WO2012068783A1 - Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative - Google Patents
Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative Download PDFInfo
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- WO2012068783A1 WO2012068783A1 PCT/CN2011/001958 CN2011001958W WO2012068783A1 WO 2012068783 A1 WO2012068783 A1 WO 2012068783A1 CN 2011001958 W CN2011001958 W CN 2011001958W WO 2012068783 A1 WO2012068783 A1 WO 2012068783A1
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the disclosure relates to a composition of rotigotine, its derivatives, or the pharmaceutically acceptable salts of rotigotine or its derivatives.
- the oral bioavailability of rotigotine is low (about l %-5%), and thus rotigotine is not suitable for oral administration.
- the first transdermal patch for treating Parkinson's disease a transdermal patch under the trademark Neupro® developed by Schwarz Pharma AG, is on the market in Germany, England, Australia, etc.
- crystallized rotigotine may be formed during the course of using that product.
- cold-chain storage and distribution at a temperature of 2-8°C are employed, and each prescription must not be longer than one month so as to avoid crystallization, which will apparently increase patients' difficulty in using that product.
- CN 1762495 A discloses a microsphere formulation comprising rotigotine and degradable polymer auxiliary materials.
- the rotigotine microsphere formulation as disclosed in CN 1762495 A may achieve the effect of long-acting sustained release, but a problem of burst release may occur.
- Fig. 17 in vivo test, with a drug-loading rate of 8%
- Fig. 12 in vivo test, with a drug-loading rate of 20%
- Fig. 20 in vivo test, with a drug-loading rate of 40%
- the drug-loading rate is 20% or 40%
- the burst release effect is obvious. It may also be seen from Fig.
- the administered dosage should be also increased gradually during the treatment.
- the daily dose intake of the drug will need to be increased significantly.
- the drug-loading rate of the active component should not be too low.
- microspheres having a higher drug-loading rate microspheres having a lower drug-loading rate would have to be administered in a relatively larger amount, which may cause pain to patients.
- the drug-loading rate of the microspheres is too high, when administered to patients, the drug may experience a sudden release, which may cause drug overdose.
- the present disclosure provides a composition of a drug, such as rotigotine, its derivatives, or the pharmaceutically acceptable salts of rotigotine or its derivatives, which substantially reduces burst releasing of the drug.
- the composition comprises rotigogine, its derivatives, or the pharmaceutically acceptable salts of rotigotine or its derivatives;
- PLGA poly(lactide-co-glycolide)
- At least one fatty acid wherein the at least one fatty acid is at least about 0.5%, e.g., about
- the composition is in the form of microspheres.
- the particle diameter of microsphere can be about 1-250 microns, e.g., about 10-200 microns.
- the compound is rotigotine , or a pharmaceutically acceptable salt thereof.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 20-40% in weight relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof may be about 25-35%, about 25-30%, about 20-30%, about 20-35%, about 25-40%, about 30-35%, about 30-40%, or about 35-40% in weight relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof may be about 21%, 22%, 23%, 24%, 25%, 26%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% in weight relative to the total weight of the composition.
- the at least one PLGA is about 45-79% in weight relative to the total amount of the composition.
- the at least one PLGA may comprise two, three, four, or five different types of PLGA polymers, which may be different, e.g., in molecular weight and/or polymerization ratio.
- the at least one PLGA is about 47.5-77.5%, about 50-77.5%, about 52.5-72.5%, about 55-72.5%, about 55-69%, about 57.5-72.5%, about 57.5-77.5%, about 60-72.5%, about 60-70%, about 62.5-67.5%, about 45-50%, about 47.5-60%, or about 50-60% in weight relative to the total amount of the composition.
- the at least one PLGA is about 45%, about 47.5%, about 50%, about 52.5%, about 55%, about 57.5%, about 60%, about 62.5%, about 65%, about 67.5%, about 70%, about 72.5%, about 75%, about 77.5%, about 78%, or about 79% in weight relative to the total amount of the composition.
- the pharmaceutically acceptable salt is formed by rotigotine and an inorganic acid or an organic acid.
- the inorganic acid may be chosen from hydrochloric acid, sulphuric acid, phosphoric acid, and nitric acid.
- the organic acid is chosen from citric acid, fumaric acid, maleic acid, acetic acid, benzoic acid, lactic acid, methane sulfonic acid, naphthalene sulfonic acid, and toluene-p-sulfonic acid.
- the organic acid can be an acidic amino acid, such as glutamic acid and aspartic acid.
- the at least one PLGA is about 5,000-100,000 Da in molecular weight.
- the at least one PLGA may be about 5,500-99,000 Da, about 6,000-98,000 Da, about 6,500-97,000 Da, about 7,000-96,000 Da, about 7,500-95,000 Da, about 8,000-94,000 Da, about 8,500-93,000 Da, about 9,000-92,000 Da, about 9,500-91 ,000 Da, about 10,000-90,000 Da, about 10,500-89,000 Da, about 1 1 ,000-88,000 Da, about 10,500-87,000 Da, about 1 1 ,000-86,000 Da, about 1 1 ,500-85,000 Da, about 12,000-84,000 Da, about 12,500-83,000 Da, about 13,000-82,000 Da, about 13,500-81 ,000 Da, about 14,000-80,000 Da, about 14,500-79,000 Da, about 15,000-78,000 Da, about 15,500-77,000 Da, about 16,000-76,000 Da, about 16,500-75,000 Da, about 17,000-74,000 Da, about 17,500-73,000 Da, about 18,000-72,000 Da,
- the at least one PLGA has a polymerization ratio of lactide to glycolide ranging from about 95:5 to 5:95.
- the polymerization ratio of lactide to glycolide can be about 90: 10 to 10:90, about 85: 15 to 15:85, about 80:20 to 20:80, about 75:25 to 25:75, about 70:30 to 30:70, about 65:35 to 35:65, about 60:40 to 40:60, or about 55:45 to 45:55.
- the polymerization ratio of lactide to glycolide can be about 50:50.
- the polymerization ratio of lactide to glycolide ranges from about 75:25 to 25:75.
- the at least one fatty acid is chosen from fatty acids having 8-24 carbon atoms.
- the at least one fatty acid may be chosen from stearic acid, palmitic acid, oleic acid, decanoic acid, octanoic acid, and lignoceric acid.
- the at least one fatty acid can be stearic acid.
- the at least one fatty acid is at least 0.5% in weight relative to the total weight of the composition.
- the at least one fatty acid can be about 1 -15%, about 2-15%, about 3-15%, about 4-15%, about 5-15%, about 6-15%, about 7-15%, about 8-15%, about 9-15%, about 10-15%, about 1 1 -15%, about 12-15%, about 13-15%, about 14-15%, about 1 -12.5%, about 2-12.5%, about 3-12.5%, about 4-12.5%, about 5-12.5%, about 6-12.5%, about 7-12.5%, about 8-12.5%, about 9-12.5%, about 10-12.5%, about 1 1-12.5%, about 1-10%, about 2-10%, about 3-10%, about 4-10%, about 5-10%, about 6-10%, about 7-10%, about 8-10%, about 9-10%, about 1 -7.5%, about 2-7.5%, about 3-7.5%, about 4-7.5%, about 5-7.
- the at least one fatty acid can be about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 10%, about 10.5%, about 1 1%, about 1 1.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, or about 15%.
- rotigotine or a pharmaceutically acceptable salt thereof is about 20-40% in weight relative to the total weight of the composition, the at least one PLGA is about 57.5-72.5%, and the at least one fatty acid is about 2.5-7.5%.
- rotigotine or a pharmaceutically acceptable salt thereof is about 20-40% in weight relative to the total weight of the composition, the at least one PLGA is about 57.5-77.5%, and the at least one fatty acid is about 2.5%.
- rotigotine or a pharmaceutically acceptable salt thereof is about 30% in weight relative to the total weight of the composition, the at least one PLGA is about 55.5-69%, and the at least one fatty acid is about 1 -15%.
- rotigotine or a pharmaceutically acceptable salt thereof is about 30% in weight relative to the total weight of the composition, the at least one PLGA is about 62.5-67.5%, and the at least one fatty acid is about 2.5-7.5%.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 30%, the at least one PLGA is about 67.5%, and the fatty acid is about 2.5% relative to the total weight of the composition.
- the at least one PLGA comprises a first PLGA and a second PLGA, wherein the first PLGA has a molecular weight of about 42,000-75,000 Da, the second PLGA has a molecular weight of about 15,000-35,000 Da, and the weight ratio of the first PLGA and the second PLGA is about 95:5 to 5:95.
- the first PLGA has a molecular weight of about 15,000-30,000 Da, about 15,000-25,000 Da, about 15,000-20,000 Da, about 20,000-35,000 Da, about 20,000-30,000 Da, about 20,000-25,000 Da, about 25,000-35,000 Da, about 25,000-30,000 Da, or about 30,000-35,000 Da.
- the second PLGA has a molecular weight of about 45,000-70,000 Da, about 50,000-65,000 Da, about 55,000-60,000 Da, about 45,000-65,000 Da, about 45,000-60,000 Da, about 45,000-55,000 Da, about 45,000-50,000 Da, about 50,000-70,000 Da, about 50,000-55,000 Da, about 60,000-65,000 Da, about 60,000-70,000 Da, about 45,000-75,000 Da, about 50,000-75,000 Da, about 55,000-75,000 Da, about 60,000-75,000 Da, about 65,000-75,000 Da, or about 70,000-75,000 Da.
- the weight ratio of the first PLGA and the second PLGA can be about 90: 10 to 10:90, about 85: 15 to 15:85, about 80:20 to 20:80, about 75:25 to 25:75, about 70:30 to 30:70, about 65:35 to 35:65, about 60:40 to 40:60, or about 55:45 to 45:55.
- the first PLGA is chosen from PLGA (7525 4A) and PLGA (7525 5A), and the second PLGA is PLGA (5050 2.5A).
- the weight ratio of the first PLGA and the second PLGA is about 50:50.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 20-40%, the amount of the first PLGA and the second PLGA is about 57.5-72.5% , and the fatty acid is about 2.5-7.5% relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 20-40%, the amount of the first PLGA and the second PLGA is about 57.5-77.5%, and the fatty acid is about 2.5% relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 30%, the amount of the first PLGA and the second PLGA is about 55-69%, and the fatty acid is about 1 -15% relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 30%, the amount of the first PLGA and the second PLGA is about 62.5-67.5%), and the fatty acid is about 2.5-7.5% relative to the total weight of the composition.
- the rotigotine or a pharmaceutically acceptable salt thereof is about 30%, the amount of the first PLGA and the second PLGA is about 67.5%, and the fatty acid is about 2.5% relative to the total weight of the composition.
- the composition as disclosed herein may provide a long-acting sustained release of the compound, such as rotigotine, or a pharmaceutically acceptable salt thereof.
- a microsphere preparation comprising rotigotine or a pharmaceutically acceptable salt thereof, PLGA, and a fatty acid may reduce the low drug release effect that may occur after the microsphere preparation is administered for 1 -4 days and in the meantime have reduced burst release effect.
- the microspheres prepared as disclosed herein also provide good batch-to-batch consistency. The variation of the drug concentrations in blood among individual animals may also be significantly reduced.
- composition as disclosed herein may reduce the burst release effect, especially when the compound, such as rotigotine, or a pharmaceutically acceptable salt thereof, is above 20% in weight relative to the total weight of the composition.
- the weight percentage of the compound, such as rotigotine, or a pharmaceutically acceptable salt thereof relative to the total weight of the composition is also referred herein as the "drug-loading rate.”
- composition as disclosed herein releases the drug stably in a long term without significant burst release, thus achieving the purpose of long-acting sustained release.
- the PLGA as disclosed herein is also known as poly(lactide-co-glycolide), which is a lactide/glycolide copolymer.
- the polymerization ratio of lactide to glycolide within poly(lactide-co-glycolide) can be any appropriate ratio.
- the polymerization ratio of lactide to glycolide can be about 95 :5 to 5 :95, such as about 75 :25 to 25:75.
- PLGA may be represented by the following structure:
- microspheres as disclosed herein are of a matrix type comprising a drug dissolved and/or dispersed homogeneously throughout a polymer matrix.
- the microspheres as disclosed herein may range in size of about 1-250 ⁇ such as about 10-240 ⁇ , about 20-230 ⁇ , about 40-210 ⁇ , about 50-200 ⁇ , about 60-190 ⁇ , about 70-180 ⁇ , about 80-170 ⁇ , about 90-160 ⁇ , about 100-150 ⁇ , about 1 10-140 ⁇ , or about 120-130 ⁇ m.
- the microspheres as disclosed herein may be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 ⁇ .
- microspheres as disclosed herein may be prepared by any conventional method in the art, including but not limited to, a spray drying method, a solvent volatilization method, or a spray extraction method.
- the microspheres are prepared by the solvent volatilization method
- the compound such as rotigotine, or a pharmaceutically acceptable salt thereof, PLGA and the fatty acid are first dissolved in an organic solvent to prepare an organic phase.
- a continuous aqueous phase is prepared from water-soluble pharmaceutical polymer auxiliary materials.
- the organic phase is then injected into the continuous aqueous phase through a small tube to form a mixture, which is emulsified under vigorous mechanical stirring or ultrasonic stirring so as to form microspheres.
- the organic solvent is evaporated, and the resulting microspheres are filtered and dried.
- the microspheres may also be post-treated by washing, grading, etc., according to a conventional method, dried by vacuum drying or lyophilizing, and finally subpackaged.
- the organic solvent may be those with sufficient volatility, low-residue, and low boiling point.
- the organic solvent may be dichloromethane, chloroform, ethyl acetate, diethyl ether, or any combination thereof.
- the water-soluble pharmaceutical polymer auxiliary materials used for forming the continuous water phase may be chosen from, but not limited to, polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, sodium polymethacrylate, sodium polyacrylate, and any combination thereof.
- the amounts of the compound, such as rotigotine, or a pharmaceutically acceptable salt thereof, poly(lactide-co-glycolide), and the fatty acid in the organic solvent are not particularly limited, provided that they can be dissolved in the organic solvent.
- poly(lactide-co-glycolide) and the fatty acid can be about 1 -30% (w/v), such as about 5-25% (w/v) or about 10-20% (w/v), in the organic solvent.
- the continuous aqueous phase is prepared from polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, sodium polymefhacrylate, sodium polyacrylate, or any combination thereof
- concentration of these polymer auxiliary materials can be 0.01 -12.0% (w/v), such as 0.01-10.0% (w/v), such as 0.1 -5%) (w/v), in the aqueous phase based on their solubility in water.
- the volume ratio of the aqueous phase to the organic phase should be large enough to sufficiently disperse the organic phase in the aqueous phase so as to form the microspheres with sufficiently small particle size and good uniformity. But if the amount of the aqueous phase is more than needed, post-treatment may be complicated, thus increasing cost.
- the volume ratio of the organic phase to the aqueous phase can be about 1 :4 to 1 : 100, such as about 1 :5, about 1 : 10, about 1 :20, about 1 :30, about 1 :40, about 1 :50, about 1 :60, about 1 :70, about 1 :80, about 1 :90, or about 1 : 100.
- the microspheres may also be prepared by a spray drying method.
- the compound, such as rotigotine, or a pharmaceutically acceptable salt thereof, PLGA, and other excipients are dissolved in an organic solvent sufficiently to prepare an organic solution.
- the organic solution is filtered and dried by a conventional spray drying method to form microspheres.
- the microspheres may also be post-treated by washing, grading, etc., according to conventional method, and then subpackaged.
- the organic solvent may be chosen from, but not limited to, dichloromethane, chloroform, ethyl acetate, dioxane, diethyl ether, acetone, tetrahydrofuran, glacial acetic acid, and any combination thereof.
- the concentration of PLGA can be about l -30%> (w/v), such as about 5-25% (w/v) or about 10-20% (w/v).
- the microspheres may also be prepared by a spray extraction method.
- the compound, such as Rotigotine, or a pharmaceutically acceptable salt thereof, PLGA, and other excipients are dissolved sufficiently in an organic solvent A (in which the compound, such as Rotigotine, or a pharmaceutically acceptable salt thereof, PLGA, and fatty acid can be dissolved) to prepare an organic solution.
- the organic solution is sprayed into water or an organic solvent B (in which Rotigotine or a pharmaceutically acceptable salt thereof, PLGA, and fatty acid have limited solubility) and extracted to form microspheres.
- the microspheres may also be post-treated by washing, grading, etc., according to conventional method, and then subpackaged.
- the organic solvent A may be at least one chosen from dichloromethane, chloroform, ethyl acetate, dioxane, diethyl ether, acetone, tetrahydrofuran, benzene, toluene, and glacial acetic acid.
- the organic solvent B may be at least one chosen from methanol, ethanol, propanol, isopropanol, petroleum ether, alkane, and paraffinum liquidum.
- the amount of PLGA in the organic solvent A there are no special limits on the amount of PLGA in the organic solvent A, provided that PLGA can be dissolved in the organic solvent A.
- the concentration of PLGA in the organic solvent A can be about 1 -30% (w/v), such as about 5-25% (w/v) or about 1 0-20% (w/v).
- the spray drying method may be preferred over the solvent volatilization method and spray extraction method.
- the solvent volatilization method may be preferred.
- the microspheres may be subjected to particle-size grading, cleaning, drying, and subpackaged according to a predetermined dosage to prepare powder injections. If the particle size is of sufficient uniformity, the step of particle-size grading may be eliminated.
- the disclosure also provides powder injections prepared using the composition disclosed herein.
- the powder injections may be converted into injections in situ when in use.
- the powder injections may be prepared directly from the composition, such as in a microsphere form, as disclosed herein, and mixed uniformly with a sodium carboxymethyl cellulose injectable before use.
- the powder injections may also be prepared by mixing the composition, such as in a microsphere form, as disclosed herein, with an appropriate amount of sodium carboxymethyl cellulose, mannitol, glucose, etc. An appropriate amount of purified water can be added thereto prior to use to prepare an injectable.
- the disclosure also provides a method of treating a disease associated with dopamine receptors and/or Parkinson's disease comprising administering an effective amount of the composition as disclosed herein to a subject in need thereof.
- the method may comprise administering a composition comprising rotigotine or a pharmaceutically acceptable salt thereof in an amount of about 20-35%) in weight relative to the total weight of the composition, at least one fatty acid in an amount of about 2.5- 10%) in weight relative to the total weight of the composition, and at least one PLGA in an amount of about 55-77.5% in weight relative to the total amount of the composition, wherein the composition is in a form of microspheres.
- the method may comprise administering a composition comprising rotigotine or a pharmaceutically acceptable salt thereof in an amount of about 30% in weight relative to the total weight of the composition, at least one fatty acid in an amount of about 2.5% in weight relative to the total weight of the composition, and at least one PLGA, such as a first PLA and a second PLGA as disclosed herein, in an amount of about 67.5% in weight relative to the total amount of the composition, wherein the composition is in a form of microspheres.
- a composition comprising rotigotine or a pharmaceutically acceptable salt thereof in an amount of about 30% in weight relative to the total weight of the composition, at least one fatty acid in an amount of about 2.5% in weight relative to the total weight of the composition, and at least one PLGA, such as a first PLA and a second PLGA as disclosed herein, in an amount of about 67.5% in weight relative to the total amount of the composition, wherein the composition is in a form of microspheres.
- composition as disclosed herein can be administered parenterally to a subject in need thereof.
- the composition can be administered by intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection, etc.
- the composition as disclosed herein can be administered via intramuscular injection or subcutaneous injection.
- composition as disclosed herein may be administered at intervals of at least about two weeks, such as about three weeks, about four weeks, about five weeks, etc.
- Fig. 1 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 20%) comprising a single PLGA prepared in Example 1 , in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 2 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 25%) comprising a single PLGA prepared in Example 2, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 3 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 30%) comprising a single PLGA prepared in Example 3, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 4 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 35%) comprising a single PLGA prepared in Example 4, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 5 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 40%) comprising a single PLGA prepared in Example 5, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 6 shows the in vivo concentration curves of the microspheres prepared in Example 3 and Example 8, in which ⁇ represents the in vivo release drug-time curve of the microspheres (PLGA 7525 4A) prepared in Example 3, and Arepresents the in vivo release drug-time curve of the microspheres (containing 2.5% stearic acid and PLGA 7525 4A) prepared in Example 8.
- Fig. 7 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 20%) comprising a single PLGA and stearic acid prepared in Example 6, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 8 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 25%) comprising a single PLGA and stearic acid prepared in Example 7, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 9 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 30%) comprising a single PLGA and stearic acid prepared in Example 8, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 10 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 35%) comprising a single PLGA and stearic acid prepared in Example 9, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 1 1 is the in vitro release diagram of the microspheres (with a theoretical drug-loading rate of 40%) comprising a single PLGA and stearic acid prepared in Example 10, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 12 is the in vitro release diagram of the microspheres comprising 2.5% octanoic acid (C8) prepared in Example 1 1 , in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 13 is the in vitro release diagram of the microspheres comprising 2.5% lignoceric acid (C24) prepared in Example 12, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 14 is the in vitro release diagram of the microspheres comprising 0.5% stearic acid prepared in Example 13, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 15 is the in vitro release diagram of the microspheres comprising 1% stearic acid prepared in Example 14, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 16 is the in vitro release diagram of the microspheres comprising 5% stearic acid prepared in Example 15, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 17 is the in vitro release diagram of the microspheres comprising 10% stearic acid prepared in Example 16, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 18 is the in vitro release diagram of the microspheres comprising 15% stearic acid prepared in Example 17, in which ⁇ represents the daily released amount, and ⁇ represents the cumulative released amount.
- Fig. 19 is the in vivo drug-time curve diagram of the microspheres comprising PLGA 5050 2.5A.
- Fig. 32 is the in vitro-in vivo correlation diagram of the rotigotine microspheres prepared in Example 22.
- Fig. 33 is the in vitro release diagram of 5 batches microspheres prepared in Example 3.
- Fig. 34 is the in vitro release diagram of 5 batches microspheres prepared in Example 8.
- Fig. 35 is the in vitro release diagram of 5 batches microspheres prepared in Example 14.
- Fig. 36 is the in vitro release diagram of 5 batches microspheres prepared in Example 16.
- Fig. 37 is the in vitro release diagram of 5 batches microspheres prepared in Example 1 1.
- Fig. 38 is the in vitro release diagram of 5 batches microspheres prepared in Example 12.
- EXAMPLE 1 Microspheres Comprising A Single PLGA (With A Theoretical Drug-Loading Rate of 20%)
- EXAMPLE 2 Microspheres Comprising A Single PLGA (With A Theoretical Drug-Loading Rate of 25%)
- the rotigotine microspheres were prepared from 0.3752 g of rotigotine and 1.1291 g of PLGA 7525 4A according to the method of EXAMPLE 1.
- EXAMPLE 3 Microspheres Comprising A Single PLGA (With A Theoretical Drug-Loading Rate of 30%)
- EXAMPLE 4 Microspheres Comprising A Single PLGA (With A Theoretical Drug-Loading Rate of 35%)
- the rotigotine microspheres were prepared from 0.5268 g of rotigotine and 0.9790 g of PLGA 7525 4A according to the method of EXAMPLE 1.
- EXAMPLE 5 Microspheres Comprising A Single PLGA (With A Theoretical Drug-Loading Rate of 40%)
- the rotigotine microspheres were prepared from 0.6043 g of rotigotine and 0.9019 g of PLGA 7525 4A according to the method of EXAMPLE 1.
- Test Condition temperature: 37 ⁇ 0.5°C, rotation speed: 50 rpm
- Test Method Assays according to the Drug Release test (Chinese Pharmacopeia 2005, vol. II, appendix X D). 3 aliquots of 6 mg of the microspheres were placed in a centrifuge tube with a plug (10 mL), respectively. To the centrifuge tube was added 9 mL of a release medium of phosphate buffer containing 0.2% SDS. After shaking to suspension, each centrifuge tube was placed in a water bath shaker at 37 ⁇ 0.5°C, and vibrated at a speed of 50 ⁇ 3 rpm.
- the centrifuge tubes were taken out. At 5-8°C, the centrifuge tubes were centrifuged at a rotation speed of 3600 rpm for 10 min. Then 6 mL of supernatant was taken out from each centrifuge tube and used as a test solution, and 6.0 mL of a release medium of phosphate buffer at the same temperature was added to the centrifuge tube. After shaking to suspension, the centrifuge tube was placed back in a water bath shaker and vibrated. The above test solution was analyzed by HPLC, and the cumulative released amount was calculated according to the external standard method. Under pH 7.4, the in vitro release data are shown in Table 1 , and the in vitro release curves are shown in Figs. 1 -5. Table 1. The results of different theoretical drug-loading rates
- Test EXAMPLE 2 The In Vivo Release Test of The Rotigotine Microspheres
- Chromatographic condition Mobile phase (A) : (ImM NH4Ac) water (B): acetonitrile; gradient elute for 0-0.8min: B 70-90%, 0.8-3.5min: B 90-90%, 3.5 ⁇ 3.6min: B 90-70%, 3.6 ⁇ 7.5min: B 70-70%; flow rate: 0.35ml/min column temperature: 35 ° C ; sample size: 10 ⁇ L.
- Ion source ion spray ionization source; ion spray voltage: 5500 V; temperature: 500°C; GS 1 : 50psi; GS2: 50psi; the pressure of curtain gas (CUR) in the source: 15 psi; the pressure of collision gas (CAD): 8 psi; cation detection mode; scanning mode: multiple reaction monitoring (MRM); DP voltage of Rotigotine and diazepam are separately 50V and 88V; CE are separately 36V and 47V; CXP are both 10V; the ionic reaction for quantitative analysis are separately 316.2/147.1 (rotigotine) and 256.1/167.1 (diazepam).
- MRM multiple reaction monitoring
- 0.2 mL of blank plasma was added to 100 ⁇ . of rotigotine standard solution and ⁇ ⁇ of internal standard (500ng/ml diazepam) to prepare plasma samples corresponding to plasma concentrations of 0.05, 0.25, 1.00, 2.50, 1.00, 2.50, 5.00 and 12.5 ng/mL, respectively.
- the plasma samples were operated according to "the analyzing method of the plasma sample" in Chinese Pharmacopeia 2005, vol. II to create standard curves.
- the plasma was analyzed according to the above analytical method, and the in vivo release is shown in Fig. 6.
- Table 1 the cumulative released amount of the microsphere prepared in EXAMPLE 3 within 0.125 day and 1 day were 2.00% and 9.53% respectively. It may be seen from Fig. 6 that, there was an apparent burst release of the microspheres in the body of the beagles, then the blood drug level decreased; after 96 hr, the blood drug level increased, and after 192 hr, the blood drug level increased to C ma .
- the blood drug levels at 0.125 day and 1 day were higher than C max , which indicates that there was an apparent burst release in the microspheres prepared in EXAMPLE 3.
- EXAMPLE 6 Microspheres Comprising A Single PLGA And Stearic Acid (With A Theoretical Drug-Loading Rate of 20%)
- the rotigotine microspheres were prepared from 0.3104 g of rotigotine, 1.1603 g of PLGA 7525 4A and 0.0370 g of stearic acid according to the method of EXAMPLE 1.
- EXAMPLE 7 Microspheres Comprising A Single PLGA And Stearic Acid (With A Theoretical Drug-Loading Rate of 25%)
- the rotigotine microspheres were prepared from 0.3712 g of rotigotine, 1.0891 g of PLGA 7525 4A and 0.0379 g of stearic acid according to the method of EXAMPLE 1.
- EXAMPLE 8 Microspheres Comprising A Single PLGA And Stearic Acid (With A Theoretical Drug-Loading Rate of 30%)
- the rotigotine microspheres were prepared from 0.4522 g of rotigotine, 1.0136 g of PLGA 7525 4 A and 0.0371 g of stearic acid according to the method of EXAMPLE 1.
- EXAMPLE 9 Microspheres Comprising A Single PLGA And Stearic Acid (With A Theoretical Drug-Loading Rate of 35%)
- the rotigotine microspheres were prepared from 0.5258 g of rotigotine, 0.9790 g of PLGA 7525 4A and 0.0374 g of stearic acid according to the method of EXAMPLE 1.
- EXAMPLE 10 Microspheres Comprising A Single PLGA And Stearic Acid (With A Theoretical Drug-Loading Rate of 40%)
- the rotigotine microspheres were prepared from 0.6083 g of rotigotine, 0.8619 g of PLGA 7525 4A and 0.0367 g of stearic acid according to the method of EXAMPLE 1.
- the rotigotine microspheres were prepared from 0.4520 g of rotigotine, 1.01 19 g of PLGA 7525 4A and 0.0371 g of octanoic acid (2.5%) according to the method of EXAMPLE 1.
- Microspheres Comprising Lignoceric Acid And A Single PLGA
- the rotigotine microspheres were prepared from 0.4489 g of rotigotine, 1.0130 g of PLGA 7525 4A and 0.0373 g of lignoceric acid (2.5%) according to the method of EXAMPLE 1.
- Test EXAMPLE 5 Influence of Fatty Acids Having Different Numbers of Carbon Atoms on drug Release of The Rotigotine Microspheres
- EXAMPLE 13 Microspheres Comprising A Single PLGA And 0.5% Stearic Acid
- the rotigotine microspheres were prepared from 0.4528 g of rotigotine, 1.0432 g of PLGA 7525 4A and 0.0078 g of stearic acid (0.5%) according to the method of EXAMPLE 1.
- EXAMPLE 14 Microspheres Comprising A Single PLGA And 1% Stearic Acid
- the rotigotine microspheres were prepared from 0.4528 g of rotigotine, 1.0362 g of PLGA 7525 4A and 0.0158 g of stearic acid (1 %) according to the method of EXAMPLE 1. [0152] EXAMPLE 15 Microspheres Comprising A Single PLGA And 5% Stearic Acid
- the rotigotine microspheres were prepared from 0.4528 g of rotigotine, 0.9751 g of PLGA 7525 4A and 0.0758 g of stearic acid (5%) according to the method of EXAMPLE 1.
- EXAMPLE 16 A Microsphere Comprising A Single PLGA And 10% Stearic Acid
- the rotigotine microsphere were prepared from 0.4492 g of rotigotine, 0.9028 g of PLGA 7525 4A and 0.1532 g of stearic acid (10%) according to the method of EXAMPLE 1.
- EXAMPLE 17 Microsphere Comprising A Single PLGA And 15% Stearic Acid
- the rotigotine microspheres were prepared from 0.4528 g of rotigotine, 0.8261 g of PLGA 7525 4A and 0.2258 g of stearic acid (15%) according to the method of EXAMPLE 1.
- the released amount of rotigotine in 0.125 day and the cumulative released amount of rotigotine within 1 day for the microsphere comprising 1 to 15% of stearic acid were reduced to 0.75%-1.26% and 1.90%-5.70% respectively, thus effectively reduced the burst release of the drug.
- the release of the drug was slowed down.
- Test EXAMPLE 7 In Vivo Test of The Microspheres Comprising PLGA 5050 2.5 A
- EXAMPLE 18 Rotigotine Microspheres Comprising A Combination of Two PLGAs With Different Molecular Weights (95:5)
- the rotigotine microspheres were prepared from 0.4504 g of rotigotine, and a combination of 0.9973 g of PLGA 7525 4A and 0.0521 g of PLGA 5050 2.5A (with a weight ratio of 95:5) according to the method of EXAMPLE 1.
- the rotigotine microspheres were prepared from 0.4489 g of rotigotine, and a combination of 0.5261 g of PLGA 7525 4A and 0.5256 g of PLGA 5050 2.5A (with a weight ratio of 50:50) according to the method of EXAMPLE 1.
- the rotigotine microspheres were prepared from 0.4508 g of rotigotine, and a combination of 0.0519 g of PLGA 7525 4A and 0.9968 g of PLGA 5050 2.5A (with a weight ratio of 5:95) according to the method of EXAMPLE 1.
- the rotigotine microspheres were prepared from 0.4507 g of rotigotine, a combination of 0.5170 g of PLGA 7525 4A and 0.5177 g of PLGA 5050 2.5A (with a weight ratio of 50:50), and 0.0155 g of stearic acid (1%) according to the method of EXAMPLE 1.
- EXAMPLE 22 Microspheres Comprising Stearic Acid (2.5%) and A Combination of Two PLGAs With Different Molecular Weights (50:50)
- the rotigotine microspheres were prepared from 0.4491 g of rotigotine, a combination of 0.5060 g of PLGA 7525 4A and 0.5055 g of PLGA 5050 2.5A (with a weight ratio of 50:50), and 0.0371 g of stearic acid (2.5%) according to the method of EXAMPLE 1.
- EXAMPLE 23 Microspheres Comprising Stearic Acid (7.5%) and A Combination of Two PLGAs With Different Molecular Weights (50:50)
- the rotigotine microspheres were prepared from 0.4510 g of rotigotine, a combination of 0.4680 g of PLGA 7525 4A and 0.4701 g of PLGA 5050 2.5 A (with a weight ratio of 50:50), and 0.1 1 19 g of stearic acid (7.5%) according to the method of EXAMPLE 1 .
- EXAMPLE 24 Microspheres Comprising Stearic Acid (10%) and A Combination of Two PLGAs With Different Molecular Weights (50:50)
- the rotigotine microspheres were prepared from 0.4503 g of rotigotine, a combination of 0.4479 g of PLGA 7525 4A and 0.4501 g of PLGA 5050 2.5A (with a weight ratio of 50:50), and 0.1520 g of stearic acid (10%) according to the method of EXAMPLE 1.
- EXAMPLE 25 Microspheres Comprising Octanoic Acid (2.5%) and A Combination of Two PLGAs With Different Molecular Weights (50:50)
- the rotigotine microspheres were prepared from 0.4490 g of rotigotine, a combination of 0.5101 g of PLGA 7525 4A and 0.5091 g of PLGA 5050 2.5A (with a weight ratio of 50:50), and 0.0380 g of octanoic acid (2.5%) according to the method of EXAMPLE 1.
- EXAMPLE 26 A Microsphere Comprising Lignoceric Acid (2.5%) and A Combination of Two PLGAs With Different Molecular Weights (50:50)
- the rotigotine microspheres were prepared from 0.4520 g of rotigotine, a combination of 0.5055 g of PLGA 7525 4A and 0.5062 g of PLGA 5050 2.5A (with a weight ratio of 50:50), and 0.0379 g of lignoceric acid (2.5%) according to the method of EXAMPLE 1.
- EXAMPLE 27 Microspheres Comprising Stearic Acid (2.5%) and A Combination of Two PLGAs With Different Molecular Weights (95:5)
- the rotigotine microspheres were prepared from 0.4507 g of rotigotine, a combination of 0.9621 g of PLGA 7525 4A and 0.0505 g of PLGA 5050 2.5A (with a weight ratio of 95:5), and 0.0369 g of stearic acid (2.5%) according to the method of EXAMPLE 1.
- EXAMPLE 28 Microsphere Comprising Stearic Acid (2.5%) and A Combination of Two PLGAs With Different Molecular Weights (5:95)
- the rotigotine microspheres were prepared from 0.4514 g of rotigotine, a combination of 0.0501 g of PLGA 7525 4A and 0.9610 g of PLGA 5050 2.5A (with a weight ratio of 5:95), and 0.0370 g of stearic acid (2.5%) according to the method of EXAMPLE 1.
- Test EXAMPLE 9 In Vitro Test of The Rotigotine Microspheres Comprising Stearic Acid With Different Contents And A Combination of PLGAs With Different Molecular Weights
- Test EXAMPLE 10 In Vitro Test of The Rotigotine Microspheres Comprising Fatty Acids With Different Molecular Weights And A Combination of PLGAs With Different Molecular Weights
- Test EXAMPLE 12 In Vivo Test of The Microspheres with a . drug-loading rate Comprising Stearic Acid (2.5%) And A Combination of PLGA 7525 4A and PLGA 5050 2.5A With Different Weight Ratios
- microspheres were prepared according to EXAMPLE 8, but with different weight ratios of PLGA 7525 4A to PLGA 5050 2.5A of 90: 10, 80:20, 70:30 and 50:50.
- the in vivo release tests were carried out for the microspheres according to the method of Test EXAMPLE 2. The results are shown in Fig. 31. [0201] It may be seen from the in vivo release (Fig.
- PLGA with a molecular weight of 15000-30000 may increase the drug release amount of the microsphere in 1-4 days
- PLGA with a molecular weight of 42000-75000 (PLGA 4A) may prolong the drug release period, thus obtaining microspheres with more stable in vivo drug release.
- Test EXAMPLE 13 In Vitro Test of The Microspheres with a drug-loading rate Comprising Stearic Acid (2.5%) And A Combination of PLGA 7525 5A and PLGA 5050 2:5 A With Different Weight Ratios
- microspheres were prepared according to EXAMPLE 8, but with different weight ratios of PLGA 7525 5A to PLGA 5050 2.5A of 90: 10, 80:20 and 70:30.
- the in vitro release tests were carried out for the microspheres according to the method of Test EXAMPLE 1.
- the in vitro release data are shown in Table 9.
- Test EXAMPLE 15 The Determination of The Molecular Weight of PLGA
- Agilent 1 100 high performance liquid chromatograph comprising a quatpump, a column oven, an automatic sampler, a RID detector and HP-ChemStation with GPC software
- chromatographic column Styragel ® HT3 (7.8x300 mm, 10 ⁇ , molecular weight range: 500-30000), Styragel ® 6E (7.8x300 mm, 10 ⁇ , molecular weight range: 5000-600000); tetrahydrofuran (chromatographic pure, SK CHEMICAL, G6EE3H); polystyrene molecular weight standard (Fluka, 1226627); Sample: PLGA 7525 5A, PLGA 7525 4A, PLGA 5050 2.5A (Lakeshore Biomaterials, Inc.).
- Styragel ® HT3 (7.8x300 mm, 10 ⁇ , molecular weight range: 500-30,000) and Styragel ® 6E (7.8x300 mm, 10 ⁇ ⁇ , molecular weight range: 5,000-600,000) were connected in series for use. Because the property of PLGA is similar to that of polystyrene, a polystyrene mixed standard (molecular weight range: 500-2,500,000) comprising a molecular weight range of the samples available from Fluka Chemical Corp. was selected.
- PLGA 5050 2.5A PLGA 7525 4A PLGA 7525 5A
- PLGA 5050 2.5A PLGA 7525 4A PLGA 7525 5A
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CA2816288A CA2816288C (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
AU2011334494A AU2011334494B2 (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
ES11843219.4T ES2572948T3 (en) | 2010-11-25 | 2011-11-25 | Rotigotine compositions or pharmaceutically acceptable salts of rotigotine |
JP2013540214A JP6006225B2 (en) | 2010-11-25 | 2011-11-25 | Rotigotine, a derivative thereof, or a composition of a pharmaceutically acceptable salt of rotigotine or a derivative thereof |
RU2013128430/15A RU2589700C2 (en) | 2010-11-25 | 2011-11-25 | Rotigotine compositions, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or derivatives thereof |
BR112013012726-0A BR112013012726B1 (en) | 2010-11-25 | 2011-11-25 | Rotigotine compositions, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or derivatives thereof |
EP11843219.4A EP2642993B1 (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine or pharmaceutically acceptable salts of rotigotine |
US13/989,550 US9265835B2 (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
CN201180049447.2A CN103458895B (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
KR20137013119A KR101481643B1 (en) | 2010-11-25 | 2011-11-25 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
HK14100062.7A HK1186978A1 (en) | 2010-11-25 | 2014-01-03 | Compositions of rotigotine, derivatives thereof, or pharmaceutically acceptable salts of rotigotine or its derivative |
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US (1) | US9265835B2 (en) |
EP (1) | EP2642993B1 (en) |
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KR (1) | KR101481643B1 (en) |
CN (1) | CN103458895B (en) |
AU (1) | AU2011334494B2 (en) |
BR (1) | BR112013012726B1 (en) |
CA (1) | CA2816288C (en) |
ES (1) | ES2572948T3 (en) |
HK (1) | HK1186978A1 (en) |
MY (1) | MY165003A (en) |
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WO2013026547A1 (en) | 2011-08-19 | 2013-02-28 | Ucb Pharma Gmbh | Rotigotine in the treatment of hemispatial neglect and other deficits following stroke |
WO2014007579A1 (en) * | 2012-07-05 | 2014-01-09 | 에스케이케미칼(주) | Transdermally absorbable preparation containing rotigotine |
WO2015101625A1 (en) * | 2013-12-31 | 2015-07-09 | Pb&B Sa | Controlled release fatty acid compositions for use in body reconstruction and body-shaping |
CN106474070A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | A kind of overcome lag phase, the microsphere of constant release hydrophobic drug and preparation method |
US10669249B2 (en) | 2016-07-21 | 2020-06-02 | Shandong Luye Pharmaceutical Co., Ltd. | Rotigotine behenate, and manufacturing method and application thereof |
US11110061B2 (en) | 2017-11-01 | 2021-09-07 | Korea Research Institute Of Chemical Technology | Microspherical sustained-release injection containing escitalopram and method for preparing same |
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US11074031B1 (en) | 2016-09-06 | 2021-07-27 | Colin Leonard | Systems and methods for dynamic audio processing |
US8682462B2 (en) | 2011-08-13 | 2014-03-25 | Colin M. Leonard | Systems and methods for dynamic audio processing |
CN105310974B (en) * | 2014-08-01 | 2019-08-23 | 山东绿叶制药有限公司 | The implant of rotigotine and its derivative or its pharmaceutical salts |
CN105963253A (en) * | 2016-06-19 | 2016-09-28 | 朱武欣 | Rotigotine long-acting waterborne suspension type injection |
US10214490B2 (en) | 2016-08-30 | 2019-02-26 | Dow Agrosciences Llc | Picolinamides as fungicides |
WO2018096560A1 (en) * | 2016-11-23 | 2018-05-31 | Cipla Limited | Long acting depot formulation for the continuous dopaminergic stimulation |
KR102181231B1 (en) * | 2018-11-22 | 2020-11-20 | 주식회사 메디포럼제약 | Preparation method of polymeric microspheres loaded with rotigotine |
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Cited By (10)
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WO2013026547A1 (en) | 2011-08-19 | 2013-02-28 | Ucb Pharma Gmbh | Rotigotine in the treatment of hemispatial neglect and other deficits following stroke |
WO2014007579A1 (en) * | 2012-07-05 | 2014-01-09 | 에스케이케미칼(주) | Transdermally absorbable preparation containing rotigotine |
WO2015101625A1 (en) * | 2013-12-31 | 2015-07-09 | Pb&B Sa | Controlled release fatty acid compositions for use in body reconstruction and body-shaping |
RU2684611C2 (en) * | 2013-12-31 | 2019-04-10 | ПБ энд Б СА | Compositions for controlled release of fatty acids for use in reconstructing and correcting body-shaping |
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AU2014375268B2 (en) * | 2013-12-31 | 2019-11-14 | Pb & B Sa | Controlled release fatty acid compositions for use in body reconstruction and body-shaping |
CN106474070A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | A kind of overcome lag phase, the microsphere of constant release hydrophobic drug and preparation method |
US10669249B2 (en) | 2016-07-21 | 2020-06-02 | Shandong Luye Pharmaceutical Co., Ltd. | Rotigotine behenate, and manufacturing method and application thereof |
US11111227B2 (en) | 2016-07-21 | 2021-09-07 | Shandong Luye Pharmaceutical Co., Ltd. | Rotigotine behenate, and manufacturing method and application thereof |
US11110061B2 (en) | 2017-11-01 | 2021-09-07 | Korea Research Institute Of Chemical Technology | Microspherical sustained-release injection containing escitalopram and method for preparing same |
Also Published As
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JP2013543874A (en) | 2013-12-09 |
BR112013012726A2 (en) | 2017-04-04 |
HK1186978A1 (en) | 2014-03-28 |
ES2572948T3 (en) | 2016-06-03 |
CA2816288C (en) | 2016-01-26 |
KR101481643B1 (en) | 2015-01-12 |
CN103458895A (en) | 2013-12-18 |
PL2642993T3 (en) | 2016-09-30 |
RU2013128430A (en) | 2014-12-27 |
JP6006225B2 (en) | 2016-10-12 |
US20130309314A1 (en) | 2013-11-21 |
US9265835B2 (en) | 2016-02-23 |
MY165003A (en) | 2018-02-28 |
JP6067803B2 (en) | 2017-01-25 |
EP2642993A1 (en) | 2013-10-02 |
JP2016028043A (en) | 2016-02-25 |
CA2816288A1 (en) | 2012-05-31 |
US20140377369A2 (en) | 2014-12-25 |
RU2589700C2 (en) | 2016-07-10 |
AU2011334494A1 (en) | 2013-07-11 |
BR112013012726B1 (en) | 2022-03-29 |
EP2642993A4 (en) | 2014-05-14 |
KR20130130727A (en) | 2013-12-02 |
AU2011334494B2 (en) | 2015-11-05 |
CN103458895B (en) | 2014-07-09 |
EP2642993B1 (en) | 2016-03-02 |
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