CA2136704A1 - Medicinal aerosol formulation - Google Patents
Medicinal aerosol formulationInfo
- Publication number
- CA2136704A1 CA2136704A1 CA002136704A CA2136704A CA2136704A1 CA 2136704 A1 CA2136704 A1 CA 2136704A1 CA 002136704 A CA002136704 A CA 002136704A CA 2136704 A CA2136704 A CA 2136704A CA 2136704 A1 CA2136704 A1 CA 2136704A1
- Authority
- CA
- Canada
- Prior art keywords
- medicinal
- medicinal substance
- substance
- spray
- propellant
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
Abstract
The invention related to a medicinal substance preparation in the form of a suspension aerosol which comprises a spray-dried product which is composed of a medicinal substance, of a surface-active, physiologically tolerated substance which is insoluble in the liquefied propellant, where appropriate a masking flavor and/or a customary auxiliary substance, in a liquefiable, hydrogenated or partially hydrogenated fluorocarbon as propellant. The invention furthermore relates to a process for the production of the medicinal substance preparation which comprises medicinal substances suitable for inhalation and acting locally on the lung for the treatment of airway disorders or asthma.
Description
HOECHST A~L~ SELLSCHAFT HOE 93/F 393 Dr.D/PP
Description A medicinal aerosol formulation Modern aerosol technology, which is predominantly based on the use of liquefiable safety propellants under moderate pressure, has a number of significant advantages and, furthermore, has opened up numerous novel possibil-ities of use. The following advantages should be specifi-cally emphasized:
Each compressed gas pack is an automatic device which allows, by finger pressure on an applicator, the product to be removed or applied in a form suitable for optimal effect. Using this control it is possible easily, and thus also economically, to divide up the quantity of product to be used. Where it is appropriate for a small dose which is always the same to be removed, a metering valve undertakes this quantity limitation automatically.
The convenience of handling of compressed gas packs of this type is a crucial advantage of this medicinal form.
The one-hand devices are practical to use and simple to handle. The automatically closing valve means that the contents cannot run out or be spilt. Volatile substances cannot evaporate, and the contents cannot dry out. The gas-tight closure of the pack prevents entry of air and hence the possible contamination by dust, moisture or germs.
Oxidation-sensitive products can be packaged with exclusion of atmospheric oxygen. A compressed gas pack also provides excellent protection from light for sensi-tive active substances.
The product packed in the compressed gas packs is fre-quently composed of a powdered substance (for example a 21367!~4 medicinal substance) which is suspended in the liquefied propellant, and of a surface-active substance which is used to stabilize the suspension, for example sorbitan trioleate, oleic acid or lecithin. The propellants used to date for medicinal aerosols have been almost exclusively chlorofluorocarbons, eg. trichlorofluorometh-ane (~Frigen 11), dichlorodifluoromethane (Frigen 12), 1,2-dichlorotetrafluoroethane (Frigen 114), and mixtures thereof. The powder, which must have the smallest poss-ible particle size in order to prevent sedimentation, i8dispersed in a considerably larger quantity of propel-lant. The proportionate quantity of propellant must also be, to reduce the risk of impairments of the valve, at least 85 % by weight and will, in many cases, be con-siderably above this value. Aerosols of this type arefrequently encountered as inhaler aerosols.
Inhaler aerosol~ are suitable for administering medicinal substances for the therapy of disorders of the airways, for example the administration of beta-sympathomimetics, steroids, anticholinergics, antihistamines, mast-cell stabilizers such as cromoglicic acid or nedocromil, PAF
antagonists, leukotriene antagonists, bradykinin antagon-ists or potassium channel activators for the local therapy of asthma. Inhaler aerosols are also suitable for the systemic therapy of diseases because the pulmonary epithelium has sufficient permeability for low molecular weight medicinal substances. Pulmonary administration by means of inhaler aerosol is particularly suitable for highly active medicinal substance~, for example peptides and proteins such as insulin, LHRH analogs, oxytocin, vasopressin analogs, calcitonin analogs or interferon (compare, for example, Banga and Chien, Int. J. Pharm.
48, 15-50 (1988)). Suspension aerosol formulations of LHRH analogs with chlorofluorocarbon as propellant are described, for example, in EP-A 0 510 731.
Discussions about the cause of the damage to the ozone layer by chlorofluorocarbons (CFCs) have led to the use 2l367n~
of these eubstances being restricted or, in some cases, even prohibited in many countries. It is known from investigations that one of the causes le~i ng to damage to the ozone layer is the reaction of ozone with free radicals produced from chlorine atoms in the CFCs. This is why non-ozone-damaging propellants, for example carbon dioxide, dinitrogen oxide, dimethyl ether, short-chain hydrocarbons (propane or butane) or hydrogenated fluoro-carbons (HFCs) have been used recently for aerosols.
Particularly suitable propellants for pharmaceutical aerosols are those propellant gases which can be liquefied under pressure at room temperature and, on inhalation or topical use, are safe, toxicologically innocuous and free of side effects. These properties relate in particular to hydrogenated fluorocarbons (HFCs) such as, for example, tetrafluoroethane (R134a) and heptafluoropropane (R227), with heptafluoropropane being more suitable, because of its lower vapor pressure at room temperature, of about 4 bar, because it is possible to dispense with a pressure-reducing additive. Tetra-fluoroethane cannot, because of its higher vapor pressure of 6 bar at room temperature, be used as sole propellant because at 50C it exceeds the maximum permissible pressure of 12 bar specified in the TRG300 (industrial guidelines on gases) for aluminum cans with a pressure of about 13 bar.
The technology hitherto used to produce medicinal suspen-~ion aerosols i~ based on a ~olubility of the surface-active substances in the liquefied propellant (the medicinal substance is suspended in the propellant). This property no longer exists on use of novel, alternative propellants such as tetrafluoroethane or heptafluoro-propane, because of their higher polarity. This means that formulations with chlorofluorocarbons cannot be modified simply by replacing the propellant by hydrogen-ated fluorocarbons as described in EP-A 0 513 099, EP-A 0 518 600, EP-A 0 518 601 and EP-A 0 550 031. It is 213670~
not possible in this way to produce stable suspensions with the surface-active substances used hitherto in inhaler aerosols.
Hence, according to EP-B O 372 777 and EP-A O 499 344, cosolvents with a higher polarity, such as, for example, ethanol, are used to achieve a sufficient solubility of the surface-active substance in the liquefied propellant (HFC). The use of other surface-active substances which dissolve in the liquefied propellant (HFC) but have not hitherto been used in medicinal aerosols is described in EP-A O 504 112 (monoacetylated or diacetylated monogly-cerides), EP-A O 536 204, EP-A O 513 127 and EP-A O 526 481 (fluorinated surfactants), EP-A O 536 235 (block copolymers of ethylene oxide and propylene oxide as well as polysorbates) and EP-A O 534 731 (polyvinyl-pyrrolidone and polyvinyl alcohol). However, the said substances have the crucial disadvantage that they have not undergone toxicological testing for inhalation use or in fact have proved unsuitable because tissue-damaging.
Furthermore, the Patent Applications WO 92/08446 and WO 92/08447 describe a process in which active substances are coated with the surface-active substance. This process starts from an active substance which is already micronized, and is suspended in a solution of the sur-face-active substance in an organic solvent, ~uch as, for example, isopentane, in which the active substance is virtually insoluble. After a certain time, the solvent is removed. The active substances modified in this way can be suspended in hydrogenated fluorocarbons (HFCs), where appropriate with the addition of a cosolvent. One disad-vantage of this process is that the previously micronized active substance must be suspended and redried. Agglomer-ation of the particles may occur during this. The process does not ensure uniform dispersion of the surface-active substance. The use of an additional organic solvent such as isopentane must also be judged negatively.
2136~04 The invention was thus based on the object of formulating a Rtable suspension metered aerosol for medicinal use cont~;n;ng a pharmaceutical active substance, a physio-logically tolerated surface-active substance which is insoluble in the liquefied propellant, for example sorbitan trioleate, oleic acid and lecithin, where appropriate a masking flavor, for example a sweetener such as saccharin, acesulfame R or aspartame, or an essential oil, where appropriate a generally customary ancillary substance from the group of sugars or sugar alcohols, such as lactose, glucose or mannitol, and as propellant a hydrogenated fluorocarbon, preferably heptafluoropropane (R227).
The object is achieved according to the invention by converting the active substance and surface-active substance, where appropriate with the said additional ancillary substances, by spray drying into a form in which they are present finely dispersed together in a matrix. It has been found, surprisingly, that this spray-dried product subsequently forms, without further addi-tives, a fine, stable, homogeneous suspen~ion in the liquefied propellant.
The invention therefore relates to a medicinal substance preparation in the form of a suspension aerosol, which comprises a) a spray-dried product composed of a medicinal sub-stance and of a physiologically tolerated surface-active substance which is insoluble in the liquefied propellant, and, where appropriate, a masking flavor and, where appropriate, a generally customary phy8iologically tolerated auxiliary 8ub8tance and b) a liquefiable, hydro~enated or partially hydro~enated ated fluorocarbon as propellant.
The active substances and ancillary substances (including surface-active substances) are present finely dispersed in a matrix in the spray-dried product. Addition of the propellant results in a fine, stable, homogeneous suspen-sion. The product particles have a particle size customary for aerosols.
The invention furthermore relates to a process for the production of a medicinal substance preparation in the form of a suspension aerosol, which comprises dissolving the medicinal substance, the physiologically tolerated surface-active substance and, where appropriate, a masking flavor and, where appropriate, other generally customary physiologically tolerated auxiliary substances in a suitable solvent, subjecting the resulting solution to a spray drying, metering the spray-dried product into a compressed gas pack, closing the latter with a metering valve, and metering in the quantity of the liquefiable, hydrogenated or partially hydro~enated fluorocarbon required to form the euspension aero~ol.
Suitable medicinal substances are those which act locally on the lung and are suitable for inhalation, that is to say, for example, medicinal substances for the treatment of airway disorders or asthma, such as beta-sympatho-mimetic B, steroids, anticholinergics, antihistamines, antiallergics, mast-cell stabilizers such as cromoglicic acid or nedocromil, PAF antagonists, leukotriene antagon-ists, bradykinin antagonists or potassium channel activators.
The spray drying iB also suitable for pharmaceutical active substances which cannot be micronized by conven-tional methods such as milling and thus converted into a particle size necessary for inhalation. This particularly applies to peptides and proteins obtained by freeze drying and in amorphous form.
Suitable active substances are therefore also peptides and proteins of natural or synthetic origin and their physiologically tolerated salts. Examples which may be mentioned are: insulins, ~HRH analogs, oxytocin, va~opressin analogs, calcitonin analogs and interferon and their physiologically tolerated salts.
The suspension aerosols according to the invention preferably contain as medicinal substance an insulin, a bradykinin antagonist, an LHRH analog such as bu~erelin or their physiologically tolerated salts.
The suspension aerosols according to the invention are particularly suitable for asthma treatment and contain, for example, the bradykinin antagonist icatibant (= H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140)) or an icatibant salt or the potassium channel activator rilmakalim ((+)-(3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate).
Particularly preferred surface-active substances are sorbitan trioleate, oleic acid or lecithin. Suitable as lecithin are all natural lecithins such as egg or soybean lecithin, partially hydrogenated and hydrogenated lecith-ins, and highly purified phosphatidylcholines.
Examples of suitable masking flavors are sweeteners such as saccharin, aspartame and acesulfame R, or e~sential oils.
The generally customary physiologically tolerated ancil-lary substances must, just like the active substances, surface-active substances and masking flavors, be soluble in the common solvent. The nature of these ancillary substances therefore depends on the solvent used. Parti-cularly suitable ancillary substances are from the group of sugars and sugar alcohols, such as lactose, glucose or mannitol.
The spray-dried product contains one or more active substances, one or more surface-active substances and, where appropriate, one or more other ancillary substances and masking flavors.
2l367n4 Examples of suitable propellants are heptafluoropropane (R227) and tetrafluoroethane (R134a), preferably mixed with R227.
Examples of suitable common solvents for the ingredients in the spray-dried product are mixtures of lower alcohols (with up to 6 carbon atoms) or ketones with water.
The content of active substance in the spray-dried product depend~ in particular on the level of dosage reguired.
The content of surface-active substance dispersed in the active substance matrix is relatively small and i8, for example, from 0.01 to 1.0 % by weight, preferably from 0.05 to 0.5 % by weight, based on the content of active substance.
The spray-drying is carried out by conventional methods as described in the literature (compare, for example, J. Broadhead et al., Drug Development and Industrial Pharmacy, 18, 1169-1206 (1992)). It is preferably carried out at elevated temperature, the level dep~n~i ng, inter alia, on the active substance and solvent used.
The spray-drying process confer~ on the active substance particles a spherical aerodynamic shape which favors movement in the airstream during inhalation and thus increase~ the proportion of particles entering the lungs.
In addition, adhesion and agglomeration forces both in the suspen~ion and during the spraying-out process are reduced. The ~pray-drying proces~ to produce powders to be used for inhalation has already been disclosed in the Patents GB 1 520 248 and GB 1 569 612. However, in these ca~e~ only the pure active substances were spray dried without addition of surface-active substances, masking flavors or other ancillary substances, and sub~equently formulated in the form of a powder inhalant and not as suspension aero~ol.
213670~
The invention i8 illustrated by means of the following examples:
Example 1 1968 mg of icatibant acetate, 2.0 mg of soybean lecithin S100 (Lipoid R.G.) and 30 mg of saccharin are converted into a clear solution in an ethanol/water mixture (25 %
w/w) and spray dried in a spray-drying apparatus at 110C
under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can iB closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the intro-duction a fine homogeneous suspension of primary medici-nal substance particles in R227 is formed. One actuationof the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of suspension, contA;n;ng 100 ~g of medicinal substance, per administration.
Example 2 430 mg of icatibant acetate, 3566 mg of lactose and 4 mg of hydrogenated egg lecithin (EPC-3, Lipoid R.G.) are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a ~pray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subse~uently 10 g of R227 are introduced through the metering valve. Immedi-ately after the introduction a fine homogeneous suspen-sion of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of su~pension, contA;n;ng 10 ~g of medicinal substance, per admini-~tration.
213670~
Example 3 1968 mg of icatibant acetate, 2 mg of sorbitan trioleate and 30 mg of aspartame are converted into a clear 801-ution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 110C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of ~uspension, conta;n;ng 100 ~g of medicinal substance, per administration.
Example 4 1000 mg of human insulin, 2 mg of soybean lecithin S100 and 1000 mg of lactose are converted into a clear ~ol-ution in an ethanol/water mixture (25 % w/w) and spraydried in a spray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 50 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of suspension, corr~espsn~;ng to 3 I.U. of insulin, per a~; n; stration.
Example 5 1998 mg of buserelin acetate and 2 mg of soybean lecithin S100 are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 iB formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~in;ng 100 ~g of medicinal substance, per administration.
Example 6 1998 mg of rilmakalim hemihydrate and 2.0 mg of soybean lecithin S100 are converted into a clear solution in an ethanol/water mixture (50 % w/w) and spray dried in a spray-drying apparatus at 100C under inert conditions (N2). The product results from this as a fine white powder. The powder i8 metered in 100 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~;n;ng 1000 ~g of medicinal substance, per administration.
Example 7 1998 mg of icatibant acetate and 2.0 mg of sorbitan trioleate (Span~85) are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 100C under inert conditions 21367Q~
(N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, conta;n;ng 100 ~g of medicinal substance, per administration.
Example 8 1998 mg of icatibant acetate and 2.0 mg of oleic acid are converted into a clear solution in an acetone/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can iB
closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, containing 100 ~g of medicinal sub-stance, per A~;n; stration.
Example 9 200 mg of salbutamol, 2.0 mg of soybean lecithin S100 and 1798 mg of lactose are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 50 mg portions into an aluminum monobloc can prescribed for metered aerosols, 2l367n~
the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering ~alve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~;ning 50 ~g of medicinal substance, per administration.
Example 10 1998 mg of prednisolone and 2.0 mg of soybean lecithin S100 are converted into a clear solution in an ethanol-/water mixture (50 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering ~alve, and subsequently 10 g of R227 are introduced through the metering valve. Immedi-ately after the introduction a fine homogeneous suspen-sion of primary medicinal substance particles in R227 isformed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, con~in;ng 100 ~g of medicinal substance, per administration.
Description A medicinal aerosol formulation Modern aerosol technology, which is predominantly based on the use of liquefiable safety propellants under moderate pressure, has a number of significant advantages and, furthermore, has opened up numerous novel possibil-ities of use. The following advantages should be specifi-cally emphasized:
Each compressed gas pack is an automatic device which allows, by finger pressure on an applicator, the product to be removed or applied in a form suitable for optimal effect. Using this control it is possible easily, and thus also economically, to divide up the quantity of product to be used. Where it is appropriate for a small dose which is always the same to be removed, a metering valve undertakes this quantity limitation automatically.
The convenience of handling of compressed gas packs of this type is a crucial advantage of this medicinal form.
The one-hand devices are practical to use and simple to handle. The automatically closing valve means that the contents cannot run out or be spilt. Volatile substances cannot evaporate, and the contents cannot dry out. The gas-tight closure of the pack prevents entry of air and hence the possible contamination by dust, moisture or germs.
Oxidation-sensitive products can be packaged with exclusion of atmospheric oxygen. A compressed gas pack also provides excellent protection from light for sensi-tive active substances.
The product packed in the compressed gas packs is fre-quently composed of a powdered substance (for example a 21367!~4 medicinal substance) which is suspended in the liquefied propellant, and of a surface-active substance which is used to stabilize the suspension, for example sorbitan trioleate, oleic acid or lecithin. The propellants used to date for medicinal aerosols have been almost exclusively chlorofluorocarbons, eg. trichlorofluorometh-ane (~Frigen 11), dichlorodifluoromethane (Frigen 12), 1,2-dichlorotetrafluoroethane (Frigen 114), and mixtures thereof. The powder, which must have the smallest poss-ible particle size in order to prevent sedimentation, i8dispersed in a considerably larger quantity of propel-lant. The proportionate quantity of propellant must also be, to reduce the risk of impairments of the valve, at least 85 % by weight and will, in many cases, be con-siderably above this value. Aerosols of this type arefrequently encountered as inhaler aerosols.
Inhaler aerosol~ are suitable for administering medicinal substances for the therapy of disorders of the airways, for example the administration of beta-sympathomimetics, steroids, anticholinergics, antihistamines, mast-cell stabilizers such as cromoglicic acid or nedocromil, PAF
antagonists, leukotriene antagonists, bradykinin antagon-ists or potassium channel activators for the local therapy of asthma. Inhaler aerosols are also suitable for the systemic therapy of diseases because the pulmonary epithelium has sufficient permeability for low molecular weight medicinal substances. Pulmonary administration by means of inhaler aerosol is particularly suitable for highly active medicinal substance~, for example peptides and proteins such as insulin, LHRH analogs, oxytocin, vasopressin analogs, calcitonin analogs or interferon (compare, for example, Banga and Chien, Int. J. Pharm.
48, 15-50 (1988)). Suspension aerosol formulations of LHRH analogs with chlorofluorocarbon as propellant are described, for example, in EP-A 0 510 731.
Discussions about the cause of the damage to the ozone layer by chlorofluorocarbons (CFCs) have led to the use 2l367n~
of these eubstances being restricted or, in some cases, even prohibited in many countries. It is known from investigations that one of the causes le~i ng to damage to the ozone layer is the reaction of ozone with free radicals produced from chlorine atoms in the CFCs. This is why non-ozone-damaging propellants, for example carbon dioxide, dinitrogen oxide, dimethyl ether, short-chain hydrocarbons (propane or butane) or hydrogenated fluoro-carbons (HFCs) have been used recently for aerosols.
Particularly suitable propellants for pharmaceutical aerosols are those propellant gases which can be liquefied under pressure at room temperature and, on inhalation or topical use, are safe, toxicologically innocuous and free of side effects. These properties relate in particular to hydrogenated fluorocarbons (HFCs) such as, for example, tetrafluoroethane (R134a) and heptafluoropropane (R227), with heptafluoropropane being more suitable, because of its lower vapor pressure at room temperature, of about 4 bar, because it is possible to dispense with a pressure-reducing additive. Tetra-fluoroethane cannot, because of its higher vapor pressure of 6 bar at room temperature, be used as sole propellant because at 50C it exceeds the maximum permissible pressure of 12 bar specified in the TRG300 (industrial guidelines on gases) for aluminum cans with a pressure of about 13 bar.
The technology hitherto used to produce medicinal suspen-~ion aerosols i~ based on a ~olubility of the surface-active substances in the liquefied propellant (the medicinal substance is suspended in the propellant). This property no longer exists on use of novel, alternative propellants such as tetrafluoroethane or heptafluoro-propane, because of their higher polarity. This means that formulations with chlorofluorocarbons cannot be modified simply by replacing the propellant by hydrogen-ated fluorocarbons as described in EP-A 0 513 099, EP-A 0 518 600, EP-A 0 518 601 and EP-A 0 550 031. It is 213670~
not possible in this way to produce stable suspensions with the surface-active substances used hitherto in inhaler aerosols.
Hence, according to EP-B O 372 777 and EP-A O 499 344, cosolvents with a higher polarity, such as, for example, ethanol, are used to achieve a sufficient solubility of the surface-active substance in the liquefied propellant (HFC). The use of other surface-active substances which dissolve in the liquefied propellant (HFC) but have not hitherto been used in medicinal aerosols is described in EP-A O 504 112 (monoacetylated or diacetylated monogly-cerides), EP-A O 536 204, EP-A O 513 127 and EP-A O 526 481 (fluorinated surfactants), EP-A O 536 235 (block copolymers of ethylene oxide and propylene oxide as well as polysorbates) and EP-A O 534 731 (polyvinyl-pyrrolidone and polyvinyl alcohol). However, the said substances have the crucial disadvantage that they have not undergone toxicological testing for inhalation use or in fact have proved unsuitable because tissue-damaging.
Furthermore, the Patent Applications WO 92/08446 and WO 92/08447 describe a process in which active substances are coated with the surface-active substance. This process starts from an active substance which is already micronized, and is suspended in a solution of the sur-face-active substance in an organic solvent, ~uch as, for example, isopentane, in which the active substance is virtually insoluble. After a certain time, the solvent is removed. The active substances modified in this way can be suspended in hydrogenated fluorocarbons (HFCs), where appropriate with the addition of a cosolvent. One disad-vantage of this process is that the previously micronized active substance must be suspended and redried. Agglomer-ation of the particles may occur during this. The process does not ensure uniform dispersion of the surface-active substance. The use of an additional organic solvent such as isopentane must also be judged negatively.
2136~04 The invention was thus based on the object of formulating a Rtable suspension metered aerosol for medicinal use cont~;n;ng a pharmaceutical active substance, a physio-logically tolerated surface-active substance which is insoluble in the liquefied propellant, for example sorbitan trioleate, oleic acid and lecithin, where appropriate a masking flavor, for example a sweetener such as saccharin, acesulfame R or aspartame, or an essential oil, where appropriate a generally customary ancillary substance from the group of sugars or sugar alcohols, such as lactose, glucose or mannitol, and as propellant a hydrogenated fluorocarbon, preferably heptafluoropropane (R227).
The object is achieved according to the invention by converting the active substance and surface-active substance, where appropriate with the said additional ancillary substances, by spray drying into a form in which they are present finely dispersed together in a matrix. It has been found, surprisingly, that this spray-dried product subsequently forms, without further addi-tives, a fine, stable, homogeneous suspen~ion in the liquefied propellant.
The invention therefore relates to a medicinal substance preparation in the form of a suspension aerosol, which comprises a) a spray-dried product composed of a medicinal sub-stance and of a physiologically tolerated surface-active substance which is insoluble in the liquefied propellant, and, where appropriate, a masking flavor and, where appropriate, a generally customary phy8iologically tolerated auxiliary 8ub8tance and b) a liquefiable, hydro~enated or partially hydro~enated ated fluorocarbon as propellant.
The active substances and ancillary substances (including surface-active substances) are present finely dispersed in a matrix in the spray-dried product. Addition of the propellant results in a fine, stable, homogeneous suspen-sion. The product particles have a particle size customary for aerosols.
The invention furthermore relates to a process for the production of a medicinal substance preparation in the form of a suspension aerosol, which comprises dissolving the medicinal substance, the physiologically tolerated surface-active substance and, where appropriate, a masking flavor and, where appropriate, other generally customary physiologically tolerated auxiliary substances in a suitable solvent, subjecting the resulting solution to a spray drying, metering the spray-dried product into a compressed gas pack, closing the latter with a metering valve, and metering in the quantity of the liquefiable, hydrogenated or partially hydro~enated fluorocarbon required to form the euspension aero~ol.
Suitable medicinal substances are those which act locally on the lung and are suitable for inhalation, that is to say, for example, medicinal substances for the treatment of airway disorders or asthma, such as beta-sympatho-mimetic B, steroids, anticholinergics, antihistamines, antiallergics, mast-cell stabilizers such as cromoglicic acid or nedocromil, PAF antagonists, leukotriene antagon-ists, bradykinin antagonists or potassium channel activators.
The spray drying iB also suitable for pharmaceutical active substances which cannot be micronized by conven-tional methods such as milling and thus converted into a particle size necessary for inhalation. This particularly applies to peptides and proteins obtained by freeze drying and in amorphous form.
Suitable active substances are therefore also peptides and proteins of natural or synthetic origin and their physiologically tolerated salts. Examples which may be mentioned are: insulins, ~HRH analogs, oxytocin, va~opressin analogs, calcitonin analogs and interferon and their physiologically tolerated salts.
The suspension aerosols according to the invention preferably contain as medicinal substance an insulin, a bradykinin antagonist, an LHRH analog such as bu~erelin or their physiologically tolerated salts.
The suspension aerosols according to the invention are particularly suitable for asthma treatment and contain, for example, the bradykinin antagonist icatibant (= H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140)) or an icatibant salt or the potassium channel activator rilmakalim ((+)-(3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate).
Particularly preferred surface-active substances are sorbitan trioleate, oleic acid or lecithin. Suitable as lecithin are all natural lecithins such as egg or soybean lecithin, partially hydrogenated and hydrogenated lecith-ins, and highly purified phosphatidylcholines.
Examples of suitable masking flavors are sweeteners such as saccharin, aspartame and acesulfame R, or e~sential oils.
The generally customary physiologically tolerated ancil-lary substances must, just like the active substances, surface-active substances and masking flavors, be soluble in the common solvent. The nature of these ancillary substances therefore depends on the solvent used. Parti-cularly suitable ancillary substances are from the group of sugars and sugar alcohols, such as lactose, glucose or mannitol.
The spray-dried product contains one or more active substances, one or more surface-active substances and, where appropriate, one or more other ancillary substances and masking flavors.
2l367n4 Examples of suitable propellants are heptafluoropropane (R227) and tetrafluoroethane (R134a), preferably mixed with R227.
Examples of suitable common solvents for the ingredients in the spray-dried product are mixtures of lower alcohols (with up to 6 carbon atoms) or ketones with water.
The content of active substance in the spray-dried product depend~ in particular on the level of dosage reguired.
The content of surface-active substance dispersed in the active substance matrix is relatively small and i8, for example, from 0.01 to 1.0 % by weight, preferably from 0.05 to 0.5 % by weight, based on the content of active substance.
The spray-drying is carried out by conventional methods as described in the literature (compare, for example, J. Broadhead et al., Drug Development and Industrial Pharmacy, 18, 1169-1206 (1992)). It is preferably carried out at elevated temperature, the level dep~n~i ng, inter alia, on the active substance and solvent used.
The spray-drying process confer~ on the active substance particles a spherical aerodynamic shape which favors movement in the airstream during inhalation and thus increase~ the proportion of particles entering the lungs.
In addition, adhesion and agglomeration forces both in the suspen~ion and during the spraying-out process are reduced. The ~pray-drying proces~ to produce powders to be used for inhalation has already been disclosed in the Patents GB 1 520 248 and GB 1 569 612. However, in these ca~e~ only the pure active substances were spray dried without addition of surface-active substances, masking flavors or other ancillary substances, and sub~equently formulated in the form of a powder inhalant and not as suspension aero~ol.
213670~
The invention i8 illustrated by means of the following examples:
Example 1 1968 mg of icatibant acetate, 2.0 mg of soybean lecithin S100 (Lipoid R.G.) and 30 mg of saccharin are converted into a clear solution in an ethanol/water mixture (25 %
w/w) and spray dried in a spray-drying apparatus at 110C
under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can iB closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the intro-duction a fine homogeneous suspension of primary medici-nal substance particles in R227 is formed. One actuationof the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of suspension, contA;n;ng 100 ~g of medicinal substance, per administration.
Example 2 430 mg of icatibant acetate, 3566 mg of lactose and 4 mg of hydrogenated egg lecithin (EPC-3, Lipoid R.G.) are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a ~pray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subse~uently 10 g of R227 are introduced through the metering valve. Immedi-ately after the introduction a fine homogeneous suspen-sion of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of su~pension, contA;n;ng 10 ~g of medicinal substance, per admini-~tration.
213670~
Example 3 1968 mg of icatibant acetate, 2 mg of sorbitan trioleate and 30 mg of aspartame are converted into a clear 801-ution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 110C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of ~uspension, conta;n;ng 100 ~g of medicinal substance, per administration.
Example 4 1000 mg of human insulin, 2 mg of soybean lecithin S100 and 1000 mg of lactose are converted into a clear ~ol-ution in an ethanol/water mixture (25 % w/w) and spraydried in a spray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 50 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve. Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by the process contains 100 ~1 of suspension, corr~espsn~;ng to 3 I.U. of insulin, per a~; n; stration.
Example 5 1998 mg of buserelin acetate and 2 mg of soybean lecithin S100 are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 90C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 iB formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~in;ng 100 ~g of medicinal substance, per administration.
Example 6 1998 mg of rilmakalim hemihydrate and 2.0 mg of soybean lecithin S100 are converted into a clear solution in an ethanol/water mixture (50 % w/w) and spray dried in a spray-drying apparatus at 100C under inert conditions (N2). The product results from this as a fine white powder. The powder i8 metered in 100 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~;n;ng 1000 ~g of medicinal substance, per administration.
Example 7 1998 mg of icatibant acetate and 2.0 mg of sorbitan trioleate (Span~85) are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 100C under inert conditions 21367Q~
(N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, conta;n;ng 100 ~g of medicinal substance, per administration.
Example 8 1998 mg of icatibant acetate and 2.0 mg of oleic acid are converted into a clear solution in an acetone/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can iB
closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering valve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, containing 100 ~g of medicinal sub-stance, per A~;n; stration.
Example 9 200 mg of salbutamol, 2.0 mg of soybean lecithin S100 and 1798 mg of lactose are converted into a clear solution in an ethanol/water mixture (25 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 50 mg portions into an aluminum monobloc can prescribed for metered aerosols, 2l367n~
the can is closed with a metering valve, and subsequently 10 g of R227 are introduced through the metering ~alve.
Immediately after the introduction a fine homogeneous suspension of primary medicinal substance particles in R227 is formed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, cont~;ning 50 ~g of medicinal substance, per administration.
Example 10 1998 mg of prednisolone and 2.0 mg of soybean lecithin S100 are converted into a clear solution in an ethanol-/water mixture (50 % w/w) and spray dried in a spray-drying apparatus at 80C under inert conditions (N2). The product results from this as a fine white powder. The powder is metered in 10 mg portions into an aluminum monobloc can prescribed for metered aerosols, the can is closed with a metering ~alve, and subsequently 10 g of R227 are introduced through the metering valve. Immedi-ately after the introduction a fine homogeneous suspen-sion of primary medicinal substance particles in R227 isformed. One actuation of the inhaler aerosol (suspension aerosol) produced by this process contains 100 ~1 of suspension, con~in;ng 100 ~g of medicinal substance, per administration.
Claims (8)
1. A medicinal substance preparation in the form of a suspension aerosol, which comprises a) a spray-dried product composed of a medicinal substance and of a physiologically tolerated surface-active substance which is insoluble in the liquefied propellant, and, where appropriate, a masking flavor and, where appropriate, a generally customary physiologically tolerated auxiliary substance and b) a liquefiable, hydrogenated or partially hydrogenated fluorocarbon as propellant.
2. A process for the production of a medicinal substance preparation in the formof a suspension aerosol as claimed in claim 1, which comprises dissolving the medicinal substance, the physiologically tolerated surface-active substance and, where appropriate, a masking flavor and, where appropriate, other generally customary physiologically tolerated auxiliary substances in a suitablesolvent, subjecting the resulting solution to a spray drying, metering the spray-dried product into a compressed gas pack, closing the latter with a metering valve, and metering in the quantity of the liquefiable, hydrogenated or partially hydrogenated fluorocarbon required to form the suspension aerosol.
3. A medicinal substance preparation as claimed in claim 1, which comprises medicinal substances suitable for inhalation and acting locally on the lung for the treatment of airway disorders or asthma.
4. A medicinal substance preparation as claimed in claim 1, which comprises as medicinal substance a peptide or protein or physiologically tolerated salts thereof.
5. A medicinal substance preparation as claimed in claim 1, which comprises icatibant or its physio-logically tolerated salt.
6. A medicinal substance preparation as claimed in claim 1, wherein the surface-active substance is sorbitan trioleate, oleic acid or lecithin.
7. A medicinal substance preparation as claimed in claim 1, wherein the propellant is heptafluoro-propane.
8. A medicinal substance preparation as claimed in claim 1, wherein the masking flavor is a sweetener and/or an essential oil, and the other ancillary substances are selected from the group of sugars and sugar alcohols.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4340434 | 1993-11-27 | ||
| DEP4340434.0 | 1993-11-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2136704A1 true CA2136704A1 (en) | 1995-05-28 |
Family
ID=6503581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136704A Abandoned CA2136704A1 (en) | 1993-11-27 | 1994-11-25 | Medicinal aerosol formulation |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0655237A1 (en) |
| JP (1) | JPH07187996A (en) |
| KR (1) | KR950013499A (en) |
| AU (1) | AU676390B2 (en) |
| CA (1) | CA2136704A1 (en) |
| FI (1) | FI945524A (en) |
| HU (1) | HUT75152A (en) |
| NO (1) | NO944526L (en) |
| NZ (1) | NZ264993A (en) |
| ZA (1) | ZA949378B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7908791A (en) * | 1990-05-08 | 1991-11-27 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
| DE4123663A1 (en) * | 1991-07-17 | 1993-01-21 | Schwabe Willmar Gmbh & Co | Medicinal aerosol free from fluoro:chlorocarbon(s) - contains active agent in suspending or dispersing aid and alcohol with hepta:fluoro:propane as propellant |
-
1994
- 1994-11-21 EP EP94118290A patent/EP0655237A1/en not_active Withdrawn
- 1994-11-24 FI FI945524A patent/FI945524A/en unknown
- 1994-11-25 AU AU79051/94A patent/AU676390B2/en not_active Ceased
- 1994-11-25 KR KR1019940031147A patent/KR950013499A/en not_active Application Discontinuation
- 1994-11-25 CA CA002136704A patent/CA2136704A1/en not_active Abandoned
- 1994-11-25 HU HU9403396A patent/HUT75152A/en unknown
- 1994-11-25 NZ NZ264993A patent/NZ264993A/en unknown
- 1994-11-25 NO NO944526A patent/NO944526L/en unknown
- 1994-11-25 JP JP6290268A patent/JPH07187996A/en active Pending
- 1994-11-25 ZA ZA949378A patent/ZA949378B/en unknown
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| US6638495B2 (en) | 1997-09-29 | 2003-10-28 | Nektar Therapeutics | Stabilized preparation for use in metered dose inhalers |
| US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
| US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
| US8080263B2 (en) | 1997-09-29 | 2011-12-20 | Novartis Ag | Dispersion for pulmonary delivery of a bioactive agent |
| US7393544B2 (en) | 1997-09-29 | 2008-07-01 | Nektar Therapeutics | Dispersion for pulmonary delivery of a bioactive agent |
| US6926908B2 (en) | 1998-06-30 | 2005-08-09 | Quadrant Drug Delivery Limited | Formulation for inhalation |
| US6451349B1 (en) | 1998-08-19 | 2002-09-17 | Quadrant Healthcare (Uk) Limited | Spray-drying process for the preparation of microparticles |
| US6645528B1 (en) | 1999-05-27 | 2003-11-11 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| USRE40493E1 (en) | 1999-05-27 | 2008-09-09 | Acusphere, Inc. | Porous paclitaxel matrices and methods of manufacture thereof |
| US7919119B2 (en) | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| US8821938B2 (en) | 1999-05-27 | 2014-09-02 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| US6932983B1 (en) | 1999-05-27 | 2005-08-23 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| US9439862B2 (en) | 2000-05-10 | 2016-09-13 | 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 |
| 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 |
| US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
| US8933023B2 (en) | 2004-03-12 | 2015-01-13 | Biodel Inc. | Rapid acting injectable insulin compositions |
| US8084420B2 (en) | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
| US7718609B2 (en) | 2006-04-12 | 2010-05-18 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
| US7713929B2 (en) | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
| WO2010085780A1 (en) | 2009-01-26 | 2010-07-29 | Teva Pharmaceutical Industries Ltd. | Processes for coating a carrier with microparticles |
| US8889213B2 (en) | 2009-01-26 | 2014-11-18 | Teva Pharmaceutical Industries Ltd. | Processes for coating a carrier with microparticles |
| US9060927B2 (en) | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
Also Published As
| Publication number | Publication date |
|---|---|
| FI945524A (en) | 1995-05-28 |
| KR950013499A (en) | 1995-06-15 |
| NO944526L (en) | 1995-05-29 |
| NO944526D0 (en) | 1994-11-25 |
| EP0655237A1 (en) | 1995-05-31 |
| AU7905194A (en) | 1995-06-08 |
| NZ264993A (en) | 1996-03-26 |
| FI945524A0 (en) | 1994-11-24 |
| JPH07187996A (en) | 1995-07-25 |
| ZA949378B (en) | 1995-08-11 |
| AU676390B2 (en) | 1997-03-06 |
| HU9403396D0 (en) | 1995-02-28 |
| HUT75152A (en) | 1997-04-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |