US20070027105A1 - Peroxide removal from drug delivery vehicle - Google Patents
Peroxide removal from drug delivery vehicle Download PDFInfo
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- US20070027105A1 US20070027105A1 US11/492,153 US49215306A US2007027105A1 US 20070027105 A1 US20070027105 A1 US 20070027105A1 US 49215306 A US49215306 A US 49215306A US 2007027105 A1 US2007027105 A1 US 2007027105A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
Definitions
- the present invention relates to methods for reducing peroxide levels in non-polymeric preparations and to compositions used in and prepared by such methods.
- SAIB Sucrose acetate isobutyrate
- SAIB is a hydrophobic liquid with limited water solubility. It is soluble in a large number of biocompatible solvents. SAIB has an unusual property—it undergoes a dramatic change in viscosity with small additions of heat or with the addition of solvents. It is a very viscous liquid, having a viscosity of approximately 3200 poise at 37° C. SAIB is produced by the controlled esterification of natural sugar (sucrose) with acetic and isobutyric anhydrides. SAIB metabolizes to sucrose, acetic acid and isobutyric acid.
- SAIB is orally non-toxic and is currently used to stabilize emulsions in the food industry.
- SAIB is commonly found in the beverage industry, where it is used as a weighting agent to help stabilize the final beverage formula.
- SAIB has been reported to be useful as a gelling system-type drug excipient that allows for sustained or controlled release of drugs.
- SAIB can be applied via injection or an aerosol spray.
- SAIB is compatible with cellulose esters and other polymers that can affect the rate of delivery of the substance.
- SAIB is the main ingredient for the SABER drug delivery system, which also consists of a pharmaceutically acceptable solvent.
- Drug delivery systems including SAIB delivery systems, are still confronted by various issues of drug instability, as such systems are considered for longer and longer drug delivery durations.
- Drug instability can occur via a number of factors, including denaturation, precipitation, oxidation, aggregation, and others.
- a number of excipients used to facilitate delivery and release of drugs have peroxides or are susceptible to the formation of peroxides, which may lead to oxidation of active ingredient in the formulation.
- the presence of peroxides is deleterious to a drug incorporated in an SAIB drug formulation as the drug is likely to undergo oxidative degradation.
- the peroxide levels must be reduced.
- An aspect of the present invention comprises methods of treating sucrose acetate isobutyrate (SAIB) formulations to be used as drug delivery vehicles comprising adding to the formulations an amount of bisulfite salt effective to substantially remove peroxides, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a mixture thereof.
- SAIB sucrose acetate isobutyrate
- drug delivery vehicles adapted to provide prolonged stability of a drug that is to be delivered in vivo comprising sucrose acetate isobutyrate having substantially reduced levels of peroxide, the drug delivery vehicle being treated with an amount of bisulfite salt effective to substantially reduce levels of peroxide in said drug delivery vehicle, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.
- FIG. 1 illustrates a bar graph of the results of Study I—Stability of omega-interferon in untreated SAIB.
- FIG. 2 illustrates a bar graph of the results of Study IIa—Stability of omega-interferon in alumina treated SAIB.
- FIG. 3 illustrates a bar graph of the results of Study IIb—Stability of omega-interferon in alumina treated SAIB.
- FIG. 4 illustrates a bar graph of the results of Study III—Stability of omega-interferon in untreated SAIB.
- FIG. 5 illustrates a bar graph of the results of Study VIb—Stability of omega-interferon in untreated SAIB.
- FIG. 6 illustrates a bar graph of the results of Study VIa—Stability of omega-interferon in sodium metabisulfite treated SAIB.
- FIG. 7 illustrates a bar graph that provides comparisons of oxidation of omega-IFN in sodium metabisulfite treated and untreated SAIB.
- FIG. 8 illustrates an osmotically pump-driven implantable device, Duros® being an example, that facilitates in vivo delivery of an active agent in an SAIB vehicle.
- sucrose acetate isobutyrate formulations that are to be used as drug delivery vehicles comprising adding an amount of a bisulfite salt effective for substantially removing peroxide from the formulations, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.
- the bisulfite salt is sodium metabisulfite.
- a ratio ranging from about 1:1 to about 1:4 (weight:volume) SAIB:aqueous solution of bisulfite salt (“aqueous bisulfite salt”) can be used.
- the bisulfite salt is a metabisulfite salt.
- the bisulfite salt is preferably sodium metabisulfite.
- the ratio of the aqueous bisulfite salt to SAIB is 1:1.
- a volume of sodium metabisulfite solution can be made up to 1 liter, and an approximate proportion of 1:1 of SAIB:aqueous sodium metabisulfite was used.
- the aqueous bisulfite salt in SAIB can be from about 0.1% weight to volume of water (w/v) to about 50% w/v; preferably, from about 0.5% w/v to about 30% w/v.
- the aqueous bisulfite salt is preferably from about 1% w/v to about 15% w/v.
- the aqueous bisulfite salt is about 5% w/v solution in water.
- the method removes peroxide to a level that is at least less than 50% of the levels before the method, or starting levels, and, preferably, less than 20% of the starting levels. In some embodiments, peroxide is removed to less than 10% of the starting levels. While in some embodiments, the method removes peroxide to a level that is less than 5% of the starting levels. Furthermore, the method can remove peroxide so that the resulting SAIB formulation contains peroxide in amounts less than 20 ppm, and, preferably, less than 10 ppm. In some embodiments, the method removes peroxide to result in an SAIB formulation containing less than 5 ppm.
- the resulting SAIB formulation from this method can serve as a drug delivery vehicle for use with a medical delivery device, including a drug eluting stent, a catheter, or other drug delivery implants.
- the SAIB formulation can be loaded into an osmotically pump-driven implantable device of the type disclosed in U.S. Pat. No. 6,395,292, for example.
- the osmotically pump-driven implantable device is a Duros® device (Alza Corporation, Mountain View, Calif.).
- the SAIB formulation can serve as a drug depot for drug delivery.
- the step of adding the bisulfite salt comprises mixing a solution of the bisulfite salt with the sucrose acetate isobutyrate formulation.
- the SAIB formulation can be further comprised of a cosolvent, which can be selected from a number of solvents including pharmaceutically acceptable solvents, e.g., hexane, ethyl acetate, ethanol, benzyl benzoate, N-methyl pyrrolidone, and iso-propyl alcohol, among others.
- the cosolvent is hexane or ethyl acetate.
- the methods further comprise vacuum treating the formulation to remove the cosolvent.
- some embodiments comprise the additional step of removing bisulfite salt from the formulation.
- This removal step comprises washing the formulation with water to remove the bisulfite salt.
- a further step of drying the formulation over magnesium sulfate can be utilized to remove the water.
- calcium chloride anhydrous, calcium sulfate anhydrous, activated silica gel, phosphorous pentoxide, or drying under vacuum, or a combination thereof can be used to also remove the water.
- glycerin can be used to wash the bisulfite-added formulation to remove the bisulfite salt. Afterwards, residual glycerin can be removed by washing with water and then drying to remove water.
- the methods of substantially removing peroxide from a sucrose acetate isobutyrate formulation comprising the steps of adding the aqueous bisulfite salt, washing the formulation, and drying the formulation are repeated at least once. The steps can be repeated to further reduce the levels of peroxide in the SAIB formulation.
- the present invention includes a drug delivery vehicle comprising SAIB that provides for prolonged stability of a drug that is to be delivered by maintaining substantially reduced levels of peroxide, the drug delivery vehicle being treated with sodium metabisulfite.
- the prolonged stability comprises reduced oxidation, deamidation, or aggregation, e.g., dimerization, of the drug over extended periods of time in which drug is within environment of delivery vehicle.
- the prolonged stability is reduced oxidation.
- the extended periods of time can be periods from about one week to a few months, and up to about a year.
- the prolonged stability is evidenced by significant improvements in oxidation, deamidation, or aggregation levels of the drug when the delivery vehicle has been treated with a bisulfite salt versus untreated delivery vehicle.
- the prolonged stability is characterized as about 50% less oxidation, about 33% less deamidation, or about 75% less dimerization as compared to untreated delivery vehicles.
- the drug can be selected from any known and desired biomolecular material that can act as therapeutics and other therapeutic active agents that are susceptible to oxidative degradation.
- biomolecular material refers to peptides, polypeptides, proteins, nucleic acids, viruses, antibodies, small molecules susceptible to oxidation, and any other naturally derived, synthetically produced, or recombinantly produced active agent that includes nucleic or amino acid.
- drugs can be selected from among the following: a steroid, NSAIDS, peptides, proteins such as growth factors or hormones, anti-tumor agents, antibiotics, analgesics, local anesthetics, antiviral agents, antipsychotics, anticoagulants, oligonucleotides for gene therapy, active small molecules, and others.
- the term “removing” and all variations thereof, refer to decreasing by any measurable degree the level of peroxide present in a drug formulation.
- the term “substantially removing” is used herein to describe a dramatic decrease in the level of peroxide present in a drug formulation, such as SAIB formulation. The dramatic decrease is at least 50% of original levels (levels before treatment) and in some instances is 10% of original levels. In preferred aspects of the present invention, the “substantial removal” describes a decrease to less than 5% of original levels.
- drug delivery vehicle or “delivery vehicle” refers to a formulation that is biocompatible and used to carry a drug without reacting with the same drug. Also, the vehicle does not alter or minimally alters the activity of the drug. Furthermore, the vehicle allows for the transport of the drug in vivo and eventual delivery of the drug to a biological site for therapeutic effect.
- Prolonged stability is used to refer to the stabilizing effect of the drug delivery vehicles of the present invention on the carried drug. Prolonged stability can be evidenced by significant improvements in oxidation, deamidation, or aggregation of the drug over extended periods of time.
- Each of the experiments involved protein particles consisting of omega-interferon, which were suspended in SAIB at a particle loading of either 4% or 10% by weight.
- the suspensions were prepared in a dry box under nitrogen at 45° C. The suspension was mixed for 15 minutes while maintaining the temperature. Suspension mixing was performed by hand. Aliquots from the prepared suspensions were transferred to clear crimp-top glass vials and sealed under nitrogen. Each aliquot contained at least six milligrams of protein to allow for stability testing in triplicate. These samples were stored in an oven at 40° C. Samples were withdrawn at regular intervals (as indicated in Table 1) and analyzed for omega-interferon content and purity was assessed using reverse phase HPLC and size exclusion chromatography.
- Size exclusion chromatography was used to monitor the omega-interferon content and purity in the formulations. The percentages of monomer and dimer in the formulation were quantified using SEC. The stability of omega-interferon was judged by using a stability indicating chromatographic technique based on reverse phase HPLC (rp-HPLC). This technique was used to monitor the oxidation, deamidation and formation of an unknown species of omega-interferon in the formulations. The peroxide content of the vehicle was determined using EP 2002, 2.5.5 (Method A with auto titration). See Extra Pharmacopoeia, 2002 Ed. Content and purity assay of omega-interferon by size exclusion chromatography (SEC).
- SEC Size exclusion chromatography
- omega-interferon The stability of omega-interferon was monitored in two different lots of untreated SAIB (as received) and in treated SAIB (removal of peroxides), when treatment was applied.
- Study IIa Treatment of SAIB (lot #TD1030507) with neutral alumina by heating and stability in this treated SAIB for 4 weeks
- Study VIa Treatment of SAIB (lot #TD2032663) with 5% aqueous solution of sodium metabisulfite and stability in treated SAIB for 8 weeks
- Study VIb Stability in untreated SAIB (lot #TD2032663) for 8 weeks TABLE 1 Details about stability studies of omega-interferon in SAIB SAIB Particle Time Study # (Lot #) Treatment loading points Tests I TD1030507 Untreated 4% 0, 4, 7, SEC, RP-HPLC 14 days IIa TD1030507 Treated with neutral 10% 0, 2, SEC, RP-HPLC alumina by heating 4 weeks IIb TD1030507 Treated with neutral 10% 0, 2, SEC, RP-HPLC alumina using ethanol 4 weeks III TD2032663 Untreated 10% 0, 1, SEC, RP-HPLC 2 weeks IV TD2032663 Treated with basic NA NA NA alumina by heating V TD2032663 Treated with 10% NA NA NA aqueous solution of methionine VIa TD2032663 Treated with hexane 10% 0, 1, 2, 4, SEC, RP-HPLC and 8 weeks sodium metabisulfite VIb TD2032663 Untreated 10% 0, 1, 2, 4, S
- SAIB was heated to 75° C. Alumina (15% w/w) was added to the heated SAIB. The mixture was stirred for 40 minutes and filtered though a 5.0 ⁇ m filter at 75° C. The treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
- SAIB was mixed with 15% absolute ethanol to reduce the viscosity.
- Basic alumina (15% w/w) was added to the SAIB containing ethanol.
- the resulting mixture was stirred for 1 hour and filtered though a 0.2 ⁇ m filter.
- the filtered SAIB was placed overnight under vacuum at 60° C. to remove the ethanol. This treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
- SAIB was heated to 90° C.
- Basic alumina (15% w/w) was added to the heated SAIB.
- Two different grades of alumina were used—Basic Super I and Basic Standard Activity I.
- the resulting mixture was stirred for 40 minutes.
- the mixture was then centrifuged at 4000 rpm while temperature was maintained at 75° C. After centrifugation, the supernatant was collected and sampled for peroxide analysis.
- SAIB was vigorously agitated with 4 parts of 10% aqueous solution of methionine at 80° C. for 45 minutes using a magnetic stirrer. (Evaporated water was replenished as necessary) Afterwards, the methionine solution was decanted. SAIB was then washed with 4 parts of water by agitating for 15 minutes at 70°-80° C. This washing step was carried out three times. SAIB was placed overnight in vacuum oven at 70° C. to remove residual water, and, afterwards, was sampled for peroxide analysis.
- SAIB was dissolved in two parts of hexane. The resulting solution was treated with a 5% aqueous solution of sodium metabisulfite by vigorous shaking. The aqueous layer was removed and the SAIB layer was washed with water. The SAIB layer was dried with MgSO 4 . Hexane was removed from SAIB by evaporation under vacuum at 50° C. The treated SAIB was sampled for peroxide analysis and used for preparation of suspension for stability testing.
- treatment with an aqueous solution of sodium metabisulfite was effective in significantly reducing peroxide levels from 115.9 ppm to 2.6 ppm—almost 45 times, or 45 fold decrease.
- treatment with neutral alumina either with heat or with ethanol, resulting in only a nominal change in peroxide levels—a 7% or 12% decrease, respectively.
- treatment with basic alumina with heat or 10% aqueous methionine only resulted in nominal change in peroxide levels—a 6% or 18% decrease, respectively.
- FIG. 8 illustrates an osmotically pump-driven implantable device for delivering an SAIB formulation acting as a drug delivery vehicle, active agent within.
- an osmotically pump-driven implantable device 10 shown comprising an impermeable reservoir 12 .
- the reservoir 12 is divided into two chambers by a piston 16 .
- the first chamber 18 is adapted to contain an SAIB formulation 19 containing an active agent 20 and the second chamber 21 is adapted to contain a fluid-imbibing agent.
- a back-diffusion regulating outlet 22 is inserted into the open end of the first chamber 18 and a semipermeable membrane 24 encloses the open end of the second chamber 21 .
- the piston 16 is driven towards the open end of the first chamber 18 by the osmotic pressure generated by the fluid-imbibing agent in the second chamber 21 .
- the pressure created by the piston 16 can force the contents of the first chamber 18 out the opening, i.e., the SAIB formulation 19 comprising active agents 20 .
- the release rate of the active agent can be governed by the osmotic pumping rate.
Abstract
Description
- This application claims the benefit of U.S. provisional application No. 60/702,546, filed Jul. 26, 2005, which is incorporated herein in its entirety.
- The present invention relates to methods for reducing peroxide levels in non-polymeric preparations and to compositions used in and prepared by such methods.
- Sucrose acetate isobutyrate (“SAIB”) is a hydrophobic liquid with limited water solubility. It is soluble in a large number of biocompatible solvents. SAIB has an unusual property—it undergoes a dramatic change in viscosity with small additions of heat or with the addition of solvents. It is a very viscous liquid, having a viscosity of approximately 3200 poise at 37° C. SAIB is produced by the controlled esterification of natural sugar (sucrose) with acetic and isobutyric anhydrides. SAIB metabolizes to sucrose, acetic acid and isobutyric acid.
- SAIB is orally non-toxic and is currently used to stabilize emulsions in the food industry. In one example, SAIB is commonly found in the beverage industry, where it is used as a weighting agent to help stabilize the final beverage formula. Also, SAIB has been reported to be useful as a gelling system-type drug excipient that allows for sustained or controlled release of drugs. When in solution or in an emulsion, SAIB can be applied via injection or an aerosol spray. SAIB is compatible with cellulose esters and other polymers that can affect the rate of delivery of the substance. In one example, SAIB is the main ingredient for the SABER drug delivery system, which also consists of a pharmaceutically acceptable solvent.
- Drug delivery systems, including SAIB delivery systems, are still confronted by various issues of drug instability, as such systems are considered for longer and longer drug delivery durations. Drug instability can occur via a number of factors, including denaturation, precipitation, oxidation, aggregation, and others. In particular, a number of excipients used to facilitate delivery and release of drugs have peroxides or are susceptible to the formation of peroxides, which may lead to oxidation of active ingredient in the formulation. In the example of SAIB, the presence of peroxides is deleterious to a drug incorporated in an SAIB drug formulation as the drug is likely to undergo oxidative degradation. Thus, in order to formulate any drug formulation based on SAIB that provides enough of a stable environment to facilitate the delivery of a drug, the peroxide levels must be reduced.
- There is no known process for removal of peroxides from SAIB at present, despite availability of processes for the removal of peroxides from other materials such as polymers. Therefore, there still remains a need for a drug formulation of SAIB having improved properties to reduce the degradation of the drug therein.
- An aspect of the present invention comprises methods of treating sucrose acetate isobutyrate (SAIB) formulations to be used as drug delivery vehicles comprising adding to the formulations an amount of bisulfite salt effective to substantially remove peroxides, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a mixture thereof.
- In another aspect of the present invention, provided are drug delivery vehicles adapted to provide prolonged stability of a drug that is to be delivered in vivo comprising sucrose acetate isobutyrate having substantially reduced levels of peroxide, the drug delivery vehicle being treated with an amount of bisulfite salt effective to substantially reduce levels of peroxide in said drug delivery vehicle, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.
- The invention is illustrated by way of example and is not intended to be limited by the accompanying figures.
-
FIG. 1 illustrates a bar graph of the results of Study I—Stability of omega-interferon in untreated SAIB. -
FIG. 2 illustrates a bar graph of the results of Study IIa—Stability of omega-interferon in alumina treated SAIB. -
FIG. 3 illustrates a bar graph of the results of Study IIb—Stability of omega-interferon in alumina treated SAIB. -
FIG. 4 illustrates a bar graph of the results of Study III—Stability of omega-interferon in untreated SAIB. -
FIG. 5 illustrates a bar graph of the results of Study VIb—Stability of omega-interferon in untreated SAIB. -
FIG. 6 illustrates a bar graph of the results of Study VIa—Stability of omega-interferon in sodium metabisulfite treated SAIB. -
FIG. 7 illustrates a bar graph that provides comparisons of oxidation of omega-IFN in sodium metabisulfite treated and untreated SAIB. -
FIG. 8 illustrates an osmotically pump-driven implantable device, Duros® being an example, that facilitates in vivo delivery of an active agent in an SAIB vehicle. - In an aspect of the present invention, provided are methods of treating sucrose acetate isobutyrate formulations (SAIB) that are to be used as drug delivery vehicles comprising adding an amount of a bisulfite salt effective for substantially removing peroxide from the formulations, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof. Preferably, the bisulfite salt is sodium metabisulfite. A ratio ranging from about 1:1 to about 1:4 (weight:volume) SAIB:aqueous solution of bisulfite salt (“aqueous bisulfite salt”) can be used. Preferably, the bisulfite salt is a metabisulfite salt. In some embodiments, the bisulfite salt is preferably sodium metabisulfite. Preferably, the ratio of the aqueous bisulfite salt to SAIB is 1:1. In one example, to purify 1 kg of SAIB, a volume of sodium metabisulfite solution can be made up to 1 liter, and an approximate proportion of 1:1 of SAIB:aqueous sodium metabisulfite was used. The aqueous bisulfite salt in SAIB can be from about 0.1% weight to volume of water (w/v) to about 50% w/v; preferably, from about 0.5% w/v to about 30% w/v. In some embodiments, the aqueous bisulfite salt is preferably from about 1% w/v to about 15% w/v. In some embodiments, the aqueous bisulfite salt is about 5% w/v solution in water.
- The method removes peroxide to a level that is at least less than 50% of the levels before the method, or starting levels, and, preferably, less than 20% of the starting levels. In some embodiments, peroxide is removed to less than 10% of the starting levels. While in some embodiments, the method removes peroxide to a level that is less than 5% of the starting levels. Furthermore, the method can remove peroxide so that the resulting SAIB formulation contains peroxide in amounts less than 20 ppm, and, preferably, less than 10 ppm. In some embodiments, the method removes peroxide to result in an SAIB formulation containing less than 5 ppm. In some embodiments, the resulting SAIB formulation from this method can serve as a drug delivery vehicle for use with a medical delivery device, including a drug eluting stent, a catheter, or other drug delivery implants. In one example, the SAIB formulation can be loaded into an osmotically pump-driven implantable device of the type disclosed in U.S. Pat. No. 6,395,292, for example. Preferably, the osmotically pump-driven implantable device is a Duros® device (Alza Corporation, Mountain View, Calif.). In other embodiments, the SAIB formulation can serve as a drug depot for drug delivery.
- In some embodiments, the step of adding the bisulfite salt comprises mixing a solution of the bisulfite salt with the sucrose acetate isobutyrate formulation. The SAIB formulation can be further comprised of a cosolvent, which can be selected from a number of solvents including pharmaceutically acceptable solvents, e.g., hexane, ethyl acetate, ethanol, benzyl benzoate, N-methyl pyrrolidone, and iso-propyl alcohol, among others. Preferably, the cosolvent is hexane or ethyl acetate. In some embodiments, the methods further comprise vacuum treating the formulation to remove the cosolvent. Also, some embodiments comprise the additional step of removing bisulfite salt from the formulation. This removal step comprises washing the formulation with water to remove the bisulfite salt. In the embodiments that incorporate the washing step, a further step of drying the formulation over magnesium sulfate can be utilized to remove the water. Alternatively, calcium chloride anhydrous, calcium sulfate anhydrous, activated silica gel, phosphorous pentoxide, or drying under vacuum, or a combination thereof can be used to also remove the water. In alternative embodiments, glycerin can be used to wash the bisulfite-added formulation to remove the bisulfite salt. Afterwards, residual glycerin can be removed by washing with water and then drying to remove water.
- In some aspects of the present invention, the methods of substantially removing peroxide from a sucrose acetate isobutyrate formulation (SAIB) comprising the steps of adding the aqueous bisulfite salt, washing the formulation, and drying the formulation are repeated at least once. The steps can be repeated to further reduce the levels of peroxide in the SAIB formulation.
- In another aspect, the present invention includes a drug delivery vehicle comprising SAIB that provides for prolonged stability of a drug that is to be delivered by maintaining substantially reduced levels of peroxide, the drug delivery vehicle being treated with sodium metabisulfite. The prolonged stability comprises reduced oxidation, deamidation, or aggregation, e.g., dimerization, of the drug over extended periods of time in which drug is within environment of delivery vehicle. Preferably the prolonged stability is reduced oxidation. The extended periods of time can be periods from about one week to a few months, and up to about a year. Preferably, the prolonged stability is evidenced by significant improvements in oxidation, deamidation, or aggregation levels of the drug when the delivery vehicle has been treated with a bisulfite salt versus untreated delivery vehicle. In some preferred embodiments, the prolonged stability is characterized as about 50% less oxidation, about 33% less deamidation, or about 75% less dimerization as compared to untreated delivery vehicles. The drug can be selected from any known and desired biomolecular material that can act as therapeutics and other therapeutic active agents that are susceptible to oxidative degradation. As it is used herein, the term “biomolecular material” refers to peptides, polypeptides, proteins, nucleic acids, viruses, antibodies, small molecules susceptible to oxidation, and any other naturally derived, synthetically produced, or recombinantly produced active agent that includes nucleic or amino acid. In some embodiments, for example, drugs can be selected from among the following: a steroid, NSAIDS, peptides, proteins such as growth factors or hormones, anti-tumor agents, antibiotics, analgesics, local anesthetics, antiviral agents, antipsychotics, anticoagulants, oligonucleotides for gene therapy, active small molecules, and others.
- As used herein, the term “removing” and all variations thereof, refer to decreasing by any measurable degree the level of peroxide present in a drug formulation. The term “substantially removing” is used herein to describe a dramatic decrease in the level of peroxide present in a drug formulation, such as SAIB formulation. The dramatic decrease is at least 50% of original levels (levels before treatment) and in some instances is 10% of original levels. In preferred aspects of the present invention, the “substantial removal” describes a decrease to less than 5% of original levels.
- As used herein, the term “drug delivery vehicle” or “delivery vehicle” refers to a formulation that is biocompatible and used to carry a drug without reacting with the same drug. Also, the vehicle does not alter or minimally alters the activity of the drug. Furthermore, the vehicle allows for the transport of the drug in vivo and eventual delivery of the drug to a biological site for therapeutic effect.
- As used herein, the term “prolonged stability” is used to refer to the stabilizing effect of the drug delivery vehicles of the present invention on the carried drug. Prolonged stability can be evidenced by significant improvements in oxidation, deamidation, or aggregation of the drug over extended periods of time.
- Different approaches were investigated for removal of peroxides from SAIB, as indicated in Table 1.
- Preparation of Suspension
- Each of the experiments involved protein particles consisting of omega-interferon, which were suspended in SAIB at a particle loading of either 4% or 10% by weight. The suspensions were prepared in a dry box under nitrogen at 45° C. The suspension was mixed for 15 minutes while maintaining the temperature. Suspension mixing was performed by hand. Aliquots from the prepared suspensions were transferred to clear crimp-top glass vials and sealed under nitrogen. Each aliquot contained at least six milligrams of protein to allow for stability testing in triplicate. These samples were stored in an oven at 40° C. Samples were withdrawn at regular intervals (as indicated in Table 1) and analyzed for omega-interferon content and purity was assessed using reverse phase HPLC and size exclusion chromatography.
- Size Exclusion Chromatography
- Size exclusion chromatography (SEC) was used to monitor the omega-interferon content and purity in the formulations. The percentages of monomer and dimer in the formulation were quantified using SEC. The stability of omega-interferon was judged by using a stability indicating chromatographic technique based on reverse phase HPLC (rp-HPLC). This technique was used to monitor the oxidation, deamidation and formation of an unknown species of omega-interferon in the formulations. The peroxide content of the vehicle was determined using EP 2002, 2.5.5 (Method A with auto titration). See Extra Pharmacopoeia, 2002 Ed. Content and purity assay of omega-interferon by size exclusion chromatography (SEC).
- Reverse Phase High Performance Liquid Chromatography
- Purity assay and identity of omega-interferon recombinant in suspension systems by reverse phase high performance liquid chromatography (rp-HPLC).
- The stability of omega-interferon was monitored in two different lots of untreated SAIB (as received) and in treated SAIB (removal of peroxides), when treatment was applied.
- The studies are outlined below:
- Study I: Stability in untreated SAIB (lot #TD1030507) for 2 weeks
- Study IIa: Treatment of SAIB (lot #TD1030507) with neutral alumina by heating and stability in this treated SAIB for 4 weeks
- Study IIb: Treatment of SAIB (lot #TD1030507) with neutral alumina in presence of ethanol and stability in this treated SAIB for 4 weeks
- Study III: Stability in untreated SAIB (lot #TD2032663) for 2 weeks
- Study IV: Treatment of SAIB (lot #TD2032663) with basic alumina by heating
- Study V: Treatment of SAIB (lot #TD2032663) with 10% aqueous methionine solution by heating
- Study VIa: Treatment of SAIB (lot #TD2032663) with 5% aqueous solution of sodium metabisulfite and stability in treated SAIB for 8 weeks
- Study VIb: Stability in untreated SAIB (lot #TD2032663) for 8 weeks
TABLE 1 Details about stability studies of omega-interferon in SAIB SAIB Particle Time Study # (Lot #) Treatment loading points Tests I TD1030507 Untreated 4% 0, 4, 7, SEC, RP- HPLC 14 days IIa TD1030507 Treated with neutral 10% 0, 2, SEC, RP-HPLC alumina by heating 4 weeks IIb TD1030507 Treated with neutral 10% 0, 2, SEC, RP-HPLC alumina using ethanol 4 weeks III TD2032663 Untreated 10% 0, 1, SEC, RP- HPLC 2 weeks IV TD2032663 Treated with basic NA NA NA alumina by heating V TD2032663 Treated with 10% NA NA NA aqueous solution of methionine VIa TD2032663 Treated with hexane 10% 0, 1, 2, 4, SEC, RP-HPLC and 8 weeks sodium metabisulfite VIb TD2032663 Untreated 10% 0, 1, 2, 4, SEC, RP- HPLC 8 weeks
Materials and Equipment - The following tables, Table 2 and Table 3, provide a list of materials and equipment that can be utilized to perform the experiments described, below.
TABLE 2 List of materials Materials Spary dried omega-interferon particles SAIB, Eastman Chemical Company Aluminum oxide (powder) Ethanol, absolute, 200 proof, AAPER Aluminum oxide, basic, standard activity I, 50-200 μm, Sorbent Technologies Aluminum oxide, basic, Super I, 50-200 μm, Sorbent Technologies Methionine, USP, Ph Eur, JP -
TABLE 3 List of equipment Equipment Branson Ultrasonic Cleaner Model 2510 VAC Dry Box Mettler AT261 Delta Range Balance Mettler PJ3000 Balance Sartorius Genius Electronic Analytical Balance Hot plate Oven (40° C.) Millipore filter, white hydrophilic, Durapore Disc, SLVP, 25 mm, 5 μm PTFE membrane filter, 0.2 μm, Titan filtration systems - Study I: Stability in Untreated SAIB (Lot #TD1030507) for 2 Weeks
TABLE 4 Stability of omega-interferon in untreated SAIB (lot #: 1030507) - Study I Analysis by RP-HPLC (n = 3)** Initial (t = 0) (AR 48452) 4 days 7 days 14 days (protein particles)*** AR48424 AR48562 AR48450 Assay (%) NA 0.59* (0.02) 0.72 (0.00) 0.68 (0.00) % omega-IFN 93.37 (0.40) 89.06 (0.46) 87.65 (0.06) 87.67 (0.26) Purity % Oxidized 2.8 (0.71) 7.21 (0.88) 7.79 (1.09) 8.31 (0.10) % Deamidated 0.8 (0.02) 1.21 (0.00) 1.28 (0.01) 1.63 (0.03) % Unknown 3.03 (0.62) 2.25 (0.66) 3.27 (0.79) 2.39 (0.38) Analysis by SEC (n = 3)** Initial (AR 48452) 4 days 7 days 14 days (protein particles)*** AR48424 AR48562 AR48450 % Monomer 100.00 (0.00) 99.96 (0.01) 99.60 (0.02) 99.40 (0.00) % Dimer ND 0.04 (0.00) 0.38 (0.01) 0.58 (0.02) Unknown ND ND 0.01 (0.00) 0.01 (0.01)
ND = Not detected,
*sampled by scraping container walls, so values might not be representative of the bulk
**standard deviation in parenthesis;
***protein particles - t = 0 for suspension
- The preliminary stability study of omega interferon in untreated SAIB (lot # TD1030507, peroxide value—71.4 ppm) was over 2 weeks. The results indicated that up to 8.31% of omega-interferon was oxidized in two weeks, which corresponds to an increase of 5.51% with respect to particles (2.8% oxidation at t=0). See Table 4,
FIG. 1 . Furthermore, a small increase occurred in the percentage of deamidated form (+0.83%) of omega-interferon and the dimer (+0.58%). The high level of oxidation can be attributed to the high peroxide content of SAIB. - Treatment of SAIB with Neutral Alumina with Heating
- SAIB was heated to 75° C. Alumina (15% w/w) was added to the heated SAIB. The mixture was stirred for 40 minutes and filtered though a 5.0 μm filter at 75° C. The treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
- Treatment of SAIB with Neutral Alumina in Presence of Ethanol
- SAIB was mixed with 15% absolute ethanol to reduce the viscosity. Basic alumina (15% w/w) was added to the SAIB containing ethanol. The resulting mixture was stirred for 1 hour and filtered though a 0.2 μm filter. The filtered SAIB was placed overnight under vacuum at 60° C. to remove the ethanol. This treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
TABLE 5 Stability of omega-interferon in alumina treated SAIB ((lot #: 1030507) - Studies IIa and IIb SAIB treated with neutral alumina by heating - Study IIa Initial (t = 0) Initial (t = 0) 2 weeks 1 month (protein particles) AR 48570 AR 48572 AR 48565 Analysis by RP-HPLC (n = 3)** Assay (%) NA 1.68 (0.01) 1.70 (0.00) 1.72 (0.01) % omega-IFN Purity 89.08 (0.56) 87.56 (0.47) 83.90 (0.15) 82.97 (0.50) % Oxidized 1.72 (0.12) 3.45 (0.06) 6.85 (0.14) 7.39 (0.21) % Deamidated 1.49 (0.01) 1.46 (0.03) 1.84 (0.03) 2.42 (0.05) % Unknown 7.70 (0.45) 7.52 (0.45) 7.41 (0.01) 7.22 (0.46) Analysis by SEC (n = 3)** % Monomer 100.00 (0.00) 100.00 (0.00) 99.89 (0.01) 99.50 (0.02) % Dimer trace 0.00 0.11 (0.01) 0.50 (0.02) Unknown 0.00 0.00 0.00 0.00 SAIB treated with neutral alumina using ethanol - Study IIb Initial (t = 0) Initial (t = 0) 2 weeks 1 month (protein particles) AR 48570 AR 48572 AR 48565 Analysis by RP-HPLC (n = 3)** Assay (%) NA 1.66 (0.02) 1.70 (0.01) 1.70 (0.00) % omega-IFN Purity 89.08 (0.56) 88.12 (0.49) 83.76 (0.09) 82.65 (0.19) % Oxidized 1.72 (0.12) 3.08 (0.07) 6.98 (0.12) 7.42 (0.10) % Deamidated 1.49 (0.01) 1.47 (0.01) 1.88 (0.02) 2.45 (0.09) % Unknown 7.70 (0.45) 7.32 (0.48) 7.38 (0.02) 7.48 (0.05) Analysis by SEC (n = 3)** % Monomer 100.00 (0.00) 100.00 (0.00) 99.87 (0.01) 99.43 (0.02) % Dimer trace 0.00 0.13 (0.01) 0.57 (0.02) Unknown 0.00 0.00 0.00 0.00
**standard deviation in parenthesis
- The stability of omega-interferon in alumina treated SAIB was tested. After one month in the neutral alumina treated SAIB (Study IIa and IIb), oxidation of omega-interferon increased by about 5.7% for both IIa and IIb. This indicates that alumina treatment of SAIB did not improve the stability of omega-interferon in SAIB. See Table 5. In addition, this analysis is also reflected in the high peroxide content of alumina treated SAIB (66.3 and 62.9 ppm, respectively). Treatment with neutral alumina was not effective in decreasing peroxide content.
- Study III: Stability in Untreated SAIB (Lot #TD2032663) for 2 Weeks
TABLE 6 Stability of omega-interferon in untreated SAIB ((lot #: 2032663) - Study III Analysis by RP-HPLC (n = 3)** Initial (t = 0) (AR 48217 Initial (t = 0) 1 week 2 weeks (protein particles) AR 49640 AR 49644 AR 49647 Assay (%) NA 1.69 (0.01) 1.70 (0.00) 1.68 (0.01) % omega-IFN Purity 88.98 (0.09) 88.21 (0.03) 84.95 (0.58) 83.71 (0.48) % Oxidized 1.63 (0.04) 3.20 (0.03) 6.39 (0.05) 7.21 (0.10) % Deamidated 1.45 (0.01) 1.66 (0.01) 1.45 (0.40) 1.84 (0.03) % Unknown 7.94 (0.12) 6.93 (0.04) 7.22 (0.45) 7.24 (0.45) Analysis by SEC (n = 3)** Initial (t = 0) (AR 48217) Initial (t = 0)* 1 week 2 weeks (protein particles) AR 49640 AR 49644 AR 49647 % Monomer 99.93 (0.01) 99.83 (0.02) 99.75 (0.01) 99.51 (0.01) % Dimer 0.07 (0.01) 0.17 (0.02) 0.25 (0.01) 0.49 (0.01) Unknown ND ND ND ND
ND = Not detected
*n = 6
**standard deviation in parenthesis
- Stability of omega-interferon in untreated SAIB was again tested. The results of a two week stability study (Study III) of omega-interferon in SAIB (lot # TD 2032663) are comparable to studies I and II. See Table 6,
FIG. 4 . The amount of oxidation was found to have increased by 5.58%, while deamidation increased by 0.39% and dimerization increased by 0.42%. - Study IV and V: Treatment of SAIB (Lot #TD2032663) with Basic Alumina with Heating or with 10% Aqueous Methionine Solution
- Treatment of SAIB with Basic Alumina with Heating
- SAIB was heated to 90° C. Basic alumina (15% w/w) was added to the heated SAIB. Two different grades of alumina were used—Basic Super I and Basic Standard Activity I. The resulting mixture was stirred for 40 minutes. The mixture was then centrifuged at 4000 rpm while temperature was maintained at 75° C. After centrifugation, the supernatant was collected and sampled for peroxide analysis.
- Treatment of SAIB with 10% Aqueous Solution of Methionine
- One part of SAIB was vigorously agitated with 4 parts of 10% aqueous solution of methionine at 80° C. for 45 minutes using a magnetic stirrer. (Evaporated water was replenished as necessary) Afterwards, the methionine solution was decanted. SAIB was then washed with 4 parts of water by agitating for 15 minutes at 70°-80° C. This washing step was carried out three times. SAIB was placed overnight in vacuum oven at 70° C. to remove residual water, and, afterwards, was sampled for peroxide analysis.
- The peroxide content of SAIB treated with basic alumina or with aqueous methionine solution was determined to be 109.3 and 95.7 respectively (Study IV and V), indicating that these approaches were not successful in the removal of peroxides. See
FIG. 7 . - Study VIa and VIb: Stability of SAIB (Lot #TD2032663) Treated with 5% Aqueous Solution of Sodium Metabisulfite or Untreated for 8 Weeks
- Treatment of SAIB with 5% Aqueous Solution of Sodium Metabisulfite in Presence of Hexane
- SAIB was dissolved in two parts of hexane. The resulting solution was treated with a 5% aqueous solution of sodium metabisulfite by vigorous shaking. The aqueous layer was removed and the SAIB layer was washed with water. The SAIB layer was dried with MgSO4. Hexane was removed from SAIB by evaporation under vacuum at 50° C. The treated SAIB was sampled for peroxide analysis and used for preparation of suspension for stability testing.
TABLE 7 Stability of omega-interferon in untreated SAIB and treated SAIB - Study VIa and VIb Stability of omega-IFN in Untreated SAIB (Lot: TD 2032663) Analysis by RP-HPLC (n = 3)** Initial (t = 0) Protein particles Initial (t = 0) 1 week 2 weeks 4 weeks 8 weeks AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 Assay (%) 11.45 (0.24) 1.00 (0.01) 1.00 (0.01) 1.00 (0.01) 0.94 (0.01) 0.94 (0.03) % omega-IFN 88.91 (0.39) 87.29 (0.25) 83.10 (0.08) 81.62 80.17 79.35 % Oxidized 1.90 (0.39) 3.38 (0.19) 7.86 (0.14) 8.54 (0.07) 8.94 (0.08) 8.86 (0.06) % Deamidated 2.02 (0.01) 2.15 (0.03) 2.24 (0.09) 2.59 (0.15) 3.33 (0.04) 4.46 (0.07) % Unknown 7.17 (0.44) 7.18 (0.47) 6.80 (0.02) 7.25 (0.36) 7.55 (0.05) 7.33 (0.47) Analysis by SEC (n = 3)** Initial (t = 0) Protein particles Initial (t = 0) 1 week 2 weeks 4 weeks 8 weeks AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 % Monomer 99.67 (0.01) 99.57 (0.02) 99.16 (0.01) 98.93 99.15 97.18 % Dimer 0.25 (0.01) 0.31 (0.02) 0.72 (0.01) 1.01 (0.04) 0.47 (0.05) 2.53 (0.13) Unknown 0.08 (0.00) 0.12 (0.01) 0.12 (0.00) 0.06 (0.00) 0.38 (0.02) 0.30 (0.05) Note: The omega content in the suspension was 1.00% and not 1.66% because the particles contained 11.45% omega and the loading of particles in suspension was at 10% Stability of omega-IFN in Treated SAIB (Lot: TD 2032663) Analysis by RP-HPLC (n = 3)** Initial (t = 0) Protein particles Initial (t = 0) 1 week 2 weeks 4 weeks 8 weeks AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 Assay (%) 11.45 (0.24) 1.17 (0.01) 1.15 (0.00) 1.16 (0.00) 1.15 (0.00) 1.14 (0.01) % omega-IFN 88.91 (0.39) 88.11 (0.35) 86.25 (0.41) 85.83 85.41 84.52 % Oxidized 1.90 (0.39) 2.69 (0.17) 3.26 (0.07) 3.46 (0.09) 3.56 (0.05) 4.16 (0.11) % Deamidated 2.02 (0.01) 2.26 (0.04) 2.81 (0.01) 2.94 (0.04) 3.21 (0.06) 3.64 (0.06) % Unknown 7.17 (0.44) 6.97 (0.39) 7.68 (0.37) 7.77 (0.38) 7.81 (0.45) 7.77 (0.55) Analysis by SEC (n = 3)** Initial (t = 0) Protein particles Initial (t = 0) 1 week 2 weeks 4 weeks 8 weeks AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 % Monomer 99.67 (0.01) 99.59 (0.02) 99.34 (0.02) 99.41 99.42 99.00 % Dimer 0.25 (0.01) 0.35 (0.02) 0.53 (0.02) 0.54 (0.02) 0.29 (0.01) 0.94 (0.06) Unknown 0.08 (0.00) 0.05 (0.00) 0.13 (0.01) 0.05 (0.01) 0.29 (0.01) 0.06 (0.01) Note: The omega content in the suspension was 1.17% and not 1.66% because the particles contained 11.45% omega and the loading of particles in suspension was at 10%. **standard deviation in parenthesis - The stability study (Study VIa and VIb, Table 7,
FIGS. 5-7 ) conducted in treated (5% aqueous solution of sodium metabisulfite) and untreated SAIB shows that oxidation levels are reduced at 8 weeks, along with the reduction of peroxide levels—4.16% in treated SAIB versus 8.86% in untreated SAIB equivalent to a change of 2.26% and 6.96%, respectively, from t=0 values of the protein particles. (For all relative changes reported herein, the changes are based on differences between the percentage values, e.g., percent oxidation, at tn and t=0 of the particles as opposed to relative percent change from value at t=0). Deamidation increased by 2.44% and 1.62% in untreated and treated SAIB, respectively. Dimerization increased by 2.28% and 0.59% in untreated and treated SAIB %, respectively. The quantities of unknown did not change significantly over time, which indicates that the extent of oxidation, deamidation and dimerization in treated SAIB (low peroxide value of 2.6 ppm) was lower than in untreated material. This treatment decreased the peroxide content substantially.TABLE 8 Peroxide content of SAIB Peroxide Study SAIB value AR # (Lot #) Treatment (ppm)* numbers I TD1030507 Untreated 71.4 48557 IIa TD1030507 Treated with neutral 66.3 48568 alumina by heating IIb TD1030507 Treated with neutral 62.9 48568 alumina using ethanol III TD2032663 Untreated 115.9 48581 IV TD2032663 Treated with basic 109.3 48581 alumina by heating V TD2032663 Treated with 10% aqueous 95.7 48446 solution of methionine VIa TD2032663 Treated with hexane and 2.6 49648 sodium metabisulfite VIb TD2032663 Untreated 115.9** 48581
*oxidative activity equivalent to hydrogen peroxide (n = 1)
**peroxide content determined during Study III
- As shown in
FIG. 7 , along with data provided in Table 8, treatment with an aqueous solution of sodium metabisulfite was effective in significantly reducing peroxide levels from 115.9 ppm to 2.6 ppm—almost 45 times, or 45 fold decrease. In comparison, treatment with neutral alumina, either with heat or with ethanol, resulting in only a nominal change in peroxide levels—a 7% or 12% decrease, respectively. In addition, treatment with basic alumina with heat or 10% aqueous methionine only resulted in nominal change in peroxide levels—a 6% or 18% decrease, respectively. -
FIG. 8 illustrates an osmotically pump-driven implantable device for delivering an SAIB formulation acting as a drug delivery vehicle, active agent within. Depicted inFIG. 8 is an osmotically pump-drivenimplantable device 10 shown comprising animpermeable reservoir 12. Thereservoir 12 is divided into two chambers by apiston 16. Thefirst chamber 18 is adapted to contain anSAIB formulation 19 containing anactive agent 20 and thesecond chamber 21 is adapted to contain a fluid-imbibing agent. A back-diffusion regulating outlet 22 is inserted into the open end of thefirst chamber 18 and asemipermeable membrane 24 encloses the open end of thesecond chamber 21. Thepiston 16 is driven towards the open end of thefirst chamber 18 by the osmotic pressure generated by the fluid-imbibing agent in thesecond chamber 21. The pressure created by thepiston 16 can force the contents of thefirst chamber 18 out the opening, i.e., theSAIB formulation 19 comprisingactive agents 20. The release rate of the active agent can be governed by the osmotic pumping rate. - It is to be appreciated that certain features of the invention which are, for clarity, described above in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Further, reference to values stated in ranges includes each and every value within that range, unless clearly expressed otherwise.
- The entire disclosure of each patent, patent application, and publication cited or described in this document is incorporated herein by reference.
Claims (25)
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US11/492,153 US20070027105A1 (en) | 2005-07-26 | 2006-07-24 | Peroxide removal from drug delivery vehicle |
EP06788435.3A EP1917035B1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
LTEP15181255.9T LT2977061T (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
HUE14178214A HUE027925T2 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
DK14178214.4T DK2810658T3 (en) | 2005-07-26 | 2006-07-25 | REMOVAL OF PEROXIDE FROM A vehicle for the administration of drug |
KR1020087004459A KR20080059149A (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
JP2008524069A JP2009502930A (en) | 2005-07-26 | 2006-07-25 | Removal of peroxide from drug delivery vehicles |
PT141782144T PT2810658E (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
PL15181255T PL2977061T3 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
SI200631978T SI2810658T1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
SI200632182T SI2977061T1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
DK15181255.9T DK2977061T3 (en) | 2005-07-26 | 2006-07-25 | REMOVAL OF PEROXIDE FROM VEHICLE TO THE ADMINISTRATION OF THE MEDICINAL PRODUCT |
EP15181255.9A EP2977061B1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
BRPI0614156-0A BRPI0614156A2 (en) | 2005-07-26 | 2006-07-25 | drug dispensing vehicle, method for treating a sucrose acetate isobutyrate formulation, and sucrose acetate isobutyrate formulation |
PL14178214T PL2810658T3 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
EA200800415A EA200800415A1 (en) | 2005-07-26 | 2006-07-25 | REMOVAL OF PEROXIDE FROM CARRIER FOR DELIVERY OF MEDICINES |
ES15181255.9T ES2632496T3 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from a drug delivery vehicle |
CA002615688A CA2615688A1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
ES14178214.4T ES2554468T3 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from a drug delivery vehicle |
PCT/US2006/028851 WO2007016093A2 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
PT151812559T PT2977061T (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
EP17159693.5A EP3202422A1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
EP14178214.4A EP2810658B1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
AU2006275987A AU2006275987A1 (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle |
MX2008001129A MX2008001129A (en) | 2005-07-26 | 2006-07-25 | Peroxide removal from drug delivery vehicle. |
IL188991A IL188991A0 (en) | 2005-07-26 | 2008-01-24 | Peroxide removal from drug delivery vehicle |
US13/301,727 US20120330005A1 (en) | 2005-07-26 | 2011-11-21 | Peroxide removal from drug delivery vehicle |
HK15101703.9A HK1201185A1 (en) | 2005-07-26 | 2015-02-16 | Peroxide removal from drug delivery vehicle |
CY20151101018T CY1117052T1 (en) | 2005-07-26 | 2015-11-13 | PEROXIDE EXTRACTION FROM MEDICINE ADMINISTRATION |
HK16108760.3A HK1221633A1 (en) | 2005-07-26 | 2016-07-21 | Peroxide removal from drug delivery vehicle |
US15/250,822 US20160361420A1 (en) | 2005-07-26 | 2016-08-29 | Peroxide removal from drug delivery vehicle |
CY20171100745T CY1119562T1 (en) | 2005-07-26 | 2017-07-13 | PEROXIDE EXTRACTION FROM MEDICINE ADMINISTRATION |
US16/542,230 US11083796B2 (en) | 2005-07-26 | 2019-08-15 | Peroxide removal from drug delivery vehicle |
US17/364,519 US20220023424A1 (en) | 2005-07-26 | 2021-06-30 | Peroxide removal from drug delivery vehicle |
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---|---|---|---|---|
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US20050101943A1 (en) * | 2003-11-06 | 2005-05-12 | Alza Corporation | Modular imbibition rate reducer for use with implantable osmotic pump |
US20050112188A1 (en) * | 2003-11-17 | 2005-05-26 | Eliaz Rom E. | Composition and dosage form comprising an amphiphilic molecule as a suspension vehicle |
US20060184158A1 (en) * | 2002-06-17 | 2006-08-17 | Fereira Pamela J | Osmotic delivery system with early zero order push power engine |
US20060193918A1 (en) * | 2005-02-03 | 2006-08-31 | Rohloff Catherine M | Solvent/polymer solutions as suspension vehicles |
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US20070191818A1 (en) * | 2003-03-31 | 2007-08-16 | Dionne Keith E | Osmotic pump with means for dissipating internal pressure |
US20080071253A1 (en) * | 1997-07-25 | 2008-03-20 | Alza Corporation | Osmotic Delivery System Flow Modulator Apparatus and Method |
US20080091176A1 (en) * | 2006-08-09 | 2008-04-17 | Alessi Thomas R | Osmotic delivery systems and piston assemblies for use therein |
US20080112994A1 (en) * | 2004-05-25 | 2008-05-15 | Intarcia Therapeutics, Inc. | Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium |
US20080226689A1 (en) * | 1999-02-08 | 2008-09-18 | Intarcia Therapeutics, Inc. | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles |
US20080226625A1 (en) * | 1999-02-08 | 2008-09-18 | Intarcia Therapeutics, Inc. | Stable non- aqueous single phase viscous vehicles and formulations utlizing such vehicles |
US20080260840A1 (en) * | 2005-02-03 | 2008-10-23 | Alessi Thomas R | Suspension formulations of insulinotropic peptides and uses thereof |
US20080269726A1 (en) * | 2003-10-31 | 2008-10-30 | Intarcia Therapeutics, Inc. | Osmotic pump with self-retaining, fast-start membrane plug |
EP2067471A1 (en) | 2007-12-06 | 2009-06-10 | Durect Corporation | Oral pharmaceutical dosage forms |
US20090202608A1 (en) * | 2008-02-13 | 2009-08-13 | Alessi Thomas R | Devices, formulations, and methods for delivery of multiple beneficial agents |
US20100092566A1 (en) * | 2008-10-15 | 2010-04-15 | Alessi Thomas R | Highly concentrated drug particles, formulations, suspensions and uses thereof |
US20110076317A1 (en) * | 2009-09-28 | 2011-03-31 | Alessi Thomas R | Rapid establishment and/or termination of substantial steady-state drug delivery |
US8354124B2 (en) | 2002-12-13 | 2013-01-15 | Durect Corporation | Oral drug delivery system |
WO2014144975A1 (en) | 2013-03-15 | 2014-09-18 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
WO2014144984A1 (en) | 2013-03-15 | 2014-09-18 | Durect Corporation | Compositions with thixotropy and enhanced dissolution reproducibility and stability |
US9539200B2 (en) | 2005-02-03 | 2017-01-10 | Intarcia Therapeutics Inc. | Two-piece, internal-channel osmotic delivery system flow modulator |
US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
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US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
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Citations (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3473949A (en) * | 1966-05-09 | 1969-10-21 | Gen Motors Corp | Method of forming acrylic resin surface coatings |
US3797492A (en) * | 1972-12-27 | 1974-03-19 | Alza Corp | Device for dispensing product with directional guidance member |
US3962162A (en) * | 1974-02-19 | 1976-06-08 | Minnesota Mining And Manufacturing Company | Rigidly bonded green ceramics and processes |
US3987790A (en) * | 1975-10-01 | 1976-10-26 | Alza Corporation | Osmotically driven fluid dispenser |
US4008719A (en) * | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4305927A (en) * | 1979-02-05 | 1981-12-15 | Alza Corporation | Method for the management of intraocular pressure |
US4865845A (en) * | 1986-03-21 | 1989-09-12 | Alza Corporation | Release rate adjustment of osmotic or diffusional delivery devices |
US4874388A (en) * | 1987-06-25 | 1989-10-17 | Alza Corporation | Multi-layer delivery system |
US5034229A (en) * | 1988-12-13 | 1991-07-23 | Alza Corporation | Dispenser for increasing feed conversion of hog |
US5057318A (en) * | 1988-12-13 | 1991-10-15 | Alza Corporation | Delivery system for beneficial agent over a broad range of rates |
US5059423A (en) * | 1988-12-13 | 1991-10-22 | Alza Corporation | Delivery system comprising biocompatible beneficial agent formulation |
US5110596A (en) * | 1988-12-13 | 1992-05-05 | Alza Corporation | Delivery system comprising means for delivering agent to livestock |
US5112614A (en) * | 1989-09-14 | 1992-05-12 | Alza Corporation | Implantable delivery dispenser |
US5137727A (en) * | 1991-06-12 | 1992-08-11 | Alza Corporation | Delivery device providing beneficial agent stability |
US5151093A (en) * | 1990-10-29 | 1992-09-29 | Alza Corporation | Osmotically driven syringe with programmable agent delivery |
US5219572A (en) * | 1989-03-17 | 1993-06-15 | Pitman-Moore, Inc. | Controlled release delivery device for macromolecular proteins |
US5234692A (en) * | 1990-07-11 | 1993-08-10 | Alza Corporation | Delivery device with a protective sleeve |
US5234693A (en) * | 1990-07-11 | 1993-08-10 | Alza Corporation | Delivery device with a protective sleeve |
US5279608A (en) * | 1990-12-18 | 1994-01-18 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Osmotic pumps |
US5308348A (en) * | 1992-02-18 | 1994-05-03 | Alza Corporation | Delivery devices with pulsatile effect |
US5336057A (en) * | 1991-09-30 | 1994-08-09 | Nippon Densan Corporation | Micropump with liquid-absorptive polymer gel actuator |
US5368588A (en) * | 1993-02-26 | 1994-11-29 | Bettinger; David S. | Parenteral fluid medication reservoir pump |
US5511355A (en) * | 1991-11-15 | 1996-04-30 | Dingler; Gerhard | Construction element |
US5557318A (en) * | 1994-07-12 | 1996-09-17 | Koninklijke Ptt Nederland N.V. | Method and apparatus for permitting a viewer to scan through a plurality of video signals provided by a transmitter |
US5713847A (en) * | 1994-02-09 | 1998-02-03 | The University Of Iowa Research Foundation | Human drug delivery device for tinnitus |
US5728396A (en) * | 1996-02-02 | 1998-03-17 | Alza Corporation | Sustained delivery of leuprolide using an implantable system |
US5836935A (en) * | 1994-11-10 | 1998-11-17 | Ashton; Paul | Implantable refillable controlled release device to deliver drugs directly to an internal portion of the body |
US5874388A (en) * | 1997-04-02 | 1999-02-23 | Dow Corning Corporation | Lubricant composition for disc brake caliper pin and a disc brake asembly containing the lubricant |
US5976109A (en) * | 1996-04-30 | 1999-11-02 | Medtronic, Inc. | Apparatus for drug infusion implanted within a living body |
US5997527A (en) * | 1997-03-24 | 1999-12-07 | Alza Corporation | Self adjustable exit port |
US5997902A (en) * | 1993-06-23 | 1999-12-07 | Alza Corporation | Ruminal drug delivery device |
US6113938A (en) * | 1997-12-30 | 2000-09-05 | Alza Corporation | Beneficial agent delivery system with membrane plug and method for controlling delivery of beneficial agents |
US6132420A (en) * | 1996-02-02 | 2000-10-17 | Alza Corporation | Osmotic delivery system and method for enhancing start-up and performance of osmotic delivery systems |
US6156331A (en) * | 1996-02-02 | 2000-12-05 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6261584B1 (en) * | 1996-02-02 | 2001-07-17 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6270787B1 (en) * | 1997-12-29 | 2001-08-07 | Alza Corporation | Osmotic delivery system with membrane plug retention mechanism |
US6283949B1 (en) * | 1999-12-27 | 2001-09-04 | Advanced Cardiovascular Systems, Inc. | Refillable implantable drug delivery pump |
US6375978B1 (en) * | 1997-12-22 | 2002-04-23 | Alza Corporation | Rate controlling membranes for controlled drug delivery devices |
US6395292B2 (en) * | 1996-02-02 | 2002-05-28 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6508808B1 (en) * | 1999-12-21 | 2003-01-21 | Alza Corporation | Valve for osmotic devices |
US20030044467A1 (en) * | 1996-12-20 | 2003-03-06 | Brodbeck Kevin J. | Gel composition and methods |
US20030059376A1 (en) * | 1999-06-04 | 2003-03-27 | Libbey Miles A. | Formulations comprising dehydrated particles of pharmaceutical agents and process for preparing the same |
US20030180364A1 (en) * | 2001-11-14 | 2003-09-25 | Guohua Chen | Catheter injectable depot compositions and uses thereof |
US20030215515A1 (en) * | 2002-04-11 | 2003-11-20 | Medimmune Vaccines, Inc. | Preservation of bioactive materials by spray drying |
US6840931B2 (en) * | 1997-07-25 | 2005-01-11 | Alza Corporation | Osmotic delivery system flow modulator apparatus and method |
US20050008661A1 (en) * | 2003-03-31 | 2005-01-13 | Fereira Pamela J. | Non-aqueous single phase vehicles and formulations utilizing such vehicles |
US20050095284A1 (en) * | 2003-10-31 | 2005-05-05 | Alza Corporation | Osmotic pump with self-retaining, fast-start membrane plug |
Family Cites Families (205)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2931802A (en) | 1958-04-30 | 1960-04-05 | Eastman Kodak Co | Mixed esters of glucose and sucrose |
US3215137A (en) | 1960-08-03 | 1965-11-02 | Kendall & Co | Immobilizing bandage and method of application |
GB1088992A (en) | 1963-09-19 | 1967-10-25 | Squibb & Sons Inc | Protective dressings |
US3346381A (en) * | 1964-07-30 | 1967-10-10 | Rca Corp | Electrostatic recording element |
US3755466A (en) * | 1968-11-04 | 1973-08-28 | Marathon Oil Co | Selective decomposition of hydroperoxides in the presence of polymeric peroxides and recovery of the polymeric peroxides |
US4069251A (en) | 1969-02-08 | 1978-01-17 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler | Continuous process for the manufacture of methionine |
US4411890A (en) | 1981-04-14 | 1983-10-25 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
US3743398A (en) | 1971-03-22 | 1973-07-03 | Eastman Kodak Co | Motion picture projector |
US3763018A (en) * | 1971-04-01 | 1973-10-02 | Basf Ag | Prevention of fouling in hydrocarbon separation |
NO139560C (en) | 1972-04-29 | 1979-04-04 | Takeda Chemical Industries Ltd | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE NONAPEPTIDAMIDE DERIVATIVES |
US3992365A (en) | 1973-11-01 | 1976-11-16 | Burroughs Wellcome Co. | Agonist analogues of luteinizing hormone releasing hormone |
DE2438350C3 (en) | 1974-08-09 | 1979-06-13 | Hoechst Ag, 6000 Frankfurt | Peptides with a strong LH-RH / FSH-RH action, process for their production and pharmaceutical preparations containing them |
DE2438352A1 (en) | 1974-08-09 | 1976-02-26 | Hoechst Ag | PEPTIDE CYCLOPROPYLAMIDE WITH LH-RH / FSHRH EFFECT |
GB1524747A (en) | 1976-05-11 | 1978-09-13 | Ici Ltd | Polypeptide |
JPS55154991A (en) | 1979-05-23 | 1980-12-02 | Hisamitsu Pharmaceut Co Inc | Beta-d-fructopyranoside derivative |
NZ194405A (en) | 1979-08-02 | 1982-05-25 | Dut Pty Ltd | Producing liquid hydrocarbon streams by hydrogenation of fossil-based feedstock |
US4692147A (en) | 1980-04-02 | 1987-09-08 | Medtronic, Inc. | Drug administration device |
US4304767A (en) | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4562024A (en) | 1982-07-06 | 1985-12-31 | Sterling Drug Inc. | Process for preparing granulate containing poorly compressible medicinally active matter |
US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
US4487603A (en) | 1982-11-26 | 1984-12-11 | Cordis Corporation | Implantable microinfusion pump system |
DE3716302C2 (en) | 1987-05-15 | 1996-02-01 | Henkel Kgaa | Improved absorbable bone waxes and their use |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
JPS59210024A (en) | 1983-05-13 | 1984-11-28 | Taiyo Kagaku Kk | Emulsified tocopherol |
US4725442A (en) | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
US4622219A (en) | 1983-06-17 | 1986-11-11 | Haynes Duncan H | Method of inducing local anesthesia using microdroplets of a general anesthetic |
US4891225A (en) | 1984-05-21 | 1990-01-02 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4630019A (en) | 1984-09-28 | 1986-12-16 | Westinghouse Electric Corp. | Molded case circuit breaker with calibration adjusting means for a bimetal |
US4725852A (en) | 1985-05-09 | 1988-02-16 | Burlington Industries, Inc. | Random artificially perturbed liquid apparatus and method |
JPS61260860A (en) * | 1985-05-15 | 1986-11-19 | T Hasegawa Co Ltd | Method of providing acidic drink with fragrance, color or turbidity |
JPS62419A (en) | 1985-06-26 | 1987-01-06 | Shiseido Co Ltd | Water-soluble agent containing fat-soluble vitamin |
US4780320A (en) | 1986-04-29 | 1988-10-25 | Pharmetrix Corp. | Controlled release drug delivery system for the periodontal pocket |
JPH0657722B2 (en) | 1986-05-27 | 1994-08-03 | 三菱化成株式会社 | Water-soluble polymer composition |
ES2058111T3 (en) | 1986-06-10 | 1994-11-01 | Euro Celtique Sa | COMPOSITION OF CONTROLLED RELEASE OF DIHYDROCODEIN. |
DE3620685A1 (en) | 1986-06-20 | 1987-12-23 | Henkel Kgaa | NEW AGENTS FOR COVERING INJURED AND / OR INJURED AREAS OF HUMAN OR ANIMAL SKIN |
US4861598A (en) | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
US4970075A (en) | 1986-07-18 | 1990-11-13 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
IT1198449B (en) | 1986-10-13 | 1988-12-21 | F I D I Farmaceutici Italiani | ESTERS OF POLYVALENT ALCOHOLS OF HYALURONIC ACID |
GB8626098D0 (en) | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
US5091171B2 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
US5391381A (en) | 1987-06-25 | 1995-02-21 | Alza Corporation | Dispenser capable of delivering plurality of drug units |
US4795641A (en) | 1987-08-20 | 1989-01-03 | Eastman Kodak Company | Polymer blends having reverse phase morphology for controlled delivery of bioactive agents |
US5350741A (en) | 1988-07-30 | 1994-09-27 | Kanji Takada | Enteric formulations of physiologically active peptides and proteins |
JPH0296516A (en) | 1988-09-29 | 1990-04-09 | Dainippon Pharmaceut Co Ltd | Granule and production thereof |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US5702716A (en) | 1988-10-03 | 1997-12-30 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
US4987893A (en) | 1988-10-12 | 1991-01-29 | Rochal Industries, Inc. | Conformable bandage and coating material |
US5324520A (en) | 1988-12-19 | 1994-06-28 | Vipont Pharmaceutical, Inc. | Intragingival delivery systems for treatment of periodontal disease |
US5324519A (en) | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
US5188837A (en) | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
GB8926612D0 (en) | 1989-11-24 | 1990-01-17 | Erba Farmitalia | Pharmaceutical compositions |
DE69129110T2 (en) | 1990-05-10 | 1998-12-10 | Bechgaard Int Res | PHARMACEUTICAL PREPARATION CONTAINING N-GLYCOFUROLE AND N-ETHYLENE GLYCOL |
IT1240643B (en) | 1990-05-11 | 1993-12-17 | Mediolanum Farmaceutici Spa | BIOLOGICALLY ACTIVE PEPTIDES CONTAINING IN 2-ALCHYL TRIPTOFANE CHAIN |
US5110685A (en) | 1990-05-18 | 1992-05-05 | Exxon Chemical Patents, Inc. | Low friction, abrasion resistant polymer coating |
US5149543A (en) | 1990-10-05 | 1992-09-22 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5399363A (en) | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
WO1992017900A1 (en) | 1991-04-03 | 1992-10-15 | Eastman Kodak Company | HIGH DURABILITY MASK FOR DRY ETCHING OF GaAs |
US5221698A (en) | 1991-06-27 | 1993-06-22 | The Regents Of The University Of Michigan | Bioactive composition |
JP3313124B2 (en) | 1991-07-31 | 2002-08-12 | 森下仁丹株式会社 | SEAMLESS CAPSULES CONTAINING A HYDROPHILIC SUBSTANCE AND PROCESS FOR PRODUCING THE SAME |
US5487898A (en) | 1991-08-26 | 1996-01-30 | Abbott Laboratories | Compositions and method for the sublingual or buccal administration therapeutic agents |
ATE197126T1 (en) | 1991-08-26 | 2000-11-15 | Abbott Lab | COMPOUNDS AND METHODS FOR SUBLINGUAL OR BUCCAL ADMINISTRATION OF THERAPEUTIC AGENTS |
YU87892A (en) | 1991-10-01 | 1995-12-04 | Eli Lilly And Company Lilly Corporate Center | INJECTIBLE LONG TERM RELEASE FORMULATIONS AND PROCEDURES FOR THEIR OBTAINING AND USE |
IL103275A0 (en) | 1991-10-01 | 1993-02-21 | Lilly Co Eli | Injectable extended release formulations and methods |
AU2605592A (en) | 1991-10-15 | 1993-04-22 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
JP3313113B2 (en) | 1991-10-21 | 2002-08-12 | ペプテック リミテッド | Biocompatible implants for controlling ovulation in mares |
US5656295A (en) | 1991-11-27 | 1997-08-12 | Euro-Celtique, S.A. | Controlled release oxycodone compositions |
US5266331A (en) | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
ATE140620T1 (en) | 1991-12-05 | 1996-08-15 | Mallinckrodt Veterinary Inc | GLASSY CARBOHYDRATE MATRICE FOR ADMINISTRATION OF DELAYED RELEASE MEDICATIONS |
EP0616526A1 (en) | 1991-12-11 | 1994-09-28 | The Procter & Gamble Company | Cetylpyridinium chloride and domiphen bromide in organic solvent |
US5478577A (en) | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US5192743A (en) | 1992-01-16 | 1993-03-09 | Genentech, Inc. | Reconstitutable lyophilized protein formulation |
US5456679A (en) | 1992-02-18 | 1995-10-10 | Alza Corporation | Delivery devices with pulsatile effect |
WO1993019739A1 (en) | 1992-03-30 | 1993-10-14 | Alza Corporation | Viscous suspensions of controlled-release drug particles |
WO1994005265A1 (en) | 1992-09-10 | 1994-03-17 | Children's Medical Center Corporation | Biodegradable polymer matrices for sustained delivery of local anesthetic agents |
PT678018E (en) | 1993-01-06 | 2003-08-29 | Kinerton Ltd | IONIC MOLECULAR CONJUGATES OF BIODEGRADABLE POLYESTERS AND BIOACTIVE POLYPEPTIDES |
US5340572A (en) | 1993-02-08 | 1994-08-23 | Insite Vision Incorporated | Alkaline ophthalmic suspensions |
AU679510B2 (en) | 1993-03-17 | 1997-07-03 | Minnesota Mining And Manufacturing Company | Aerosol formulation containing a diol-diacid derived dispersing aid |
NZ263686A (en) | 1993-03-17 | 1997-09-22 | Minnesota Mining & Mfg | Medicinal aerosol with dispersing aid derived from a hydroxy acid, an amino acid and/or a mercapto acid |
DK44193D0 (en) | 1993-04-20 | 1993-04-20 | Euromed I S | SPECIAL CONNECTION AND ADMINISTRATIVE TO A SPECIAL CONNECTION OR SIMILAR |
US5370864A (en) | 1993-06-29 | 1994-12-06 | The Procter & Gamble Company | Breath protection microcapsules |
IL110014A (en) | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
DE4322826A1 (en) | 1993-07-08 | 1995-01-12 | Galenik Labor Freiburg Gmbh | Pharmaceutical preparation |
US5442033A (en) | 1993-07-20 | 1995-08-15 | Ethicon, Inc. | Liquid copolymers of epsilon-caprolactone and lactide |
JP3257750B2 (en) | 1993-07-20 | 2002-02-18 | エチコン・インコーポレーテツド | Liquid copolymer of ε-caprolactone and lactide |
US5879705A (en) | 1993-07-27 | 1999-03-09 | Euro-Celtique S.A. | Sustained release compositions of morphine and a method of preparing pharmaceutical compositions |
US5505922A (en) | 1993-08-13 | 1996-04-09 | University Of Maryland At Baltimore | Anesthetic pharmaceutical combination |
JPH0753356A (en) | 1993-08-16 | 1995-02-28 | Morishita Jintan Kk | Seamless capsule containing easily oxidizable oily substance and its production |
JPH07112940A (en) | 1993-08-26 | 1995-05-02 | Takeda Chem Ind Ltd | Sustained-release parenteral preparation and its production |
US5578137A (en) | 1993-08-31 | 1996-11-26 | E. I. Du Pont De Nemours And Company | Azeotropic or azeotrope-like compositions including 1,1,1,2,3,4,4,5,5,5-decafluoropentane |
WO1995009613A1 (en) | 1993-10-04 | 1995-04-13 | Mark Chasin | Controlled release microspheres |
JPH07115901A (en) | 1993-10-28 | 1995-05-09 | Fuji Bibaretsuji:Kk | Emulsified composition and drink rich in docosahexaenoic acid |
DE69431071T2 (en) | 1993-12-29 | 2003-03-20 | Matrix Pharma | COMPOSITION FOR LOCAL RELEASE OF CYTOSTATICS |
CA2582666C (en) | 1994-04-08 | 2010-05-25 | Qlt Usa, Inc. | Controlled release implant |
US5633000A (en) | 1994-06-23 | 1997-05-27 | Axxia Technologies | Subcutaneous implant |
PT782569E (en) | 1994-09-23 | 2002-09-30 | Darwin Discovery Ltd | PROCESS OF RACEMIZATION USED IN THE MANUFACTURE OF LEVOBUPIVACAINE AND ITS ANALOGS |
US5599852A (en) | 1994-10-18 | 1997-02-04 | Ethicon, Inc. | Injectable microdispersions for soft tissue repair and augmentation |
EP0788481B1 (en) | 1994-10-25 | 2003-08-27 | Darwin Discovery Limited | Process for preparing levobupivacaine and analogues thereof |
CA2200355C (en) | 1994-10-25 | 2007-03-06 | Marianne Langston | Crystallisation of levobupivacaine and analogues thereof |
US6384227B2 (en) | 1995-01-18 | 2002-05-07 | Darwin Discovery Ltd. | Racemisation process for use in the manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents |
GB9501071D0 (en) | 1995-01-18 | 1995-03-08 | Chiroscience Ltd | Racemisation |
DE19520237A1 (en) | 1995-06-02 | 1996-12-05 | Beiersdorf Ag | Cosmetic or dermatological preparations containing oligomers or polymers of alpha-hydroxycarboxylic acids |
US5747058A (en) * | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
CN1225230C (en) | 1995-06-07 | 2005-11-02 | 南方生物系统公司 | High viscosity liquid controlled delivery system |
US6413536B1 (en) | 1995-06-07 | 2002-07-02 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system and medical or surgical device |
US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
US5968542A (en) | 1995-06-07 | 1999-10-19 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system as a device |
HUP9700322A3 (en) | 1995-06-09 | 2001-03-28 | Euro Celtique Sa | Formulations and methods for providing prolonged local anesthesia |
US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
US6245351B1 (en) | 1996-03-07 | 2001-06-12 | Takeda Chemical Industries, Ltd. | Controlled-release composition |
CA2260750C (en) | 1996-06-24 | 2004-11-09 | Euro-Celtique, S.A. | Methods for providing safe local anesthesia |
WO1998001117A1 (en) | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
US5869669A (en) | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
US6046187A (en) | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
US5801012A (en) | 1996-09-17 | 1998-09-01 | Northwestern University | Methods and compositions for generating angiostatin |
US5747051A (en) | 1996-09-27 | 1998-05-05 | Elizabeth Arden Co., Division Of Conopco, Inc. | Skin care compositions containing an amide of a hydroxy fatty acid and a retinoid |
US6572880B2 (en) | 1996-10-24 | 2003-06-03 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
US6479074B2 (en) | 1996-10-24 | 2002-11-12 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
US6203813B1 (en) | 1997-01-13 | 2001-03-20 | Lance L. Gooberman | Pharmaceutical delivery device and method of preparation therefor |
US6126919A (en) | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
DE19714765A1 (en) | 1997-04-10 | 1998-10-15 | Merck Patent Gmbh | Use of low molecular weight, oligomeric esters of alpha-hydroxy acids and / or aromatic o-hydroxy acids in cosmetic formulations |
US5919473A (en) | 1997-05-12 | 1999-07-06 | Elkhoury; George F. | Methods and devices for delivering opioid analgesics to wounds via a subdermal implant |
US5840329A (en) | 1997-05-15 | 1998-11-24 | Bioadvances Llc | Pulsatile drug delivery system |
US6051558A (en) | 1997-05-28 | 2000-04-18 | Southern Biosystems, Inc. | Compositions suitable for controlled release of the hormone GnRH and its analogs |
EP0999825B1 (en) | 1997-07-29 | 2003-10-01 | Alcon Laboratories, Inc. | Ophthalmic compositions containing galactomannan polymers and borate |
HU228143B1 (en) | 1997-11-19 | 2012-12-28 | Darwin Discovery Ltd | Anaesthetic formulation |
US6241969B1 (en) | 1998-06-26 | 2001-06-05 | Elan Corporation Plc | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
PL345216A1 (en) | 1998-06-29 | 2001-12-03 | Pharmaceuticals Applic Asociat | Methods and transdermal compositions for pain relief |
US6312717B1 (en) | 1998-07-07 | 2001-11-06 | Bristol-Myers Squibb Company | Method for treatment of anxiety and depression |
US6248112B1 (en) | 1998-09-30 | 2001-06-19 | C. R. Bard, Inc. | Implant delivery system |
AU1574900A (en) | 1998-12-04 | 2000-06-26 | Provalis (Uk) Limited | Pharmaceutical compositions containing insulin |
DE19858891A1 (en) | 1998-12-19 | 2000-06-21 | Merck Patent Gmbh | Improved bone seals |
US6498153B1 (en) | 1998-12-31 | 2002-12-24 | Akzo Nobel N.V. | Extended release growth promoting two component composition |
EP1666026B2 (en) | 1999-02-08 | 2015-02-25 | Intarcia Therapeutics, Inc | Non-aqueous single phase biocompatible viscous vehicles and methods for preparing the same |
US7258869B1 (en) | 1999-02-08 | 2007-08-21 | Alza Corporation | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle |
WO2002043800A2 (en) | 2000-11-29 | 2002-06-06 | Durect Corporation | Devices and methods for controlled delivery from a drug delivery device |
US6541021B1 (en) | 1999-03-18 | 2003-04-01 | Durect Corporation | Devices and methods for pain management |
US6291013B1 (en) | 1999-05-03 | 2001-09-18 | Southern Biosystems, Inc. | Emulsion-based processes for making microparticles |
WO2000078335A1 (en) | 1999-06-18 | 2000-12-28 | Southern Biosystems, Inc. | COMPOSITIONS FOR CONTROLLED RELEASE OF THE HORMONE GnRH AND ITS ANALOGS |
US6283948B1 (en) | 1999-07-13 | 2001-09-04 | Ethicon, Inc. | Trocar obturator having grooved passageway |
IL149008A0 (en) | 1999-10-04 | 2002-11-10 | Chiron Corp | Stabilized liquid polypeptide-containing pharmaceutical compositions |
US6436091B1 (en) | 1999-11-16 | 2002-08-20 | Microsolutions, Inc. | Methods and implantable devices and systems for long term delivery of a pharmaceutical agent |
WO2001042518A1 (en) | 1999-12-13 | 2001-06-14 | Pacmin Investments Limited | Method of digesting metal containing material at elevated temperature in the presence of sulphur oxide compound source such as h2s04 |
WO2001043528A2 (en) | 1999-12-17 | 2001-06-21 | Durect Corporation | Devices and methods in intracerebrospinal delivery of morphine-6-glucuronide |
AU2001900A (en) | 1999-12-29 | 2001-07-16 | Progen S.R.L. | Biocompatible hydrogel and method of its production |
PT1248596E (en) | 2000-01-11 | 2007-06-21 | Bertex Pharma Gmbh | Implantation kit comprising a support phase and a solvent |
US6572890B2 (en) | 2000-01-13 | 2003-06-03 | Osmotica Corp. | Osmotic device containing venlafaxine and an anti-psychotic agent |
AU2001233315B2 (en) | 2000-02-08 | 2004-07-08 | Allergan Sales, Inc. | Botulinum toxin pharmaceutical compositions |
BR0002246A (en) | 2000-04-06 | 2003-04-15 | Cristalia Prod Quimicos Farm | Process for obtaining the enantiomers of racemic bupivacaine, process for obtaining pharmaceutical compositions based on levobupivacaine: pharmaceutical compositions based on levobupivacaine formulated in basic forms or pharmaceutically acceptable salts and use of pharmaceutical compositions based on levobupivacaine formulated in basic forms or pharmaceutically salts acceptable |
US20010042590A1 (en) * | 2000-04-17 | 2001-11-22 | Neuburger Carl D. | Method and device for making a magnetically mountable substrate construction form a selected substrate |
ATE309822T1 (en) | 2000-04-19 | 2005-12-15 | Genentech Inc | SUSTAINED RELEASE FORMULATIONS CONTAINING GROWTH HORMONE |
US20050042194A1 (en) | 2000-05-11 | 2005-02-24 | A.P. Pharma, Inc. | Semi-solid delivery vehicle and pharmaceutical compositions |
US6495534B2 (en) | 2000-05-15 | 2002-12-17 | Pharmacia & Upjohn Spa | Stabilized aqueous suspensions for parenteral use |
WO2002010436A2 (en) | 2000-07-28 | 2002-02-07 | The Brigham And Women's Hospital, Inc. | Prognostic classification of breast cancer |
FR2814308B1 (en) | 2000-09-15 | 2003-03-14 | France Telecom | METHOD FOR MANAGING THE USE OF A TELECOMMUNICATION LINE AND SYSTEM FOR IMPLEMENTING IT |
AU2001296770A1 (en) | 2000-10-06 | 2002-04-15 | Durect Corporation | Devices and methods for management of inflammation |
AU2738302A (en) | 2000-10-30 | 2002-05-15 | Euro Celtique Sa | Controlled release hydrocodone formulations |
CA2429898C (en) | 2000-11-16 | 2011-02-22 | Durect Corporation | Devices and methods for cholesterol management |
EP1363602A4 (en) | 2001-01-25 | 2006-01-11 | Euro Celtique Sa | Local anesthetic, and method of use |
IL157531A0 (en) | 2001-02-23 | 2004-03-28 | Genentech Inc | Erodible polymers for injection |
DE10109861A1 (en) * | 2001-03-01 | 2002-09-05 | Bayer Ag | Novel side chain halogenated aminodicarboxylic acid derivatives |
JP4460892B2 (en) | 2001-06-21 | 2010-05-12 | ジェネンテック インコーポレイテッド | Sustained release composition |
US20040142902A1 (en) | 2001-11-08 | 2004-07-22 | Struijker- Boudier Harry A.J. | Implant dosage form and use thereof for the delivery of a cholosterol lowering agent |
BR0206984A (en) | 2001-11-14 | 2004-02-03 | Alza Corp | Injectable Depot Compositions and Use of These |
GB2386066A (en) | 2002-02-28 | 2003-09-10 | Norbrook Lab Ltd | Long-acting parasiticidal composition with improved bioavailability comprising a salicylanilide, a further anti-parasitic compound & a polymeric species |
FR2838349B1 (en) | 2002-04-15 | 2004-06-25 | Laurence Paris | LIQUID COMPOSITIONS FOR SUSTAINED RELEASE SOFT CAPSULES AND PROCESS FOR PRODUCING THE SAME |
SE0201635D0 (en) | 2002-05-30 | 2002-05-30 | Astrazeneca Ab | Novel compounds |
JP4668611B2 (en) | 2002-05-31 | 2011-04-13 | タイタン ファーマシューティカルズ インコーポレイテッド | Implantable polymer device for sustained release of buprenorphine |
US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
US20040109893A1 (en) | 2002-06-25 | 2004-06-10 | Guohua Chen | Sustained release dosage forms of anesthetics for pain management |
JP4417039B2 (en) | 2002-06-28 | 2010-02-17 | 太陽化学株式会社 | Oil-in-water emulsion composition |
SE0202241D0 (en) | 2002-07-17 | 2002-07-17 | Astrazeneca Ab | Novel Compounds |
WO2004011032A1 (en) | 2002-07-26 | 2004-02-05 | Mikasa Seiyaku Co., Ltd. | External preparation |
CA2494342A1 (en) | 2002-07-31 | 2004-02-12 | Alza Corporation | Injectable depot compositions and uses thereof |
TW575722B (en) | 2002-09-02 | 2004-02-11 | Hannstar Display Corp | Planar light source device and liquid crystal display |
CA2498276A1 (en) | 2002-10-25 | 2004-05-06 | Pfizer Products Inc. | Depot formulations of arylheterocyclic active agents in the form of a suspension |
AU2003267788A1 (en) | 2002-10-25 | 2004-05-13 | Pfizer Products Inc. | Novel injectable depot formulations |
ATE418323T1 (en) | 2002-11-06 | 2009-01-15 | Alza Corp | DEPOSIT DELAYED RELEASE FORMULATIONS |
JP4865330B2 (en) | 2002-12-13 | 2012-02-01 | デュレクト コーポレーション | Oral drug delivery system |
JP2006512370A (en) * | 2002-12-19 | 2006-04-13 | アルザ・コーポレーション | A stable non-aqueous single phase gel and its formulation for delivery from an implantable device |
DE10312346A1 (en) * | 2003-03-20 | 2004-09-30 | Bayer Healthcare Ag | Controlled release system |
US7641643B2 (en) * | 2003-04-15 | 2010-01-05 | Abbott Cardiovascular Systems Inc. | Methods and compositions to treat myocardial conditions |
DE10322469A1 (en) | 2003-05-19 | 2004-12-16 | Bayer Healthcare Ag | Heterocyclic compounds |
US20050171052A1 (en) | 2003-11-14 | 2005-08-04 | Cook Phillip M. | Sucrose acetate isobutyrate formulation |
US20050118206A1 (en) | 2003-11-14 | 2005-06-02 | Luk Andrew S. | Surfactant-based gel as an injectable, sustained drug delivery vehicle |
US20050281879A1 (en) | 2003-11-14 | 2005-12-22 | Guohua Chen | Excipients in drug delivery vehicles |
US20050106214A1 (en) | 2003-11-14 | 2005-05-19 | Guohua Chen | Excipients in drug delivery vehicles |
US20050106304A1 (en) | 2003-11-14 | 2005-05-19 | Cook Phillip M. | Sucrose acetate isobutyrate formulation |
US20040224019A1 (en) | 2004-03-03 | 2004-11-11 | Adi Shefer | Oral controlled release system for targeted drug delivery into the cell and its nucleus for gene therapy, DNA vaccination, and administration of gene based drugs |
US20050232876A1 (en) | 2004-04-19 | 2005-10-20 | Robin Lynn Minga | Skin care compositions |
EP1758095A4 (en) | 2004-05-14 | 2008-10-01 | Yanmar Co Ltd | Noise suppressing structure of cabin |
US20050266087A1 (en) | 2004-05-25 | 2005-12-01 | Gunjan Junnarkar | Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium |
PT2767292T (en) | 2004-09-17 | 2016-11-23 | Durect Corp | Sustained local anesthetic composition containing saib |
WO2006083950A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Method for reducing the level of peroxides in bopcompatible polymer preparations |
JP2008528698A (en) | 2005-02-03 | 2008-07-31 | インターシア セラピューティクス,インコーポレイティド | Implantable interferon-containing devices |
JP4531582B2 (en) | 2005-02-10 | 2010-08-25 | アルパイン株式会社 | Map update processing data creation method, map update method and apparatus |
JP4501076B2 (en) | 2006-01-06 | 2010-07-14 | ソニー株式会社 | Portable wireless communication terminal |
SA07280459B1 (en) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
ES2388355T3 (en) | 2006-11-03 | 2012-10-11 | Durect Corporation | Transdemic delivery systems comprising bupivacaine |
PL2167039T3 (en) | 2007-05-18 | 2017-03-31 | Durect Corporation | Improved depot formulations |
WO2009088414A2 (en) | 2007-12-06 | 2009-07-16 | Durect Corporation | Oral pharmaceutical dosage forms |
SE531980C2 (en) | 2008-01-17 | 2009-09-22 | Avtech Sweden Ab | Flight control procedure as well as computer programs and computer program product to carry out the procedure |
US20140308352A1 (en) | 2013-03-11 | 2014-10-16 | Zogenix Inc. | Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material |
JP2016514692A (en) | 2013-03-15 | 2016-05-23 | デュレクト コーポレーション | Composition with thixotropy and enhanced dissolution reproducibility and stability |
US9572885B2 (en) | 2013-03-15 | 2017-02-21 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
-
2006
- 2006-07-24 US US11/492,153 patent/US20070027105A1/en not_active Abandoned
- 2006-07-25 MX MX2008001129A patent/MX2008001129A/en active IP Right Grant
- 2006-07-25 EP EP17159693.5A patent/EP3202422A1/en not_active Withdrawn
- 2006-07-25 KR KR1020087004459A patent/KR20080059149A/en not_active Application Discontinuation
- 2006-07-25 SI SI200631978T patent/SI2810658T1/en unknown
- 2006-07-25 ES ES15181255.9T patent/ES2632496T3/en active Active
- 2006-07-25 PL PL15181255T patent/PL2977061T3/en unknown
- 2006-07-25 PT PT151812559T patent/PT2977061T/en unknown
- 2006-07-25 PT PT141782144T patent/PT2810658E/en unknown
- 2006-07-25 JP JP2008524069A patent/JP2009502930A/en active Pending
- 2006-07-25 LT LTEP15181255.9T patent/LT2977061T/en unknown
- 2006-07-25 ES ES14178214.4T patent/ES2554468T3/en active Active
- 2006-07-25 PL PL14178214T patent/PL2810658T3/en unknown
- 2006-07-25 EP EP15181255.9A patent/EP2977061B1/en not_active Not-in-force
- 2006-07-25 DK DK14178214.4T patent/DK2810658T3/en active
- 2006-07-25 EP EP14178214.4A patent/EP2810658B1/en active Active
- 2006-07-25 SI SI200632182T patent/SI2977061T1/en unknown
- 2006-07-25 BR BRPI0614156-0A patent/BRPI0614156A2/en not_active IP Right Cessation
- 2006-07-25 EA EA200800415A patent/EA200800415A1/en unknown
- 2006-07-25 EP EP06788435.3A patent/EP1917035B1/en not_active Not-in-force
- 2006-07-25 DK DK15181255.9T patent/DK2977061T3/en active
- 2006-07-25 AU AU2006275987A patent/AU2006275987A1/en not_active Abandoned
- 2006-07-25 HU HUE14178214A patent/HUE027925T2/en unknown
- 2006-07-25 CA CA002615688A patent/CA2615688A1/en not_active Abandoned
- 2006-07-25 WO PCT/US2006/028851 patent/WO2007016093A2/en active Application Filing
-
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- 2008-01-24 IL IL188991A patent/IL188991A0/en unknown
-
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- 2011-11-21 US US13/301,727 patent/US20120330005A1/en not_active Abandoned
-
2015
- 2015-02-16 HK HK15101703.9A patent/HK1201185A1/en not_active IP Right Cessation
- 2015-11-13 CY CY20151101018T patent/CY1117052T1/en unknown
-
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- 2016-07-21 HK HK16108760.3A patent/HK1221633A1/en not_active IP Right Cessation
- 2016-08-29 US US15/250,822 patent/US20160361420A1/en not_active Abandoned
-
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- 2017-07-13 CY CY20171100745T patent/CY1119562T1/en unknown
-
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- 2019-08-15 US US16/542,230 patent/US11083796B2/en active Active
-
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- 2021-06-30 US US17/364,519 patent/US20220023424A1/en not_active Abandoned
Patent Citations (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3473949A (en) * | 1966-05-09 | 1969-10-21 | Gen Motors Corp | Method of forming acrylic resin surface coatings |
US3797492A (en) * | 1972-12-27 | 1974-03-19 | Alza Corp | Device for dispensing product with directional guidance member |
US3962162A (en) * | 1974-02-19 | 1976-06-08 | Minnesota Mining And Manufacturing Company | Rigidly bonded green ceramics and processes |
US3987790A (en) * | 1975-10-01 | 1976-10-26 | Alza Corporation | Osmotically driven fluid dispenser |
US4008719A (en) * | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4305927A (en) * | 1979-02-05 | 1981-12-15 | Alza Corporation | Method for the management of intraocular pressure |
US4865845A (en) * | 1986-03-21 | 1989-09-12 | Alza Corporation | Release rate adjustment of osmotic or diffusional delivery devices |
US4874388A (en) * | 1987-06-25 | 1989-10-17 | Alza Corporation | Multi-layer delivery system |
US5034229A (en) * | 1988-12-13 | 1991-07-23 | Alza Corporation | Dispenser for increasing feed conversion of hog |
US5057318A (en) * | 1988-12-13 | 1991-10-15 | Alza Corporation | Delivery system for beneficial agent over a broad range of rates |
US5059423A (en) * | 1988-12-13 | 1991-10-22 | Alza Corporation | Delivery system comprising biocompatible beneficial agent formulation |
US5110596A (en) * | 1988-12-13 | 1992-05-05 | Alza Corporation | Delivery system comprising means for delivering agent to livestock |
US5219572A (en) * | 1989-03-17 | 1993-06-15 | Pitman-Moore, Inc. | Controlled release delivery device for macromolecular proteins |
US5112614A (en) * | 1989-09-14 | 1992-05-12 | Alza Corporation | Implantable delivery dispenser |
US5234692A (en) * | 1990-07-11 | 1993-08-10 | Alza Corporation | Delivery device with a protective sleeve |
US5234693A (en) * | 1990-07-11 | 1993-08-10 | Alza Corporation | Delivery device with a protective sleeve |
US5151093A (en) * | 1990-10-29 | 1992-09-29 | Alza Corporation | Osmotically driven syringe with programmable agent delivery |
US5312389A (en) * | 1990-10-29 | 1994-05-17 | Felix Theeuwes | Osmotically driven syringe with programmable agent delivery |
US5279608A (en) * | 1990-12-18 | 1994-01-18 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Osmotic pumps |
US5137727A (en) * | 1991-06-12 | 1992-08-11 | Alza Corporation | Delivery device providing beneficial agent stability |
US5336057A (en) * | 1991-09-30 | 1994-08-09 | Nippon Densan Corporation | Micropump with liquid-absorptive polymer gel actuator |
US5511355A (en) * | 1991-11-15 | 1996-04-30 | Dingler; Gerhard | Construction element |
US5308348A (en) * | 1992-02-18 | 1994-05-03 | Alza Corporation | Delivery devices with pulsatile effect |
US5368588A (en) * | 1993-02-26 | 1994-11-29 | Bettinger; David S. | Parenteral fluid medication reservoir pump |
US5997902A (en) * | 1993-06-23 | 1999-12-07 | Alza Corporation | Ruminal drug delivery device |
US5713847A (en) * | 1994-02-09 | 1998-02-03 | The University Of Iowa Research Foundation | Human drug delivery device for tinnitus |
US5557318A (en) * | 1994-07-12 | 1996-09-17 | Koninklijke Ptt Nederland N.V. | Method and apparatus for permitting a viewer to scan through a plurality of video signals provided by a transmitter |
US5836935A (en) * | 1994-11-10 | 1998-11-17 | Ashton; Paul | Implantable refillable controlled release device to deliver drugs directly to an internal portion of the body |
US6156331A (en) * | 1996-02-02 | 2000-12-05 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US5985305A (en) * | 1996-02-02 | 1999-11-16 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6132420A (en) * | 1996-02-02 | 2000-10-17 | Alza Corporation | Osmotic delivery system and method for enhancing start-up and performance of osmotic delivery systems |
US6395292B2 (en) * | 1996-02-02 | 2002-05-28 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US6261584B1 (en) * | 1996-02-02 | 2001-07-17 | Alza Corporation | Sustained delivery of an active agent using an implantable system |
US5728396A (en) * | 1996-02-02 | 1998-03-17 | Alza Corporation | Sustained delivery of leuprolide using an implantable system |
US5976109A (en) * | 1996-04-30 | 1999-11-02 | Medtronic, Inc. | Apparatus for drug infusion implanted within a living body |
US20030044467A1 (en) * | 1996-12-20 | 2003-03-06 | Brodbeck Kevin J. | Gel composition and methods |
US5997527A (en) * | 1997-03-24 | 1999-12-07 | Alza Corporation | Self adjustable exit port |
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US20050276856A1 (en) * | 2003-03-31 | 2005-12-15 | Fereira Pamela J | Non-aqueous single phase vehicles and formulations utilizing such vehicles |
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