794B1 (en) 2003-04-09 2014-10-28 Novartis Pharma Ag Aerosolization apparatus with capsule puncturing member
BRPI0409380A (en) * 2003-04-14 2006-04-18 Vectura Ltd pharmaceutical compositions
US20040204439A1 (en) * 2003-04-14 2004-10-14 Staniforth John Nicholas Composition, device, and method for treating sexual dysfunction via inhalation
US7077176B2 (en) * 2003-04-28 2006-07-18 Medical Instill Technologies, Inc. Container with valve assembly for filling and dispensing substances, and apparatus and method for filling
US7192457B2 (en) * 2003-05-08 2007-03-20 Cargill, Incorporated Wax and wax-based products
KR20120080243A (en) * 2003-05-28 2012-07-16 노바르티스 아게 Spray drying of an alcoholic aqueous solution for the manufacture of a water-insoluble active agent microparticle with a partial or complete amino acid and/or phospholipid coat
US9078866B2 (en) * 2003-08-01 2015-07-14 Mannkind Corporation Method for treating hyperglycemia with GLP-1
US20050172958A1 (en) * 2003-08-20 2005-08-11 The Brigham And Women's Hospital, Inc. Inhalation device and system for the remote monitoring of drug administration
DE10339197A1 (en) * 2003-08-22 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Spray-dried amorphous powder with low residual moisture and good storage stability
EP1667659A1 (en) * 2003-09-30 2006-06-14 Acusphere, Inc. Injectable, oral, or topical sustained release pharmaceutical formulations
CA2547822A1 (en) * 2003-12-11 2005-06-30 Ares Trading S.A. Stabilized interferon liquid formulations
CN1546169A (en) * 2003-12-16 2004-11-17 上海医药工业研究院 Transnasal inhalant dry powder of calcitonin and its preparation
US7192919B2 (en) 2004-01-07 2007-03-20 Stelios Tzannis Sustained release compositions for delivery of pharmaceutical proteins
CA2552707C (en) * 2004-01-12 2018-03-27 Mannkind Corporation A method of reducing serum proinsulin levels in type 2 diabetics
WO2005077338A1 (en) * 2004-02-10 2005-08-25 Advanced Inhalation Research, Inc. Particles for inhalation rapid release properties
JP2007522246A (en) * 2004-02-12 2007-08-09 ネクター セラピューティクス Interleukin-13 antagonist powder, spray-dried particles, and method
PL2319500T3 (en) * 2004-03-12 2013-05-31 Biodel Inc Rapid acting drug delivery compositions
US20080090753A1 (en) 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
US20080248999A1 (en) * 2007-04-04 2008-10-09 Biodel Inc. Amylin formulations
US7625865B2 (en) * 2004-03-26 2009-12-01 Universita Degli Studi Di Parma Insulin highly respirable microparticles
HUE042304T2 (en) * 2004-04-23 2019-06-28 Cydex Pharmaceuticals Inc DPI Formulation Containing Sulfoalkyl Ether Cyclodextrin
US20060039985A1 (en) * 2004-04-27 2006-02-23 Bennett David B Methotrexate compositions
US7723306B2 (en) 2004-05-10 2010-05-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Spray-dried powder comprising at least one 1,4 O-linked saccharose-derivative and methods for their preparation
US7727962B2 (en) 2004-05-10 2010-06-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Powder comprising new compositions of oligosaccharides and methods for their preparation
US7611709B2 (en) 2004-05-10 2009-11-03 Boehringer Ingelheim Pharma Gmbh And Co. Kg 1,4 O-linked saccharose derivatives for stabilization of antibodies or antibody derivatives
DE102004022926A1 (en) * 2004-05-10 2005-12-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Spray-dried powders containing at least one 1,4 O-linked sucrose derivative and process for their preparation
US20050266011A1 (en) * 2004-05-19 2005-12-01 Yuh-Fun Maa Method and formulation for transdermal delivery of immunologically active agents
EP1755720A1 (en) * 2004-05-20 2007-02-28 Discovery Laboratories, Inc. Methods , systems and devices for noninvasive pulmonary delivery
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
EP1773301A2 (en) 2004-06-21 2007-04-18 Nektar Therapeutics Compositions comprising amphotericinb methods and systems
US8513204B2 (en) 2004-06-21 2013-08-20 Novartis Ag Compositions comprising amphotericin B, mehods and systems
ES2618028T3 (en) 2004-07-19 2017-06-20 Biocon Limited Insulin-oligomer conjugates, formulations and uses thereof.
DE602005027092D1 (en) * 2004-08-02 2011-05-05 Chiesi Farma Spa PROCESS FOR PREPARING A PIROXICAM: BETA-CYCLODEXTRIN INCLUSION COMPOUND
US7772182B2 (en) * 2004-08-05 2010-08-10 Alza Corporation Stable suspension formulations of erythropoietin receptor agonists
ES2385934T3 (en) 2004-08-20 2012-08-03 Mannkind Corporation CATALYSIS OF THE SYNTHESIS OF DICETOPIPERAZINA.
WO2006023943A1 (en) 2004-08-23 2006-03-02 Mannkind Corporation Diketopiperazine salts, diketomorpholine salts or diketodioxane salts for drug delivery
GB0425758D0 (en) 2004-11-23 2004-12-22 Vectura Ltd Preparation of pharmaceutical compositions
WO2006076097A2 (en) * 2004-12-07 2006-07-20 Nektar Therapeutics Stable non-crystalline formulation comprising losartan
WO2006076277A1 (en) * 2005-01-10 2006-07-20 Nektar Therapeutics Compositions and methods for increasing the bioavailability of pulmonarily administered insulin
US8221804B2 (en) 2005-02-03 2012-07-17 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
US7923041B2 (en) 2005-02-03 2011-04-12 Signum Biosciences, Inc. Compositions and methods for enhancing cognitive function
US8028697B2 (en) 2005-04-28 2011-10-04 Trudell Medical International Ventilator circuit and method for the use thereof
WO2007052154A2 (en) * 2005-04-29 2007-05-10 University Of Medicine And Dentistry Of New Jersey Erythropoietin-derived short peptide and its mimics as immuno/inflammatory modulators
US9345745B2 (en) 2005-04-29 2016-05-24 Bo Wang Methods for treating inflammatory disorders and traumatic brain injury using stabilized non-hematopoietic EPO short peptides
US9585932B2 (en) 2005-04-29 2017-03-07 Peter C. Dowling Use of EPO-derived peptide fragments for the treatment of neurodegenerative disorders
EP1893273B1 (en) 2005-05-18 2014-06-25 Nektar Therapeutics Adapter for use with aerosolization device for endobronchial therapy
WO2006128025A2 (en) * 2005-05-23 2006-11-30 Children's Hospital Medical Center Regulatory proteins in lung repair and treatment of lung disease
US20090192227A1 (en) * 2005-08-24 2009-07-30 Rabindra Tirouvanziam N-Acetylcysteine Compositions and Methods for Treating Acute Exacerbations of Inflammatory Lung Disease
CA2620123C (en) * 2005-08-24 2011-11-22 The Board Of Trustees Of The Leland Stanford Junior University Methods for treating and monitoring inflammation and redox imbalance in cystic fibrosis
US8227408B2 (en) * 2005-09-07 2012-07-24 Neurotez, Inc. Leptin as an anti-amyloidogenic biologic and methods for delaying the onset and reducing Alzheimer's disease-like pathology
ES2640282T3 (en) 2005-09-14 2017-11-02 Mannkind Corporation Drug formulation method based on increasing the affinity of crystalline microparticle surfaces for active agents
US7713929B2 (en) * 2006-04-12 2010-05-11 Biodel Inc. Rapid acting and long acting insulin combination formulations
US8084420B2 (en) * 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
AU2006297394B9 (en) * 2005-09-29 2013-09-19 Novartis Ag Receptacles and kits, such as for dry powder packaging
WO2007041481A1 (en) * 2005-09-29 2007-04-12 Biodel, Inc. Rapid acting and prolonged acting insulin preparations
US7629331B2 (en) 2005-10-26 2009-12-08 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US7827042B2 (en) 2005-11-30 2010-11-02 The Invention Science Fund I, Inc Methods and systems related to transmission of nutraceutical associated information
US8000981B2 (en) 2005-11-30 2011-08-16 The Invention Science Fund I, Llc Methods and systems related to receiving nutraceutical associated information
US7974856B2 (en) 2005-11-30 2011-07-05 The Invention Science Fund I, Llc Computational systems and methods related to nutraceuticals
US10296720B2 (en) 2005-11-30 2019-05-21 Gearbox Llc Computational systems and methods related to nutraceuticals
US7927787B2 (en) 2006-06-28 2011-04-19 The Invention Science Fund I, Llc Methods and systems for analysis of nutraceutical associated components
US20080210748A1 (en) 2005-11-30 2008-09-04 Searete Llc, A Limited Liability Corporation Of The State Of Delaware, Systems and methods for receiving pathogen related information and responding
US8297028B2 (en) 2006-06-14 2012-10-30 The Invention Science Fund I, Llc Individualized pharmaceutical selection and packaging
US8340944B2 (en) 2005-11-30 2012-12-25 The Invention Science Fund I, Llc Computational and/or control systems and methods related to nutraceutical agent selection and dosing
JP2009519970A (en) * 2005-12-15 2009-05-21 アキュスフィア, インコーポレイテッド Process for producing particle-based pharmaceutical dosage forms for oral administration
US8293869B2 (en) 2005-12-16 2012-10-23 Nektar Therapeutics Polymer conjugates of GLP-1
US8039431B2 (en) 2006-02-22 2011-10-18 Mannkind Corporation Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
EP1991532B1 (en) 2006-02-24 2017-01-11 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US7718609B2 (en) * 2006-04-12 2010-05-18 Biodel Inc. Rapid acting and long acting insulin combination formulations
JP5566101B2 (en) * 2006-04-24 2014-08-06 メディカル・インスティル・テクノロジーズ・インコーポレイテッド Needle penetrable and laser resealable freeze-drying apparatus and related methods
DE102006030164A1 (en) * 2006-06-29 2008-01-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Inhalative powders
US20080170996A1 (en) * 2006-07-28 2008-07-17 The Board Of Regents Of The University Of Texas System Compositions and Methods for Stimulation of Lung Innate Immunity
US20080063722A1 (en) * 2006-09-08 2008-03-13 Advanced Inhalation Research, Inc. Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI)
EP2668970B1 (en) 2006-10-25 2016-07-06 Novartis AG Powder dispersion apparatus
DK2155228T3 (en) 2007-01-10 2014-07-07 Purdue Research Foundation HSP27 kinase polypeptide inhibitors and applications thereof
WO2008112353A2 (en) * 2007-02-05 2008-09-18 The Brigham And Women's Hospital, Inc. Instrumented metered-dose inhaler and methods for predicting disease exacerbations
GB2448183A (en) 2007-04-05 2008-10-08 Optinose As Nasal powder delivery device
WO2008128095A1 (en) 2007-04-12 2008-10-23 Regents Of The University Of Minnesota Ischemia/reperfusion protection compositions and methods of using
US9554997B2 (en) * 2007-06-18 2017-01-31 New York University Polymer carrier
EP2185698B1 (en) 2007-08-07 2015-04-22 Purdue Research Foundation Kinase inhibitors and uses thereof
EP2207890A4 (en) 2007-10-05 2010-12-15 Barofold Inc High pressure treatment of aggregated interferons
US8268354B2 (en) 2007-11-07 2012-09-18 Aridis Pharmaceuticals Sonic low pressure spray drying
EP2213282A1 (en) 2009-01-30 2010-08-04 Laboratorios Farmaceuticos Rovi, S.A. Pharmaceutical forms for the release of active compounds
PL2234645T3 (en) * 2007-12-20 2012-10-31 Merck Serono Sa Peg-interferon-beta formulations
AU2009204309B2 (en) * 2008-01-04 2012-11-22 Biodel, Inc. Insulin formulations for insulin release as a function of tissue glucose levels
BRPI0908556B8 (en) 2008-03-17 2021-06-22 Discovery Lab Inc adapter for delivering an aerosolized active agent and system for delivering an aerosolized active agent
WO2009140587A1 (en) * 2008-05-15 2009-11-19 Novartis Ag Pulmonary delivery of a fluoroquinolone
WO2009143380A2 (en) * 2008-05-21 2009-11-26 Neurotez, Inc. Methods for treating progressive cognitive disorders related to neurofibrillary tangles
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
CN104689432B (en) 2008-06-13 2018-07-06 曼金德公司 Diskus and the system for drug conveying
CN102065942B (en) 2008-06-20 2013-12-11 曼金德公司 An interactive apparatus and method for real-time profiling of inhalation efforts
EP3327982B1 (en) 2008-06-23 2019-08-07 Sun Patent Trust Method of arranging reference signals and wireless communication system
WO2010007604A2 (en) * 2008-07-16 2010-01-21 Royal College Of Surgeons In Ireland Inhalable microparticles, and methods for the production thereof
TWI532497B (en) 2008-08-11 2016-05-11 曼凱公司 Use of ultrarapid acting insulin
WO2010030790A2 (en) * 2008-09-10 2010-03-18 The Texas A&M University System Methods and compositions for stimulation of mammalian innate immune resistance to pathogens
EP2341942A1 (en) 2008-09-19 2011-07-13 Nektar Therapeutics Polymer conjugates of therapeutic peptides
CN102239255B (en) 2008-10-03 2015-11-25 纳幕尔杜邦公司 Improve Perhydrolase to generate for enzymatic peracid
KR20170001756A (en) * 2008-10-20 2017-01-04 모레 매트릭스 인코포레이티드 Polypeptide for treating or preventing adhesions
EP2179760B1 (en) 2008-10-22 2013-02-27 Trudell Medical International Modular Aerosol Delivery System
AU2009313562B2 (en) * 2008-11-04 2012-11-15 Neurotez, Inc. Leptin compositions and methods for treating progressive cognitive function disorders resulting from accumulation of neurofibrillary tangles and amlyoid beta
JP2012509922A (en) * 2008-11-27 2012-04-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New powdered crystalline inhalant
KR101965255B1 (en) * 2008-12-10 2019-04-03 퍼듀 리서치 파운데이션 Cell-permeant peptide-based inhibitor of kinases
US9827205B2 (en) * 2008-12-12 2017-11-28 Mallinckrodt Pharma Ip Trading D.A.C. Dry powder fibrin sealant
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
CA2748490C (en) 2008-12-29 2016-10-04 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
ES2473584T3 (en) 2009-01-23 2014-07-07 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibiting the JAK route
US9060927B2 (en) * 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
CA2754595C (en) 2009-03-11 2017-06-27 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
AU2010226613B2 (en) 2009-03-18 2013-07-25 Incarda Therapeutics, Inc. Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration
WO2010107957A2 (en) 2009-03-19 2010-09-23 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2408916A2 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF CONNECTIVE TISSUE GROWTH FACTOR (CTGF) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120035247A1 (en) 2009-03-19 2012-02-09 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 6 (STAT6) Gene Expression Using Short Interfering Nucleic Acid (siNA)
US20120016010A1 (en) 2009-03-19 2012-01-19 Merck Sharp & Dohme Corp RNA Interference Mediated Inhibition of BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 1 (BACH1) Gene Expression Using Short Interfering Nucleic Acid (siNA)
MX2011010050A (en) 2009-03-25 2011-12-14 Univ Texas Compositions for stimulation of mammalian innate immune resistance to pathogens.
US20120064126A1 (en) 2009-03-26 2012-03-15 Pulmatrix, Inc. Dry powder formulations and methods for treating pulmonary diseases
AU2010229847A1 (en) 2009-03-27 2011-10-13 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of the intercellular adhesion molecule 1 (ICAM-1)gene expression using short interfering nucleic acid (siNA)
JP2012521764A (en) 2009-03-27 2012-09-20 メルク・シャープ・エンド・ドーム・コーポレイション RNA interference-mediated inhibition of thymic stromal lymphocyte formation factor (TSLP) gene expression using small interfering nucleic acids (siNA)
WO2010111468A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA)
WO2010111471A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120010272A1 (en) 2009-03-27 2012-01-12 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Apoptosis Signal-Regulating Kinase 1 (ASK1) Gene Expression Using Short Interfering Nucleic Acid (siNA)
US20100266643A1 (en) 2009-04-01 2010-10-21 Willett W Scott Pulmonary and nasal delivery of serum amyloid p
GB0908129D0 (en) * 2009-05-12 2009-06-24 Innovata Ltd Composition
US9463161B2 (en) 2009-05-29 2016-10-11 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
JP5908397B2 (en) 2009-06-09 2016-04-26 デフィルス、インコーポレイテッドDefyrus, Inc. Interferon administration to prevent or treat pathogen infection
WO2010144789A2 (en) 2009-06-12 2010-12-16 Mannkind Corporation Diketopiperazine microparticles with defined specific surface areas
SG10201500620PA (en) 2009-07-24 2015-03-30 Amazentis Sa Compounds, compositions and methods for protecting brain health in neurodegenerative disorders
US9890195B2 (en) * 2009-07-27 2018-02-13 Purdue Research Foundation MK2 inhibitor compositions and methods to enhance neurite outgrowth, neuroprotection, and nerve regeneration
US8222012B2 (en) 2009-10-01 2012-07-17 E. I. Du Pont De Nemours And Company Perhydrolase for enzymatic peracid production
CA2778698A1 (en) 2009-11-03 2011-05-12 Mannkind Corporation An apparatus and method for simulating inhalation efforts
CA2781896C (en) 2009-12-09 2021-03-30 Nitto Denko Corporation Modulation of hsp47 expression
WO2011092690A1 (en) 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions and methods for prevention and treatment of pulmonary hypertension
EP2582421A1 (en) 2010-06-21 2013-04-24 MannKind Corporation Dry powder drug delivery system and methods
JP6324069B2 (en) * 2010-08-23 2018-05-16 フラウンホーファー−ゲゼルシャフト ツル フェルデルング デル アンゲヴァンテン フォルシュング エー ファウFraunhofer−Gesellschaft zur Foerderung der angewandten Forschung e.V. Humidified particles containing therapeutically effective substances
CA2809666C (en) 2010-08-30 2020-09-22 Michael M. Lipp Dry powder formulations and methods for treating pulmonary diseases
EP2448571B1 (en) 2010-08-30 2013-06-12 Pulmatrix, Inc. Respirably dry powder comprising calcium lactate, sodium chloride and leucine
EP3173079B1 (en) 2010-09-24 2020-04-22 University of Florida Research Foundation, Inc. Materials and methods for improving gastrointestinal function
US8939388B1 (en) 2010-09-27 2015-01-27 ZoomEssence, Inc. Methods and apparatus for low heat spray drying
US9332776B1 (en) 2010-09-27 2016-05-10 ZoomEssence, Inc. Methods and apparatus for low heat spray drying
CA2812414C (en) * 2010-09-29 2020-09-22 Pulmatrix, Inc. Monovalent metal cation dry powders for inhalation
ES2899621T3 (en) 2010-09-29 2022-03-14 Pulmatrix Operating Co Inc Cationic dry powders comprising magnesium salt
US9260471B2 (en) 2010-10-29 2016-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
WO2012094381A2 (en) 2011-01-05 2012-07-12 Hospira, Inc. Spray drying vancomycin
JP6000287B2 (en) 2011-03-03 2016-09-28 クォーク ファーマシューティカルズ インコーポレーティッドQuark Pharmaceuticals,Inc. Compositions and methods for treating lung disease and injury
CA3078334C (en) 2011-04-01 2022-08-09 Mannkind Corporation Blister package for pharmaceutical cartridges
US9890200B2 (en) 2011-04-12 2018-02-13 Moerae Matrix, Inc. Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition
AU2012242768B2 (en) 2011-04-12 2017-10-12 Moerae Matrix, Inc. Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition
US9579337B2 (en) 2011-04-25 2017-02-28 Cornell University Use of uridine and deoxyuridine to treat folate-responsive pathologies
KR101763195B1 (en) 2011-05-19 2017-07-31 사바라 인코포레이티드 Dry powder vancomycin compositions and associated methods
US9572774B2 (en) 2011-05-19 2017-02-21 Savara Inc. Dry powder vancomycin compositions and associated methods
US10196637B2 (en) 2011-06-08 2019-02-05 Nitto Denko Corporation Retinoid-lipid drug carrier
DK2998289T3 (en) 2011-06-08 2019-09-16 Nitto Denko Corp RELATIONS TO TARGET PHARMACEUTICAL SUPPLY AND PROMOTE SIRNA ACTIVITY
TWI658830B (en) 2011-06-08 2019-05-11 日東電工股份有限公司 Retinoid-liposomes for enhancing modulation of hsp47 expression
US9011903B2 (en) 2011-06-08 2015-04-21 Nitto Denko Corporation Cationic lipids for therapeutic agent delivery formulations
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
MX2014004983A (en) 2011-10-24 2014-09-22 Mannkid Corp Methods and compositions for treating pain.
EA037797B1 (en) 2011-10-25 2021-05-21 Протена Байосайенсиз Лимитед Antibody formulation useful for prophylaxis and treatment of amyloidosis, variants thereof and method of making same
EP2589381B1 (en) 2011-11-04 2016-08-31 Rabindra Tirouvanziam Compositions for improving or preserving lung function in a patient with a pulmonary disorder
WO2013090841A2 (en) 2011-12-16 2013-06-20 Novartis Ag Aerosolization apparatus for inhalation profile-independent drug delivery
US20150010527A1 (en) 2012-02-01 2015-01-08 Protalix Ltd. Dnase i polypeptides, polynucleotides encoding same, methods of producing dnase i and uses thereof in therapy
WO2013130767A1 (en) 2012-02-29 2013-09-06 Pulmatrix, Inc. Inhalable dry powders
WO2013134636A1 (en) 2012-03-09 2013-09-12 Purdue Research Foundation Compositions and methods for delivery of kinase inhibiting peptides
CA2865504A1 (en) 2012-03-23 2013-09-26 Oxigene, Inc. Compositions and methods for inhibition of cathepsins
ES2691083T3 (en) 2012-04-05 2018-11-23 University Of Florida Research Foundation, Inc. Composition for the treatment of cystic fibrosis and induction of ion secretion
US8753643B1 (en) 2012-04-11 2014-06-17 Life-Science Innovations, Llc Spray dried compositions and methods of use
RU2666963C2 (en) 2012-04-13 2018-09-13 Глаксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед Aggregated particles
WO2013165574A2 (en) * 2012-05-02 2013-11-07 Brigham Young University Ceragenin particulate materials and methods for making same
CA3098386C (en) 2012-07-12 2022-11-29 Mannkind Corporation Dry powder drug delivery systems and methods
CN115414384A (en) 2012-09-04 2022-12-02 埃莱森制药有限责任公司 Prevention of pulmonary recurrence of cancer with cisplatin lipid complexes
WO2014066856A1 (en) 2012-10-26 2014-05-01 Mannkind Corporation Inhalable influenza vaccine compositions and methods
JP6378307B2 (en) 2013-03-11 2018-08-22 ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド Substances and methods for improving lung function and for preventing and / or treating radiation-induced lung complications
CN104043104B (en) 2013-03-15 2018-07-10 浙江创新生物有限公司 The spray dried powder and its industrialized process for preparing of hydrochloric vancomycin
JP6454323B2 (en) 2013-03-15 2019-01-16 パール セラピューティクス,インコーポレイテッド Method and system for conditioning particulate crystalline materials
WO2014144895A1 (en) 2013-03-15 2014-09-18 Mannkind Corporation Microcrystalline diketopiperazine compositions and methods
GB201305813D0 (en) 2013-03-28 2013-05-15 Vectura Ltd Compositions and methods
CN105324106A (en) 2013-04-01 2016-02-10 普马特里克斯营业公司 Tiotropium dry powders
EP2999460A1 (en) 2013-05-22 2016-03-30 Pearl Therapeutics, Inc. Compositions, methods&systems for respiratory delivery of three or more active agents
AU2014290438B2 (en) 2013-07-18 2019-11-07 Mannkind Corporation Heat-stable dry powder pharmaceutical compositions and methods
JP2016530930A (en) 2013-08-05 2016-10-06 マンカインド コーポレイション Ventilation device and method
CA2924062C (en) 2013-09-10 2019-05-14 Board Of Regents Of The University Of Texas System Therapeutics targeting truncated adenomatous polyposis coli (apc) proteins
CN112656780A (en) 2014-02-20 2021-04-16 奥迪托皮克股份有限公司 Dry powder formulations for inhalation
WO2015148905A1 (en) 2014-03-28 2015-10-01 Mannkind Corporation Use of ultrarapid acting insulin
US10336788B2 (en) 2014-04-17 2019-07-02 Moerae Matrix, Inc. Inhibition of cardiac fibrosis in myocardial infarction
BR112017000175B1 (en) 2014-07-08 2023-11-21 Amphastar Pharmaceuticals,Inc. METHOD OF PREPARING AN INHALABLE INSULIN SUITABLE FOR LUNG RELEASE AND MICRONIZED INSULIN PARTICLES
US10082496B2 (en) 2014-09-10 2018-09-25 Board Of Regents Of The University Of Texas System Targeting emopamil binding protein (EBP) with small molecules that induce an abnormal feedback response by lowering endogenous cholesterol biosynthesis
US10286065B2 (en) 2014-09-19 2019-05-14 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
US20170304459A1 (en) 2014-10-10 2017-10-26 Alnylam Pharmaceuticals, Inc. Methods and compositions for inhalation delivery of conjugated oligonucleotide
CA2965759C (en) 2014-10-31 2023-12-12 Glaxosmithkline Intellectual Property Development Limited Powdered polypeptides with decreased disulfide impurities comprising divalent cationic materials
RU2017121090A (en) 2014-11-17 2018-12-20 Мори Матрикс, Инк. COMPOSITIONS AND METHODS FOR PREVENTION OR TREATMENT OF DISEASES, STATE OR PROCESSES CHARACTERIZED BY ABERRANT PROLIFERATION OF FIBROBLASTS AND ACCUMULATION OF EXTRACELLULAR MATRIX
JP2017535591A (en) 2014-11-24 2017-11-30 エントリンシック ヘルス ソリューションズ インコーポレイテッド Amino acid composition for treating disease symptoms
EP3229831B1 (en) 2014-12-10 2020-03-11 Hyperstem SA Methods and compositions for reducing growth, migration and invasiveness of brain cancer stem cells and improving survival of patients with brain tumors
WO2016108244A1 (en) 2015-01-04 2016-07-07 Protalix Ltd. Modified dnase and uses thereof
CN107406489A (en) 2015-01-08 2017-11-28 莫伊莱麦屈克斯公司 The preparation of MK2 inhibitor peptides
CA2982943C (en) 2015-03-11 2019-07-23 University Of Cincinnati Compositions and methods for treating bacterial infection
CA2978941A1 (en) 2015-03-12 2016-09-15 Moerae Matrix, Inc. Use of mk2 inhibitor peptide-containing compositions for treating non-small cell lung cancer with same
US10905836B2 (en) 2015-04-02 2021-02-02 Hill-Rom Services Pte. Ltd. Manifold for respiratory device
CA2987071A1 (en) 2015-06-10 2016-12-15 Hackensack University Medical Center Use of telmisartan to prevent and treat graft versus host disease and other alloimmune and autoimmune diseases
WO2017007634A1 (en) 2015-07-06 2017-01-12 The Board Of Regents Of The University Of Texas System Benzamide or benzamine compounds useful as anticancer agents for the treatment of human cancers
WO2017011215A1 (en) 2015-07-15 2017-01-19 The Board Of Regents Of The University Of Texas System Targeting emopamil binding protein (ebp) with small molecules that induce an abnormal feedback response by lowering endogenous cholesterol biosynthesis
US10322168B2 (en) 2016-01-07 2019-06-18 Amphastar Pharmaceuticals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
US11833118B2 (en) 2016-01-20 2023-12-05 Flurry Powders, Llc Encapsulation of lipophilic ingredients in dispersible spray dried powders suitable for inhalation
EP3405175A4 (en) * 2016-01-20 2019-09-25 Flurry Powders, LLC Encapsulation of lipophilic ingredients in dispersible spray dried powders suitable for inhalation
MX2018009248A (en) 2016-02-01 2019-01-21 Incarda Therapeutics Inc Combining electronic monitoring with inhaled pharmacological therapy to manage cardiac arrhythmias including atrial fibrillation.
US10307398B2 (en) 2016-09-20 2019-06-04 Regents Of The University Of Minnesota Resuscitation composition and methods of making and using
JP7267546B2 (en) 2016-10-04 2023-05-02 ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド Amino acid composition and use thereof
WO2018078186A1 (en) 2016-10-31 2018-05-03 Vectura Limited Inhalable powder composition comprising il-13 antibody
EP3538218A4 (en) 2016-11-09 2020-06-17 The Board of Regents of The University of Texas System Methods and compositions for adaptive immune modulation
CN110267660A (en) 2016-12-16 2019-09-20 德克萨斯大学系统董事会 The inhibitor of domain protein containing Bu Luomo 4 (BRD4)
JP2020519628A (en) 2017-05-10 2020-07-02 インカーダ セラピューティクス, インコーポレイテッド Unit doses, aerosols, kits and methods for treating cardiac conditions by pulmonary administration
WO2019018338A1 (en) 2017-07-17 2019-01-24 Northriver Pharm, LLC Nasal composition comprising a mucoadhesive polymer
EP3655021B1 (en) 2017-07-19 2023-03-22 Unikeris Limited Adenosine deaminase for treating or ameliorating scleroderma-associated vasculopathy
US9861945B1 (en) 2017-08-04 2018-01-09 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
US9993787B1 (en) 2017-08-04 2018-06-12 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
US10486173B2 (en) 2017-08-04 2019-11-26 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
US10252181B2 (en) 2017-08-04 2019-04-09 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
US10155234B1 (en) 2017-08-04 2018-12-18 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
EP3749298B1 (en) 2018-02-07 2023-04-05 Lovelace Biomedical Research Institute Inhalable dry powder cytidine analogue composition and method of use as a treatment for cancer
WO2019183470A2 (en) 2018-03-22 2019-09-26 Incarda Therapeutics, Inc. A novel method to slow ventricular rate
US11786580B2 (en) 2018-04-23 2023-10-17 Emory University VIP and VIP agonists, nanoparticles, and uses in inflammatory T-cell mediated disease
US10569244B2 (en) 2018-04-28 2020-02-25 ZoomEssence, Inc. Low temperature spray drying of carrier-free compositions
US11389433B2 (en) 2018-06-18 2022-07-19 Board Of Regents, The University Of Texas System BRD4 inhibitor treatment of IgE-mediated diseases
PL3599243T3 (en) 2018-07-26 2023-08-21 Cvie Therapeutics Limited 17beta-heterocyclyl-digitalis like compounds for the treatment of heart failure
US20220000880A1 (en) 2018-11-01 2022-01-06 Rigel Pharmaceuticals, Inc. Method and composition embodiments for treating acute myeloid leukemia
BR112021013491A2 (en) * 2019-01-09 2021-09-14 Ziccum Ab STABILIZED NON-ENVELOPED VIRUS COMPOSITIONS
BR112021021775A2 (en) 2019-04-29 2022-01-04 Insmed Inc Dry powder compositions of treprostinil prodrugs and methods of use thereof
WO2020243612A1 (en) 2019-05-29 2020-12-03 Rigel Pharmaceuticals, Inc. Method of preventing and treating thrombosis
US11020384B2 (en) 2019-08-01 2021-06-01 Incarda Therapeutics, Inc. Antiarrhythmic formulation
WO2021026451A1 (en) 2019-08-08 2021-02-11 Rigel Pharmaceuticals, Inc. Compounds and method for treating cytokine release syndrome
MX2022001890A (en) 2019-08-14 2022-04-26 Rigel Pharmaceuticals Inc Method of blocking or ameliorating cytokine release syndrome.
EP3805243B1 (en) 2019-10-09 2023-11-15 Windtree Therapeutics, Inc. Androstane derivatives with activity as pure or predominantly pure stimulators of serca2a for the treatment of heart failure
WO2021216547A1 (en) 2020-04-20 2021-10-28 Sorrento Therapeutics, Inc. Pulmonary administration of ace2 polypeptides
JP2023545740A (en) 2020-10-07 2023-10-31 プロタリクス リミテッド Long-term active DNase
WO2022189662A1 (en) 2021-03-12 2022-09-15 Alvarius Pharmaceuticals Ltd. Compositions and methods for treating addictions comprising 5-meo-dmt
EP4175619A1 (en) 2021-07-09 2023-05-10 AstraZeneca Pharmaceuticals LP Compositions, methods and systems for aerosol drug delivery
WO2023119093A1 (en) 2021-12-20 2023-06-29 Astrazeneca Ab Compositions, methods and systems for aerosol drug delivery
WO2023150747A1 (en) 2022-02-07 2023-08-10 Insmed Incorporated Dry powder compositions of bedaquiline and salts and methods of use thereof
US20230303555A1 (en) 2022-03-23 2023-09-28 Rigel Pharmaceuticals, Inc. Pyrimid-2-yl-pyrazole compounds as irak inhibitors
WO2023212191A1 (en) 2022-04-28 2023-11-02 Astrazeneca Ab Combination of albuterol and budesonide for the treatment of asthma

Citations (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2598525A (en) * 1950-04-08 1952-05-27 E & J Mfg Co Automatic positive pressure breathing machine
US3202731A (en) * 1960-04-07 1965-08-24 Philips Corp Method of forming free flowing particles, containing a biologically valuable substance
US3300474A (en) * 1964-02-12 1967-01-24 Pharmacia Ab Sucrose ether copolymerizates
US3314803A (en) * 1966-01-26 1967-04-18 Gen Foods Corp Mannitol fixed flavor and method of making same
US3362405A (en) * 1964-04-06 1968-01-09 Hamilton O. Hazel Method and apparatus for admixing gas with solid particles
US3425600A (en) * 1966-08-11 1969-02-04 Abplanalp Robert H Pressurized powder dispensing device
US3540927A (en) * 1964-07-04 1970-11-17 Nippon Shiryo Kogyo Kk Granular total sugar products and process for producing
US3554768A (en) * 1967-08-01 1971-01-12 Gen Foods Corp Carbohydrate fixed acetaldehyde
US3557717A (en) * 1968-05-17 1971-01-26 Gen Mills Inc Process for making candy floss
US3594476A (en) * 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3608066A (en) * 1968-06-19 1971-09-21 En Nom Collectif Science Union Pharmaceutical preparation based on bacterial antigens
US3620776A (en) * 1968-06-28 1971-11-16 Nestle Sa Spray drying process
US3666496A (en) * 1969-09-03 1972-05-30 Firmenich Inc Water soluble,powdered,terpene-containing flavors
US3674901A (en) * 1966-07-26 1972-07-04 Nat Patent Dev Corp Surgical sutures
US3764716A (en) * 1970-11-16 1973-10-09 American Potato Co Preparation of dehydrated mashed potatoes
US3921637A (en) * 1973-07-23 1975-11-25 Bespak Industries Ltd Inhaler for powdered medicament
US3964483A (en) * 1975-01-13 1976-06-22 Syntex Puerto Rico, Inc. Inhalation device
US3971852A (en) * 1973-06-12 1976-07-27 Polak's Frutal Works, Inc. Process of encapsulating an oil and product produced thereby
US3991304A (en) * 1975-05-19 1976-11-09 Hillsman Dean Respiratory biofeedback and performance evaluation system
US3991761A (en) * 1974-03-18 1976-11-16 Salvatore Cocozza Inhaler for powdered medicaments
US3994421A (en) * 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
US4036223A (en) * 1975-01-29 1977-07-19 Obert Jean Claude Apparatus for generating aerosols of solid particles
US4069819A (en) * 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
US4098273A (en) * 1975-01-13 1978-07-04 Syntex Puerto Rico, Inc. Inhalation device
US4105027A (en) * 1975-06-13 1978-08-08 Syntex Puerto Rico, Inc. Inhalation device
US4109019A (en) * 1975-11-18 1978-08-22 William Percy Moore Process for improved ruminant feed supplements
US4153689A (en) * 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
US4192309A (en) * 1978-09-05 1980-03-11 Syntex Puerto Rico, Inc. Inhalation device with capsule opener
US4206200A (en) * 1977-10-27 1980-06-03 Behringwerke Aktiengesellschaft Stabilizer for polysaccharides
US4211769A (en) * 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
US4227522A (en) * 1978-09-05 1980-10-14 Syntex Puerto Rico, Inc. Inhalation device
US4249526A (en) * 1978-05-03 1981-02-10 Fisons Limited Inhalation device
US4253468A (en) * 1978-08-14 1981-03-03 Steven Lehmbeck Nebulizer attachment
US4294829A (en) * 1979-07-31 1981-10-13 Teijin Limited Powdery pharmaceutical composition and powdery preparation for application to the nasal mucosa, and method for administration thereof
US4294624A (en) * 1980-03-14 1981-10-13 Veltman Preston Leonard Drying co-mingled carbohydrate solution and recycled product by dielectric heating
US4338931A (en) * 1979-04-27 1982-07-13 Claudio Cavazza Device for the quick inhalation of drugs in powder form by humans suffering from asthma
US4423079A (en) * 1980-07-14 1983-12-27 Leo Kline Growth promoting compositions for Lactobacillus sanfrancisco and method of preparation
US4446862A (en) * 1979-10-30 1984-05-08 Baum Eric A Breath actuated devices for administering powdered medicaments
US4452239A (en) * 1980-03-25 1984-06-05 Hilal Malem Medical nebulizing apparatus
US4484577A (en) * 1981-07-23 1984-11-27 Key Pharmaceuticals, Inc. Drug delivery method and inhalation device therefor
US4503035A (en) * 1978-11-24 1985-03-05 Hoffmann-La Roche Inc. Protein purification process and product
US4533552A (en) * 1982-03-09 1985-08-06 Nippon Shinyaku Co., Ltd. Stabilization of azulene derivatives
US4534343A (en) * 1984-01-27 1985-08-13 Trutek Research, Inc. Metered dose inhaler
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4778054A (en) * 1982-10-08 1988-10-18 Glaxo Group Limited Pack for administering medicaments to patients
US4857311A (en) * 1987-07-31 1989-08-15 Massachusetts Institute Of Technology Polyanhydrides with improved hydrolytic degradation properties
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
US4946828A (en) * 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US5069936A (en) * 1987-06-25 1991-12-03 Yen Richard C K Manufacturing protein microspheres
US5260306A (en) * 1981-07-24 1993-11-09 Fisons Plc Inhalation pharmaceuticals
US5376386A (en) * 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
US5482927A (en) * 1991-02-20 1996-01-09 Massachusetts Institute Of Technology Controlled released microparticulate delivery system for proteins
US5518998A (en) * 1993-06-24 1996-05-21 Ab Astra Therapeutic preparation for inhalation
US5547696A (en) * 1994-10-13 1996-08-20 Novo Nordisk A/S Pharmaceutical formulation
US5554382A (en) * 1993-05-28 1996-09-10 Aphios Corporation Methods and apparatus for making liposomes
US5559298A (en) * 1993-10-13 1996-09-24 Kabushiki Kaisha Kawai Gakki Seisakusho Waveform read-out system for an electronic musical instrument
US5575987A (en) * 1992-09-02 1996-11-19 Takeda Chemical Industries, Ltd. Method of producing sustained-release microcapsules
US5590206A (en) * 1992-04-09 1996-12-31 Samsung Electronics Co., Ltd. Noise canceler
US5626871A (en) * 1992-06-12 1997-05-06 Teijin Limited Preparation for intratracheobronchial administration
US5631225A (en) * 1994-10-13 1997-05-20 Novo Nordisk A/S Pharmaceutical formulation
US5654278A (en) * 1994-10-13 1997-08-05 Novo Nordisk A/S Composition and method comprising growth hormone and leucine
US5667806A (en) * 1995-06-07 1997-09-16 Emisphere Technologies, Inc. Spray drying method and apparatus
US5705482A (en) * 1995-01-13 1998-01-06 Novo Nordisk A/S Pharmaceutical formulation
US5707644A (en) * 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5780014A (en) * 1995-04-14 1998-07-14 Inhale Therapeutic Systems Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin
US5785049A (en) * 1994-09-21 1998-07-28 Inhale Therapeutic Systems Method and apparatus for dispersion of dry powder medicaments
US5849700A (en) * 1991-12-20 1998-12-15 Novo Nordisk A/S Pharmaceutical formulation
US5849704A (en) * 1991-12-20 1998-12-15 Novo Nordisk A/S Pharmaceutical formulation
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5889110A (en) * 1992-05-28 1999-03-30 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US5952008A (en) * 1993-06-24 1999-09-14 Ab Astra Processes for preparing compositions for inhalation
US5972388A (en) * 1992-06-12 1999-10-26 Teijin Limited Ultrafine particle power for inhalation and method for production thereof
US5985309A (en) * 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5994314A (en) * 1993-04-07 1999-11-30 Inhale Therapeutic Systems, Inc. Compositions and methods for nucleic acid delivery to the lung
US5997848A (en) * 1994-03-07 1999-12-07 Inhale Therapeutic Systems Methods and compositions for pulmonary delivery of insulin
US6123936A (en) * 1994-05-18 2000-09-26 Inhale Therapeutics Systems, Inc. Methods and compositions for the dry powder formulation of interferons
US6165463A (en) * 1997-10-16 2000-12-26 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
USRE37053E1 (en) * 1996-05-24 2001-02-13 Massachusetts Institute Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6254854B1 (en) * 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US6565841B1 (en) * 1991-03-15 2003-05-20 Amgen, Inc. Pulmonary administration of granulocyte colony stimulating factor
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments

Family Cites Families (173)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1855591A (en) * 1926-02-03 1932-04-26 Wallerstein Co Inc Invertase preparation and method of making the same
DE1812574U (en) 1960-04-05 1960-06-02 Felix Duerst CONCRETE MIXER.
US3555717A (en) * 1968-10-24 1971-01-19 Victor Comptometer Corp Artificial fishing lure
DE1812574A1 (en) 1968-12-04 1970-06-11 Riedel De Haen Ag Process for the production of biocidal granules
US3632357A (en) * 1969-07-29 1972-01-04 Standard Brands Inc Method of producing hard candy
US3655442A (en) * 1969-08-27 1972-04-11 California & Hawaiian Sugar Method of making sugar and sugar products
US3937668A (en) * 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
FR2257351A1 (en) 1974-01-11 1975-08-08 Obert Jean Claude Aerosol device for solid vaccines - feed and breaker screws deliver material sideways into blower chamber
DE2415159A1 (en) 1974-03-29 1975-10-09 Hoechst Ag SPRAY PRODUCTS CONTAINING ALKALINE CANSULFONATE AND METHOD FOR THEIR MANUFACTURING
US3948263A (en) * 1974-08-14 1976-04-06 Minnesota Mining And Manufacturing Company Ballistic animal implant
JPS5134879A (en) 1974-09-19 1976-03-24 Eisai Co Ltd Bishochukuryushinoseizoho
GB1527605A (en) 1975-08-20 1978-10-04 Takeda Chemical Industries Ltd Insulin preparation for intranasal administration
US4103019A (en) * 1975-10-07 1978-07-25 Laboratorios Landerlan, S. A. Triterpene derivatives
NL7800383A (en) * 1977-01-20 1978-07-24 Rhone Poulenc Ind NEW ISOQUEINOLINE DERIVATIVES, THEIR PREPARATION AND PREPARATIONS CONTAINING THE ISOQUEINOLINE DERIVATIVES.
US4180593A (en) 1977-04-29 1979-12-25 Cohan Allan N Process for producing round spherical free flowing blown bead food products of controlled bulk density
NL7712041A (en) 1977-11-01 1979-05-03 Handelmaatschappij Voorheen Be Suction equipment for powdery material - incorporates ejector type suction pump and cyclone type separator
US4244949A (en) * 1978-04-06 1981-01-13 The Population Council, Inc. Manufacture of long term contraceptive implant
SU1003926A1 (en) 1979-01-24 1983-03-15 Всесоюзный Научно-Исследовательский И Конструкторский Институт Автогенного Машиностроения Powder feeder
DE3061384D1 (en) 1979-02-21 1983-01-27 Ici Plc A process for the extraction of poly-3-hydroxy-butyric acid from microbial cells
EP0111216A3 (en) 1980-03-31 1985-01-16 Takeda Chemical Industries, Ltd. Method for enzyme immunoassay and peptide-enzyme conjugate, its lyophilizate, antibody and kit therefor
CS217203B1 (en) * 1980-06-24 1982-12-31 Vladimir Svaty Device for simmultaneous shot of two wefts in two open sheds
US4326524A (en) * 1980-09-30 1982-04-27 Minnesota Mining And Manufacturing Company Solid dose ballistic projectile
US4327076A (en) * 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4371557A (en) * 1981-01-21 1983-02-01 General Foods Corporation Maintenance of protein quality in foods containing reducing sugars
US4327077A (en) * 1981-05-29 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
GB2105189B (en) 1981-07-24 1985-03-20 Fisons Plc Inhalation drugs
DE3268533D1 (en) 1981-07-24 1986-02-27 Fisons Plc Inhalation drugs, methods for their production and pharmaceutical formulations containing them
DE3141498A1 (en) 1981-10-20 1983-04-28 Bayer Ag, 5090 Leverkusen Pharmaceutical containing kallikrein and process for its preparation
FR2521565B1 (en) 1982-02-17 1985-07-05 Dior Sa Parfums Christian PULVERULENT MIXTURE OF LIPID COMPONENTS AND HYDROPHOBIC CONSTITUENTS, METHOD FOR PREPARING SAME, HYDRATED LIPID LAMELLAR PHASES AND MANUFACTURING METHOD, PHARMACEUTICAL OR COSMETIC COMPOSITIONS COMPRISING HYDRATED LAMID PHASES
US4823784A (en) 1982-04-30 1989-04-25 Cadema Medical Products, Inc. Aerosol inhalation apparatus
US4599311A (en) 1982-08-13 1986-07-08 Kawasaki Glenn H Glycolytic promotersfor regulated protein expression: protease inhibitor
US4457916A (en) 1982-08-31 1984-07-03 Asahi Kasei Kogyo Kabushiki Kaisha Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same
PT77471B (en) 1982-10-08 1986-08-19 Glaxo Group Ltd Devices for administering medicaments to patients
US4559298A (en) 1982-11-23 1985-12-17 American National Red Cross Cryopreservation of biological materials in a non-frozen or vitreous state
ES519619A0 (en) 1983-02-08 1984-03-16 Gandariasbeitia Aguirreche Man CONTINUOUS PROCEDURE FOR THE PRODUCTION OF PROTEOLYTIC AND AMINOLYTIC ENZYMES FROM VEGETABLE MICROORGANISMS.
JPS59163313A (en) 1983-03-09 1984-09-14 Teijin Ltd Peptide hormone composition for nasal administration
JPS6035263A (en) 1983-08-05 1985-02-23 Wako Pure Chem Ind Ltd Stabilization of immunologically active substance immobilized on non-soluble carrier and physiologically active substance measuring reagent containing the same as composition unit
US4649911A (en) 1983-09-08 1987-03-17 Baylor College Of Medicine Small particle aerosol generator for treatment of respiratory disease including the lungs
DE3345722A1 (en) 1983-12-17 1985-06-27 Boehringer Ingelheim KG, 6507 Ingelheim INHALATOR
GB8613811D0 (en) * 1986-06-06 1986-07-09 Phares Pharm Res Nv Composition & method
US4820534A (en) 1984-03-19 1989-04-11 General Foods Corporation Fixation of volatiles in extruded glass substrates
US4927763A (en) 1984-03-21 1990-05-22 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
DD238305A3 (en) 1984-04-23 1986-08-20 Maisan Werke Barby Veb PROCESS FOR THE PREPARATION OF D-GLUCOSE AND STAERKEHYDROLYSATES
US4617272A (en) 1984-04-25 1986-10-14 Economics Laboratory, Inc. Enzyme drying process
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4956295A (en) 1984-05-21 1990-09-11 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
JPS60258125A (en) 1984-06-06 1985-12-20 Hayashibara Biochem Lab Inc Water-soluble dried material containing proteinic physiologically active substance
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4624251A (en) 1984-09-13 1986-11-25 Riker Laboratories, Inc. Apparatus for administering a nebulized substance
NZ209900A (en) 1984-10-16 1989-08-29 Univ Auckland Automatic inhaler
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
FR2575678B1 (en) 1985-01-04 1988-06-03 Saint Gobain Vitrage PNEUMATIC POWDER EJECTOR
US4857319A (en) 1985-01-11 1989-08-15 The Regents Of The University Of California Method for preserving liposomes
US4830858A (en) 1985-02-11 1989-05-16 E. R. Squibb & Sons, Inc. Spray-drying method for preparing liposomes and products produced thereby
US4942544A (en) 1985-02-19 1990-07-17 Kenneth B. McIntosh Medication clock
IL78342A (en) 1985-04-04 1991-06-10 Gen Hospital Corp Pharmaceutical composition for treatment of osteoporosis in humans comprising a parathyroid hormone or a fragment thereof
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
DE229810T1 (en) 1985-07-09 1987-11-05 Quadrant Bioresources Ltd., Soulbury, Leighton Buzzard, Bedfordshire, Gb PROTECTION OF PROTEINS AND SIMILAR.
IT1195984B (en) 1985-07-30 1988-11-03 Glaxo Group Ltd DEVICE FOR ADMINISTRATING MEDIUM-ROOMS TO PATIENTS
US4719762A (en) 1985-11-21 1988-01-19 Toshiba Heating Appliances Co., Ltd. Stored ice detecting device in ice making apparatus
FR2591105B1 (en) 1985-12-11 1989-03-24 Moet Hennessy Rech PHARMACEUTICAL COMPOSITION, IN PARTICULAR DERMATOLOGICAL, OR COSMETIC, BASED ON HYDRATED LIPID LAMELLAR PHASES OR LIPOSOMES CONTAINING A RETINOIDE OR A STRUCTURAL ANALOG OF SUCH A RETINOID AS A CAROTENOID.
JPS62174094A (en) * 1985-12-16 1987-07-30 Ss Pharmaceut Co Ltd Alpha, alpha-trehalose derivative and production thereof
JPH0710344B2 (en) * 1985-12-26 1995-02-08 株式会社林原生物化学研究所 Method for dehydrating hydrated substance by anhydrous glycosyl fructose
SE453566B (en) 1986-03-07 1988-02-15 Draco Ab POWDER INHALATOR DEVICE
US4897353A (en) 1986-03-13 1990-01-30 University Of Southwestern Louisiana Cryogenic protection of phosphofructokinase using amino acids and zinc ions
US4806343A (en) 1986-03-13 1989-02-21 University Of Southwestern Louisiana Cryogenic protectant for proteins
US5017372A (en) 1986-04-14 1991-05-21 Medicis Corporation Method of producing antibody-fortified dry whey
US4739754A (en) 1986-05-06 1988-04-26 Shaner William T Suction resistant inhalator
US4926852B1 (en) 1986-06-23 1995-05-23 Univ Johns Hopkins Medication delivery system phase one
US4790305A (en) 1986-06-23 1988-12-13 The Johns Hopkins University Medication delivery system
WO1988001165A1 (en) * 1986-08-11 1988-02-25 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
DE3636669C2 (en) 1986-10-28 2001-08-16 Siemens Ag Arrangement for delivering aerosol to a patient's airways and / or lungs
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4833125A (en) 1986-12-05 1989-05-23 The General Hospital Corporation Method of increasing bone mass
US4906463A (en) * 1986-12-22 1990-03-06 Cygnus Research Corporation Transdermal drug-delivery composition
US5093316A (en) 1986-12-24 1992-03-03 John Lezdey Treatment of inflammation
JPS63186799A (en) 1987-01-29 1988-08-02 不二製油株式会社 Production of powdery oils and fats
US5089181A (en) * 1987-02-24 1992-02-18 Vestar, Inc. Method of dehydrating vesicle preparations for long term storage
FR2611501B1 (en) * 1987-03-04 1991-12-06 Corbiere Jerome NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE BASED ON LYSINE ACETYLSALIELYLATE AND PROCESS FOR OBTAINING SAME
US5387431A (en) * 1991-10-25 1995-02-07 Fuisz Technologies Ltd. Saccharide-based matrix
JP2656944B2 (en) 1987-04-30 1997-09-24 クーパー ラボラトリーズ Aerosolization of protein therapeutics
US4876241A (en) 1987-05-22 1989-10-24 Armour Pharmaceutical Company Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants
GB8715238D0 (en) 1987-06-29 1987-08-05 Quadrant Bioresources Ltd Food process
FR2618331B1 (en) * 1987-07-23 1991-10-04 Synthelabo PHARMACEUTICAL COMPOSITIONS USEFUL FOR THE TREATMENT OF UREMIA
US5139016A (en) * 1987-08-07 1992-08-18 Sorin Biomedica S.P.A. Process and device for aerosol generation for pulmonary ventilation scintigraphy
IT1222509B (en) 1987-08-17 1990-09-05 Miat Spa INSUFFLATOR FOR THE ADMINISTRATION OF DRUGS IN THE FORM OF PRE-DOSED POWDER IN OPERATIONS
GB8723846D0 (en) 1987-10-10 1987-11-11 Danbiosyst Ltd Bioadhesive microsphere drug delivery system
US4968607A (en) 1987-11-25 1990-11-06 Immunex Corporation Interleukin-1 receptors
WO1989004838A1 (en) 1987-11-25 1989-06-01 Immunex Corporation Interleukin-1 receptors
US5081228A (en) 1988-02-25 1992-01-14 Immunex Corporation Interleukin-1 receptors
GB8801338D0 (en) 1988-01-21 1988-02-17 Quadrant Bioresources Ltd Preservation of viruses
IT1217890B (en) 1988-06-22 1990-03-30 Chiesi Farma Spa DOSED AEROSOL INHALATION DEVICE
US4919962A (en) 1988-08-12 1990-04-24 General Foods Corporation Coffee flakes and process
EP0360340A1 (en) 1988-09-19 1990-03-28 Akzo N.V. Composition for nasal administration containing a peptide
ES2051371T3 (en) 1988-10-04 1994-06-16 Univ Johns Hopkins AEROSOL INHALER.
US4984158A (en) 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
GB8824897D0 (en) 1988-10-24 1988-11-30 Ici Plc Biocatalysts
US4931361A (en) 1988-11-18 1990-06-05 California Institute Of Technology Cryoprotective reagents in freeze-drying membranes
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US4906476A (en) * 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5011678A (en) 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
GB8903593D0 (en) 1989-02-16 1989-04-05 Pafra Ltd Storage of materials
CA2050905A1 (en) * 1989-02-23 1990-08-24 George R. Felt Therapeutic aerosol formulations
IT1228459B (en) 1989-02-23 1991-06-19 Phidea S R L INHALER WITH REGULAR AND COMPLETE EMPTYING OF THE CAPSULE.
SE466684B (en) 1989-03-07 1992-03-23 Draco Ab DEVICE INHALATOR AND PROCEDURE TO REGISTER WITH THE DEVICE INHALATOR MEDICATION
IT1230313B (en) 1989-07-07 1991-10-18 Somova Spa INHALER FOR CAPSULES MEDICATIONS.
US5238920A (en) 1989-08-22 1993-08-24 Abbott Laboratories Pulmonary surfactant protein fragments
IT1237118B (en) 1989-10-27 1993-05-18 Miat Spa MULTI-DOSE INHALER FOR POWDER DRUGS.
PL166277B1 (en) * 1989-11-28 1995-04-28 Syntex Inc Method of obtaining novel tricyclic compounds
GB9001635D0 (en) * 1990-01-24 1990-03-21 Ganderton David Aerosol carriers
US5113855A (en) 1990-02-14 1992-05-19 Newhouse Michael T Powder inhaler
DE4004904A1 (en) 1990-02-16 1990-09-13 Gerhard Brendel DRUM APPLICATOR
US5036237A (en) * 1990-04-09 1991-07-30 Electric Motors And Specialties, Inc. Shaded pole motor
JPH05963A (en) * 1990-04-13 1993-01-08 Toray Ind Inc Polypeptide composition
IT1246350B (en) * 1990-07-11 1994-11-17 Eurand Int METHOD FOR OBTAINING A RAPID SUSPENSION OF INSOLUBLE DRUGS IN WATER
IT1243344B (en) 1990-07-16 1994-06-10 Promo Pack Sa MULTI-DOSE INHALER FOR POWDER MEDICATIONS
US5037912A (en) 1990-07-26 1991-08-06 The Goodyear Tire & Rubber Company Polymerization of 1,3-butadiene to trans-1,4-polybutadiene with organolithium and alkali metal alkoxide
GB9016789D0 (en) 1990-07-31 1990-09-12 Lilly Industries Ltd Medicament administering devices
US5230884A (en) 1990-09-11 1993-07-27 University Of Wales College Of Cardiff Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
US5200399A (en) 1990-09-14 1993-04-06 Boyce Thompson Institute For Plant Research, Inc. Method of protecting biological materials from destructive reactions in the dry state
US5149543A (en) 1990-10-05 1992-09-22 Massachusetts Institute Of Technology Ionically cross-linked polymeric microcapsules
US5217004A (en) 1990-12-13 1993-06-08 Tenax Corporation Inhalation actuated dispensing apparatus
EP0584088B1 (en) * 1991-02-08 1999-10-27 Cambridge Neuroscience Research, Inc. Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers
US5182097A (en) * 1991-02-14 1993-01-26 Virginia Commonwealth University Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content
US5099833A (en) 1991-02-19 1992-03-31 Baxter International Inc. High efficiency nebulizer having a flexible reservoir
US5404871A (en) * 1991-03-05 1995-04-11 Aradigm Delivery of aerosol medications for inspiration
NZ241954A (en) * 1991-03-15 1994-01-26 Amgen Inc Compositions of g-csf for pulmonary administration.
US5186164A (en) 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
EP0504459B1 (en) 1991-03-21 1996-06-05 PAUL RITZAU PARI-WERK GmbH Nebulizer, in particular for use in inhalation therapy apparatus
GB9106648D0 (en) 1991-03-28 1991-05-15 Rhone Poulenc Rorer Ltd New inhaler
BR9106690A (en) 1991-04-15 1993-06-29 Huhtamaeki Yhthymae Oy PROVISION TO MEASURE A DOSE OF PULVERULENT DRUGS FOR INHALATION AND INHALATION APPARATUS EQUIPPED WITH THE SAME
US5206200A (en) 1991-04-22 1993-04-27 W. R. Grace & Co.-Conn. Tin catalysts for hydrolysis of latent amine curing agents
US6681767B1 (en) * 1991-07-02 2004-01-27 Nektar Therapeutics Method and device for delivering aerosolized medicaments
ATE359842T1 (en) * 1991-07-02 2007-05-15 Nektar Therapeutics DISPENSING DEVICE FOR MIST-FORMED MEDICATIONS
US5161524A (en) 1991-08-02 1992-11-10 Glaxo Inc. Dosage inhalator with air flow velocity regulating means
US5253468A (en) 1991-09-03 1993-10-19 Robert Raymond Crop chopping machine
US6013638A (en) * 1991-10-02 2000-01-11 The United States Of America As Represented By The Department Of Health And Human Services Adenovirus comprising deletions on the E1A, E1B and E3 regions for transfer of genes to the lung
US5124162A (en) 1991-11-26 1992-06-23 Kraft General Foods, Inc. Spray-dried fixed flavorants in a carbohydrate substrate and process
US5378720A (en) 1991-12-19 1995-01-03 Sterling Winthrop Inc. Saccharin derivative proteolytic enzyme inhibitors
AU653279B2 (en) 1991-12-30 1994-09-22 Sanofi Novel 2-saccharinylmethyl heterocyclic carboxylates useful as proteolytic enzyme inhibitors and compositions and method of use thereof
US5320094A (en) 1992-01-10 1994-06-14 The Johns Hopkins University Method of administering insulin
JPH07503154A (en) * 1992-01-21 1995-04-06 エス・アール・アイ・インターナシヨナル Improved preparation method for miniaturized polypeptide drugs
CA2094217A1 (en) * 1992-04-17 1993-10-18 Yasutaka Igari Transmucosal therapeutic composition
US5376359A (en) 1992-07-07 1994-12-27 Glaxo, Inc. Method of stabilizing aerosol formulations
US6509006B1 (en) * 1992-07-08 2003-01-21 Inhale Therapeutic Systems, Inc. Devices compositions and methods for the pulmonary delivery of aerosolized medicaments
ATE220327T1 (en) * 1992-09-29 2002-07-15 Inhale Therapeutic Syst PULMONARY RELEASE OF ACTIVE FRAGMENTS OF THE PARATHORMONE
GB9221329D0 (en) * 1992-10-10 1992-11-25 Delta Biotechnology Ltd Preparation of further diagnostic agents
US5380473A (en) * 1992-10-23 1995-01-10 Fuisz Technologies Ltd. Process for making shearform matrix
US5364838A (en) 1993-01-29 1994-11-15 Miris Medical Corporation Method of administration of insulin
US5354934A (en) * 1993-02-04 1994-10-11 Amgen Inc. Pulmonary administration of erythropoietin
US5506203C1 (en) 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
GB9314886D0 (en) * 1993-07-19 1993-09-01 Zeneca Ltd Production of a biological control agent
EP0655237A1 (en) 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medicinal aerosol formulation
GB2288732B (en) * 1994-04-13 1998-04-29 Quadrant Holdings Cambridge Pharmaceutical compositions
MY111829A (en) * 1994-05-10 2001-01-31 Zoetis W Llc Modified live brsv vaccine
US5591453A (en) * 1994-07-27 1997-01-07 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
US6290991B1 (en) * 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US5612053A (en) * 1995-04-07 1997-03-18 Edward Mendell Co., Inc. Controlled release insufflation carrier for medicaments
KR19980703876A (en) * 1995-04-14 1998-12-05 스티븐 엘. 허스트 Powdered pharmaceutical compositions with improved dispersibility
US6019968A (en) * 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
US6190859B1 (en) * 1995-04-17 2001-02-20 The United States Of America As Represented By The Secretary Of The Army Method and kit for detection of dengue virus
GB9508691D0 (en) * 1995-04-28 1995-06-14 Pafra Ltd Stable compositions
GB9515182D0 (en) 1995-07-24 1995-09-20 Co Ordinated Drug Dev Improvements in and relating to powders for use in dry powder inhalers
DE19539574A1 (en) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Preparations and processes for stabilizing biological materials by means of drying processes without freezing
TW403653B (en) 1995-12-25 2000-09-01 Otsuka Pharma Co Ltd Dry compositions
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
EP0913178A1 (en) 1997-11-03 1999-05-06 Boehringer Mannheim Gmbh Process for the manufacture of dry, amorphous products comprising biologically active material by means of convection drying and products obtainable by the process
EP0913177A1 (en) 1997-11-03 1999-05-06 Roche Diagnostics GmbH Process for producing dry, amorphous products comprising biological active materials by means of convection drying technique, especially spray drying
GB9827145D0 (en) 1998-12-09 1999-02-03 Co Ordinated Drug Dev Improvements in or relating to powders
NZ518401A (en) * 1999-10-29 2004-01-30 Nektar Therapeutics Dry powder compositions having improved dispersivity
AU2001277230A1 (en) * 2000-08-01 2002-02-13 Inhale Therapeutic Systems, Inc. Apparatus and process to produce particles having a narrow size distribution andparticles made thereby

Patent Citations (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2598525A (en) * 1950-04-08 1952-05-27 E & J Mfg Co Automatic positive pressure breathing machine
US3202731A (en) * 1960-04-07 1965-08-24 Philips Corp Method of forming free flowing particles, containing a biologically valuable substance
US3300474A (en) * 1964-02-12 1967-01-24 Pharmacia Ab Sucrose ether copolymerizates
US3362405A (en) * 1964-04-06 1968-01-09 Hamilton O. Hazel Method and apparatus for admixing gas with solid particles
US3540927A (en) * 1964-07-04 1970-11-17 Nippon Shiryo Kogyo Kk Granular total sugar products and process for producing
US3314803A (en) * 1966-01-26 1967-04-18 Gen Foods Corp Mannitol fixed flavor and method of making same
US3674901A (en) * 1966-07-26 1972-07-04 Nat Patent Dev Corp Surgical sutures
US3425600A (en) * 1966-08-11 1969-02-04 Abplanalp Robert H Pressurized powder dispensing device
US3554768A (en) * 1967-08-01 1971-01-12 Gen Foods Corp Carbohydrate fixed acetaldehyde
US3557717A (en) * 1968-05-17 1971-01-26 Gen Mills Inc Process for making candy floss
US3608066A (en) * 1968-06-19 1971-09-21 En Nom Collectif Science Union Pharmaceutical preparation based on bacterial antigens
US3620776A (en) * 1968-06-28 1971-11-16 Nestle Sa Spray drying process
US3594476A (en) * 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3666496A (en) * 1969-09-03 1972-05-30 Firmenich Inc Water soluble,powdered,terpene-containing flavors
US3764716A (en) * 1970-11-16 1973-10-09 American Potato Co Preparation of dehydrated mashed potatoes
US4069819A (en) * 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
US3971852A (en) * 1973-06-12 1976-07-27 Polak's Frutal Works, Inc. Process of encapsulating an oil and product produced thereby
US3921637A (en) * 1973-07-23 1975-11-25 Bespak Industries Ltd Inhaler for powdered medicament
US3991761A (en) * 1974-03-18 1976-11-16 Salvatore Cocozza Inhaler for powdered medicaments
US4098273A (en) * 1975-01-13 1978-07-04 Syntex Puerto Rico, Inc. Inhalation device
US3964483A (en) * 1975-01-13 1976-06-22 Syntex Puerto Rico, Inc. Inhalation device
US4036223A (en) * 1975-01-29 1977-07-19 Obert Jean Claude Apparatus for generating aerosols of solid particles
US3991304A (en) * 1975-05-19 1976-11-09 Hillsman Dean Respiratory biofeedback and performance evaluation system
US4105027A (en) * 1975-06-13 1978-08-08 Syntex Puerto Rico, Inc. Inhalation device
US4153689A (en) * 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
US3994421A (en) * 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
US4109019A (en) * 1975-11-18 1978-08-22 William Percy Moore Process for improved ruminant feed supplements
US4211769A (en) * 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
US4206200A (en) * 1977-10-27 1980-06-03 Behringwerke Aktiengesellschaft Stabilizer for polysaccharides
US4249526A (en) * 1978-05-03 1981-02-10 Fisons Limited Inhalation device
US4253468A (en) * 1978-08-14 1981-03-03 Steven Lehmbeck Nebulizer attachment
US4227522A (en) * 1978-09-05 1980-10-14 Syntex Puerto Rico, Inc. Inhalation device
US4192309A (en) * 1978-09-05 1980-03-11 Syntex Puerto Rico, Inc. Inhalation device with capsule opener
US4503035A (en) * 1978-11-24 1985-03-05 Hoffmann-La Roche Inc. Protein purification process and product
US4503035B1 (en) * 1978-11-24 1996-03-19 Hoffmann La Roche Protein purification process and product
US4338931A (en) * 1979-04-27 1982-07-13 Claudio Cavazza Device for the quick inhalation of drugs in powder form by humans suffering from asthma
US4294829A (en) * 1979-07-31 1981-10-13 Teijin Limited Powdery pharmaceutical composition and powdery preparation for application to the nasal mucosa, and method for administration thereof
US4446862A (en) * 1979-10-30 1984-05-08 Baum Eric A Breath actuated devices for administering powdered medicaments
US4294624A (en) * 1980-03-14 1981-10-13 Veltman Preston Leonard Drying co-mingled carbohydrate solution and recycled product by dielectric heating
US4452239A (en) * 1980-03-25 1984-06-05 Hilal Malem Medical nebulizing apparatus
US4423079A (en) * 1980-07-14 1983-12-27 Leo Kline Growth promoting compositions for Lactobacillus sanfrancisco and method of preparation
US4484577A (en) * 1981-07-23 1984-11-27 Key Pharmaceuticals, Inc. Drug delivery method and inhalation device therefor
US5260306A (en) * 1981-07-24 1993-11-09 Fisons Plc Inhalation pharmaceuticals
US4533552A (en) * 1982-03-09 1985-08-06 Nippon Shinyaku Co., Ltd. Stabilization of azulene derivatives
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4778054A (en) * 1982-10-08 1988-10-18 Glaxo Group Limited Pack for administering medicaments to patients
US4534343A (en) * 1984-01-27 1985-08-13 Trutek Research, Inc. Metered dose inhaler
US4946828A (en) * 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US5069936A (en) * 1987-06-25 1991-12-03 Yen Richard C K Manufacturing protein microspheres
US4857311A (en) * 1987-07-31 1989-08-15 Massachusetts Institute Of Technology Polyanhydrides with improved hydrolytic degradation properties
US5707644A (en) * 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5376386A (en) * 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
US5482927A (en) * 1991-02-20 1996-01-09 Massachusetts Institute Of Technology Controlled released microparticulate delivery system for proteins
US6565841B1 (en) * 1991-03-15 2003-05-20 Amgen, Inc. Pulmonary administration of granulocyte colony stimulating factor
US5849704A (en) * 1991-12-20 1998-12-15 Novo Nordisk A/S Pharmaceutical formulation
US5849700A (en) * 1991-12-20 1998-12-15 Novo Nordisk A/S Pharmaceutical formulation
US5590206A (en) * 1992-04-09 1996-12-31 Samsung Electronics Co., Ltd. Noise canceler
US5889110A (en) * 1992-05-28 1999-03-30 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US5972388A (en) * 1992-06-12 1999-10-26 Teijin Limited Ultrafine particle power for inhalation and method for production thereof
US5626871A (en) * 1992-06-12 1997-05-06 Teijin Limited Preparation for intratracheobronchial administration
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6797258B2 (en) * 1992-07-08 2004-09-28 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized macromolecules
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
US5575987A (en) * 1992-09-02 1996-11-19 Takeda Chemical Industries, Ltd. Method of producing sustained-release microcapsules
US5994314A (en) * 1993-04-07 1999-11-30 Inhale Therapeutic Systems, Inc. Compositions and methods for nucleic acid delivery to the lung
US6303582B1 (en) * 1993-04-07 2001-10-16 Inhale Therapeutic Systems, Inc. Compositions and methods for nucleic acid delivery to the lung
US5554382A (en) * 1993-05-28 1996-09-10 Aphios Corporation Methods and apparatus for making liposomes
US5518998C1 (en) * 1993-06-24 2001-02-13 Astra Ab Therapeutic preparation for inhalation
US5518998A (en) * 1993-06-24 1996-05-21 Ab Astra Therapeutic preparation for inhalation
US5952008A (en) * 1993-06-24 1999-09-14 Ab Astra Processes for preparing compositions for inhalation
US5559298A (en) * 1993-10-13 1996-09-24 Kabushiki Kaisha Kawai Gakki Seisakusho Waveform read-out system for an electronic musical instrument
US5997848A (en) * 1994-03-07 1999-12-07 Inhale Therapeutic Systems Methods and compositions for pulmonary delivery of insulin
US6123936A (en) * 1994-05-18 2000-09-26 Inhale Therapeutics Systems, Inc. Methods and compositions for the dry powder formulation of interferons
US5785049A (en) * 1994-09-21 1998-07-28 Inhale Therapeutic Systems Method and apparatus for dispersion of dry powder medicaments
US5547696A (en) * 1994-10-13 1996-08-20 Novo Nordisk A/S Pharmaceutical formulation
US5631225A (en) * 1994-10-13 1997-05-20 Novo Nordisk A/S Pharmaceutical formulation
US5654278A (en) * 1994-10-13 1997-08-05 Novo Nordisk A/S Composition and method comprising growth hormone and leucine
US5705482A (en) * 1995-01-13 1998-01-06 Novo Nordisk A/S Pharmaceutical formulation
US5780014A (en) * 1995-04-14 1998-07-14 Inhale Therapeutic Systems Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin
US5667806A (en) * 1995-06-07 1997-09-16 Emisphere Technologies, Inc. Spray drying method and apparatus
US6136295A (en) * 1996-05-24 2000-10-24 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
USRE37053E1 (en) * 1996-05-24 2001-02-13 Massachusetts Institute Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6254854B1 (en) * 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US5985309A (en) * 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6165463A (en) * 1997-10-16 2000-12-26 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7744925B2 (en) 1994-12-02 2010-06-29 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US20050276846A1 (en) * 1994-12-02 2005-12-15 Roser Bruce J Solid dose delivery vehicle and methods of making same
US7785631B2 (en) 1994-12-02 2010-08-31 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US7780991B2 (en) 1994-12-02 2010-08-24 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US9439862B2 (en) 2000-05-10 2016-09-13 Novartis Ag Phospholipid-based powders for drug delivery
US7709461B2 (en) 2000-10-18 2010-05-04 Massachusetts Institute Of Technology Methods and products related to pulmonary delivery of polysaccharides
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside
US20040087543A1 (en) * 2002-04-25 2004-05-06 Zachary Shriver Methods and products for mucosal delivery
US7928089B2 (en) 2003-09-15 2011-04-19 Vectura Limited Mucoactive agents for treating a pulmonary disease
US7560444B2 (en) 2003-10-01 2009-07-14 Momenta Pharmaceuticals, Inc. Polysaccharides for pulmonary delivery of active agents
US20050207988A1 (en) * 2003-10-01 2005-09-22 Thomas Richardson Polysaccharides for pulmonary delivery of active agents
US8322046B2 (en) * 2003-12-22 2012-12-04 Zhaolin Wang Powder formation by atmospheric spray-freeze drying
US20070037776A1 (en) * 2005-08-08 2007-02-15 Tom Richardson Polysaccharides for delivery of active agents

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