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WO2010111264A2 - Préparations de rasagiline - Google Patents

Préparations de rasagiline Download PDF

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Publication number
WO2010111264A2
WO2010111264A2 PCT/US2010/028314 US2010028314W WO2010111264A2 WO 2010111264 A2 WO2010111264 A2 WO 2010111264A2 US 2010028314 W US2010028314 W US 2010028314W WO 2010111264 A2 WO2010111264 A2 WO 2010111264A2
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WO
WIPO (PCT)
Prior art keywords
rasagiline
pharmaceutical composition
pharmaceutically acceptable
particle size
ingredient
Prior art date
Application number
PCT/US2010/028314
Other languages
English (en)
Other versions
WO2010111264A3 (fr
Inventor
Deepak Gupta
Nagesh Nagaraju
Sanjay Tripathi
M. Pavan Kumar
Shrikant Vitthalrao Dhoke
Suryakumar Jayanthi
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2010111264A2 publication Critical patent/WO2010111264A2/fr
Publication of WO2010111264A3 publication Critical patent/WO2010111264A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds

Definitions

  • aspects of the present invention relate to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof. Further aspects of the invention relate to processes for making pharmaceutical formulations and to methods of using pharmaceutical formulations for the management of diseases, such as for the treatment of Parkinson's disease.
  • the drug compound having the adopted name "rasagiline mesylate” has chemical names: (1 R)-N-prop-2-ynyl-2,3-dihydro-1 H-inden-1 -amine methanesulfonate; or 1 H-inden-1 -amine, 2,3-dihydro-N-2-propynyl-, (1 R)-, methanesulfonate; and has structural Formula I.
  • Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol.
  • Rasagiline mesylate is the active ingredient in AZI LECT ® tablets from Teva Neuroscience, Inc., intended for oral administration and containing 0.5 mg and 1 mg of rasagiline free base equivalent.
  • Each AZILECT ® tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid, and talc.
  • Rasagiline mesylate is prescribed for the treatment of idiopathic Parkinson's disease, as initial monotherapy and as adjuvant therapy with levodopa.
  • U.S. Patent No. 5,457,133 discloses rasagiline and its pharmaceutically acceptable salts
  • U. S. Patent No. 5,532,415 discloses the mesylate salt of rasagiline.
  • U. S. Patent Nos. 5,387,612 and 5,453,446 relate to methods of treating Parkinson's disease using rasagiline or a pharmaceutically acceptable salt.
  • Various other patent documents relate to pharmaceutical formulations containing rasagiline or pharmaceutically acceptable salts.
  • U. S. Patent No. 5,786,390 discloses pharmaceutical formulations of rasagiline or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • U. S. Patent No. 6,126,968 relates to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof and at least one alcohol selected from the group consisting of pentahydric and hexahydric alcohols. According to the patent, the presence of certain alcohols significantly improves stability of pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salts. Formulations disclosed include alcohols selected from mannitol, xylitol and sorbitol.
  • U.S. Patent Application Publication No. 2006/0188581 describes pharmaceutical preparations of rasagiline or salts having enhanced content uniformity of the active agent.
  • the publication teaches that a homogeneous distribution of the drug substance can be achieved by certain particle size distributions that can be obtained by milling or other methods for altering particle sizes.
  • the publication discloses a mixture of particles of a pharmaceutically acceptable salt of rasagiline having reduced particle sizes less than 250 ⁇ m.
  • aspects of the present invention relate to pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof.
  • the present invention provides pharmaceutical formulations comprising rasagiline mesylate.
  • formulations of the present invention comprise rasagiline mesylate in crystalline form, amorphous form, or mixtures of such forms. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 1000 ⁇ m.
  • formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles have particle sizes from about 0.1 ⁇ m to about 1000 ⁇ m, or about 1 ⁇ m to about 500 ⁇ m, or about 10 ⁇ m to about 250 ⁇ m, or about 100 ⁇ m to about 150 ⁇ m.
  • formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 6 ⁇ m. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are larger than about 200 ⁇ m, or larger than about 250 ⁇ m.
  • formulations of the present invention comprise rasagiline mesylate having particle surface areas about 0.01 to about 100 m 2 /g. In embodiments, formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein about 90% of the particles are smaller than about 250 ⁇ m, the particle sizes being obtained without using a procedure for alteration of particle size such as milling, or any other technique.
  • formulations of the present invention comprise rasagiline mesylate having particle size distributions wherein 90% of the particles have particle sizes from about 10 ⁇ m to about 250 ⁇ m, or from about 100 ⁇ m to about 150 ⁇ m, said particle sizes being obtained without using any procedure for alteration of particle sizes such as milling, or any other technique.
  • compositions of the present invention have a content uniformity of a lubricated blend ranging from about 90% to about 1 10% of the label content of rasagiline mesylate, and a relative standard deviation not more than about 5%, or not more than about 2%.
  • the present invention includes stable pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • the present invention relates to stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier.
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of a sugar alcohol.
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of a pentahydric or hexahydric sugar alcohol.
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable carrier, free of mannitol, xylitol, and sorbitol.
  • stable pharmaceutical formulations of the present invention have total amounts of drug-related impurities less than about 5%, or less than about 2%, of the label rasagiline content after storage in a closed HDPE container at accelerated stability testing conditions of 4O 0 C and 75% relative humidity (RH), for at least 3 months.
  • the present invention provides processes for preparing pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof.
  • pharmaceutical formulations of the present invention can be prepared using any of techniques including wet granulation, dry granulation, spray granulation, direct compression, and the like.
  • pharmaceutical formulations of the present invention provide in vitro drug release profiles such that more than 20%, or more than 50%, or more than 90%, of contained rasagiline mesylate is dissolved in less than 15 minutes, following immersion into an aqueous fluid.
  • the present invention provides methods of using pharmaceutical formulations comprising rasagiline or a salt thereof for the management of diseases or disorders, comprising administering a formulation containing an effective amount of the active agent.
  • the present invention provides methods of treatment of Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt. In an aspect, the present invention provides methods of treatment of Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt, wherein the formulations are used as a monotherapy. In an aspect, the present invention provides methods of treatment of
  • Parkinson's disease using pharmaceutical formulations comprising rasagiline or its pharmaceutically acceptable salt, wherein the formulations are used as an adjuvant to therapy with levodopa.
  • aspects of the present invention provide pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof.
  • rasagiline is in the form of its mesylate salt.
  • rasagiline wherever it appears includes rasagiline in the form of the free base, in the form of a pharmaceutically acceptable salt thereof, or any isomer, derivative, hydrate, solvate, or prodrug thereof.
  • the particle size distribution of a material can be described in terms of Di 0 , D 5 O, D 90 , and D[4,3], used routinely to describe the particle sizes or size distributions. It is expressed as a volume, weight or surface percentage.
  • D x values are the sizes of particles for which x volume or weight percentage of the particles have sizes less than the value given.
  • D[4,3] is the volume mean diameter of the particles.
  • D 90 for example, means that 90% of the particles are below the specified particle size.
  • Particle sizes or particle size distributions of the pharmaceutical formulations of rasagiline of the present invention can be determined using any techniques that are known to the person skilled in the art, including but not limited to microscopy, sieve analysis, size analysis by laser light diffraction, such as using a Malvern particle size analyzer (Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom), use of a Coulter counter, and the like.
  • mean particle size refers to the distribution of particles wherein about 50 volume percent of all particles measured have particle sizes less than the defined mean particle size value, and about 50 volume percent of all measurable particles measured have particle sizes greater than the defined mean particle size value; this can be identified by the term “D 50 .”
  • D90 a particle size distribution where 90 volume percent of the particles have sizes less than a specified size
  • D 10 a distribution where 10 volume percent of particles have sizes less than a specified size
  • the formulations comprise rasagiline mesylate having particle size distributions such that D 90 is less than about 1000 ⁇ m.
  • the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D 90 is in the range of from about 0.1 ⁇ m to about 1000 ⁇ m, or about 1 ⁇ m to about 500 ⁇ m, or from about 10 ⁇ m to about 250 ⁇ m, or from about 100 ⁇ m to about 150 ⁇ m.
  • the formulations of the present invention comprise rasagiline mesylate having particle size distributions where about 90% of the particles are smaller than about 6 ⁇ m.
  • the formulations of the present invention comprise rasagiline mesylate having particle size distributions where about 90% of the particles are larger than about 200 ⁇ m, or larger than about 250 ⁇ m.
  • the formulations of the present invention comprise rasagiline mesylate having particle surface areas of about 0.01 to about 100 m 2 /g.
  • the formulations comprise rasagiline mesylate having particle size distributions where D 50 is less than about 800 ⁇ m, or less than about 500 ⁇ m.
  • the formulations comprise rasagiline mesylate having particle size distributions where D 1 0 is less than about 400 ⁇ m, or less than about 200 ⁇ m. In embodiments, the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D 90 Of rasagiline mesylate is smaller than about 250 ⁇ m, said particles being obtained without using any process for alteration of particle size.
  • the formulations of the present invention comprise rasagiline mesylate having particle size distributions where D 90 is in the range of from about 10 ⁇ m to about 250 ⁇ m, or from about 100 ⁇ m to about 150 ⁇ m, wherein the rasagiline mesylate is obtained without using any process for alteration of particle size.
  • the present invention includes stable pharmaceutical formulations comprising rasagiline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention includes stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier.
  • the present invention includes stable formulations comprising rasagiline mesylate and at least one pharmaceutically acceptable carrier, wherein any rasagiline-related impurities, such as degradants formed during processing or storage, are not present at more than about 5% by weight of the label rasagiline content.
  • formulations of the present invention include rasagiline or its pharmaceutically acceptable salt, present in crystalline form.
  • the formulations of the present invention include rasagiline or its pharmaceutically acceptable salt, which is substantially free from the amorphous form.
  • substantially free of amorphous form means not more than about 5%, or not more than about 10%, by weight of the amorphous form of the rasagiline is present.
  • content uniformity of the compositions is achieved by using appropriate particle sizes of the drug particles and making a homogeneous mixture of drug and the excipients. The particle sizes play a role in forming such homogeneous mixtures.
  • the particle sizes of the drug particles should be appropriate to provide a desired uniformity of content to the blends, so as to ensure that an optimum quantity of drug is present in a unit dosage form prepared using the blends.
  • Content uniformity can be determined using test 905 "Uniformity of Dosage Units," in United States Pharmacopeia 29, United States Pharmacopeial Convention, Rockville, Maryland 2005.
  • Useful techniques of altering particle sizes according to the present invention include techniques such as, without limitation thereto, pulverizing, air jet milling (using compressed air or an inert gas), ball milling, homogenization using, for example, a high speed homogenizer, a high pressure homogenizer, an EmulsiFlexTM homogenizer (Avestin Inc., Ottawa, Canada), etc., colloid milling, microfluidizing, bead milling, and the like.
  • the particle sizes of rasagiline mesylate are adequate to maintain acceptable content uniformity of the blend that is used to make the pharmaceutical formulations of the present invention.
  • the particle sizes of rasagiline mesylate are adequate to maintain content uniformity of blends with excipients that are used to make pharmaceutical formulations of the present invention, such particle sizes being obtained inherently in a synthetic process for preparing rasagiline mesylate and without using any techniques to alter the particle sizes.
  • compositions of the present invention have a content uniformity of a lubricated blend ranging from about 90% to about 110% of the theoretical content of rasagiline or a salt thereof, and a relative standard deviation value not more than about 5%, or not more than about 2%.
  • Finished pharmaceutical formulations of the present invention have similar content uniformity and standard deviation values.
  • compositions of the present invention can be made into solid dosage forms such as solid dispersions, tablets, capsules, granules, pellets, beads, particles, mini-tablets, or orally disintegrating tablets, as well as liquid dosage forms such as solutions, suspensions, syrups, and the like.
  • a solid dispersion is a dispersion of one or more active ingredients in an inert carrier or matrix, in a solid state, prepared by melting (fusion), solvent, or melting-solvent methods. Dispersions obtained through the fusion process are often called melts, and those obtained by the solvent method are frequently referred to as coprecipitates or coevaporates.
  • compositions include any one or more of fillers, binders, diluents, disintegrants, glidants, lubricants, antioxidants, pH modifiers, buffering agents, organic acids, basifying agents, complexing agents, plasticizers, sweetners, flavors, colorants, film coating polymers, and the like.
  • Suitable fillers or diluents include, but are not limited to, different varieties and grades of starches like pregelatinized starch and maize starch, sugars such as lactose, sucrose, and trehalose, cellulose derivatives such as microcrystalline celluloses, and the like.
  • Other useful diluents include but are not limited to carmelloses; calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and thbasic calcium phosphate.
  • binders include, but are not limited to, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones, copovidones, powdered acacia, gelatin, guar gum, carbomers (e.g., CarbopolTM products), methylcelluloses, polymethacrylates, and starches.
  • Various useful disintegrants include natural starches such as maize starch and potato starch; directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch and sodium starch glycolate, starch derivatives such as amylase, various grades of crospovidones, croscarmellose sodium, alginic acid and sodium alginate, microcrystalline celluloses, cross-linked polymers, cross-linked starches, and the like.
  • glidants or anti-adherents include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide, and the like, and mixtures thereof.
  • plasticizers that can be used include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, and thethyl citrate.
  • Various lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, zinc stearate, castor oils, and waxes.
  • stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, zinc stearate, castor oils, and waxes.
  • excipients particularly useful in making orally disintegrating dosage forms according to the present invention include sweetners, flavors, colors, and the like.
  • Suitable sweeteners include, but are not limited to, natural sweeteners such as sucrose, dextrose, fructose, and invert sugar, and synthetic sweeteners such as saccharin, aspartame, acesulfame potassium, cyclamates, and the like.
  • Various useful flavoring agents include, but are not limited to, various fruit flavors, mint flavors, and other natural or synthetic flavors.
  • Various useful coloring agents include, but are not limited to, iron oxides, which can be red, yellow, black, or blends thereof, as well as other synthetic and natural agents that are used in pharmaceutical products.
  • Various film-forming agents that are useful include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses (HPMC or hypromellose, different grades such as HPMC 6 cps, HPMC 15 cps, HPMC 50 cps being available), sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate thmellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc., insoluble cellulose derivatives such as
  • permeability and/or solubility include salt formation, particle size reduction, pH adjustment, use of surfactants, emulsifiers, solubilizers, inclusion complexes with cyclodextrins, use of oily formulations, use of self-emulsifying drug delivery systems, formation of co- precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients, to name a few.
  • surfactants improve the wettability of the active agent.
  • various useful surfactants include, but are not limited to, sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycehdes available commercially such as GELUCIRE ® 40/14, GELUCIRE ® 42/12, and GELUCIRE ® 50/13, vitamin E TGPS, TWEEN ® surfactants, SPAN ® surfactants, and mixtures thereof.
  • Emulsifying agents can include any of a wide variety of cationic, anionic, zwittehonic, and amphoteric surfactants, many of which are known in the art.
  • anionic emulsifying agents include the alkoyl isothionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and alkali metal salts including sodium or potassium salts of long chain fatty acids.
  • amphoteric and zwitterionic emulsifying agents include, but are not limited to, carboxy, sulfonate, sulfate, phosphate, or phosphonate compounds.
  • examples are alkylimino acetates and iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives betaines, sultaines, hydroxysultaines, alkyl sarcosinates and alkanoyl sarcosinates, and the like.
  • emulsifying agents examples include disodium cocoampho diacetate, oxyethylenated glyceryl cocoate (7 EO), PEG-20 hexadecenyl succinate, PEG-15 stearyl ether, the ricinoleic monoethanolamide monosulfosuccinate salts, oxyethylenated hydrogenated ricinoleic triglyceride, poloxamers, non-solid fatty substances such as sesame oil, almond oil, apricot stone oil, sunflower oil, octoxyglyceryl palmitate (or 2-ethylhexyl glyceryl ether palmitate), octoxyglyceryl behenate (or 2-ethylhexyl glyceryl ether behenate), dioctyl adipate, tartrates of branched dialcohols, and the like.
  • Other useful non- ionic emulsifying agents include alkylene oxide esters of
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from a sugar alcohol.
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from a pentahydric or hexahydhc sugar alcohol.
  • stable pharmaceutical formulations of the present invention comprise rasagiline mesylate and at least one pharmaceutically acceptable excipient, free from mannitol, xylitol, and sorbitol.
  • Free from means that the ingredient is not intentionally added as a major ingredient during preparation of a composition; the composition can contain trace amounts of the ingredient, such as less than about 2%, or 1 %, or 0.5%, by weight. “Substantially free from” is similar, but with an upper concentration limit of about 5% by weight.
  • the present invention provides processes for preparing pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt.
  • the pharmaceutical formulations may be prepared using any of process operations such as wet granulation, dry granulation, spray granulation, direct compression, spheronization, and the like.
  • compositions of the present invention can be subjected to in vitro dissolution evaluations as described in Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Rockville, Maryland, 2005 (“USP”), to determine the release of drug from the dosage forms, and drug content can conveniently be determined in solutions using techniques such as high performance liquid chromatography.
  • in vitro dissolution studies can be carried out using USP type Il apparatus and 500 ml_ of 0.1 N hydrochloric acid, pH 4.5 acetate buffer, or pH 6.8 phosphate buffer, as a dissolution medium, with a 50 rpm stirring speed.
  • pharmaceutical formulations of the present invention provide in vitro dissolution profiles of rasagiline wherein more than about 20%, or more than about 50%, or more than about 90%, of the contained drug is dissolved within about 15 minutes after immersion of a dosage form into an aqueous medium.
  • tablets prepared according to the invention and containing rasagiline mesylate equivalent to 1 mg of rasagiline provide comparable bioavailability to that of AZILECT ® 1 mg tablets, after oral administration of single doses to healthy humans. Comparable bioavailability is shown by pharmacokinetic parameters for a test product being 80% to 125% of the values for a reference product.
  • administration of a dose containing 1 mg of rasagiline produces maximum fasting state plasma concentrations (C ma ⁇ ) about 5000 to about 8000 pg/mL, and maximum fed state plasma concentrations (C ma ⁇ ) about 2000 to about 5000 pg/mL.
  • administration of a dose containing 1 mg of rasagiline produces areas under the fasting state plasma concentration vs. time curve (AUCo-t) about 3000 to about 7000 pg hour/mL, and areas under the fed state plasma concentration vs. time curve (AUCo-t) about 2000 to about 5000 pg-hour/mL
  • the present invention provides methods of using pharmaceutical formulations of rasagiline or its salt for the management of diseases or disorders, comprising administering a formulation containing an effective amount of the active agent.
  • the formulations of the present invention are useful for prophylaxis, amelioration, or treatment of a disease state in a subject in need thereof.
  • the present invention also provides methods of treating Parkinson's disease using pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt, comprising administering to a subject in need thereof a required quantity of rasagiline or a pharmaceutically acceptable salt thereof.
  • the present invention also provides methods of treatment of Parkinson's disease, using pharmaceutical formulations of rasagiline mesylate, which comprise administering to a subject in need thereof a required quantity of rasagiline mesylate.
  • the present invention also provides methods of treatment of Parkinson's disease using the pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salts, wherein a pharmaceutical formulation can be used as a monotherapy.
  • the present invention also provides methods of treatment of Parkinson's disease using the pharmaceutical formulations of rasagiline or its pharmaceutically acceptable salt, wherein a pharmaceutical formulation can be used as as adjuvant therapy together with levodopa.
  • the present invention includes the use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc. which are useful in packing the pharmaceutical formulations of the present invention.
  • packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc. which are useful in packing the pharmaceutical formulations of the present invention.
  • packaging materials are only representative, as many other materials will be suitable.
  • step 3 Granulate the mixture of step 1 by spraying the solution of step 2 in the fluidized bed processor, then dry the granules.
  • step 4 Sift the dried granules of step 3 through a #40 mesh sieve.
  • step 6 Blend the granules of step 4 with the mixture of step 5.
  • step 6 Blend the mixture of step 6 with stearic acid of step 7.
  • EXAMPLE 2 Pharmaceutical formulation of rasagiline.
  • Manufacturing process 1 . Sift powder blend colloidal silicon dioxide and dicalcium phosphate through a #40 mesh sieve and mix.
  • step 5 Granulate the mixture of step 3 using binder of step 4 and dry the granules.
  • step 6 Blend the granules of step 6 with the mixture of step 7.
  • step 4 Compress the blend of step 4 into tablets.
  • step 4 Dry the granules of step 3 at about 50 0 C until the loss on drying obtained is less than 3%.
  • step 4 Sift the dried granules of step 4 through a #30 mesh sieve.
  • MicroceLac 100 is a commercially available spray-dried composition containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose. t Evaporates during processing. Manufacturing process:
  • step 3 Granulate the blend of step 2 by spraying the solution of step 1 , and dry the granules.
  • step 4 Sift the dried granules of step 3 through a #24 mesh sieve.
  • Opadry White includes hypromellose, titanium dioxide and polyethylene glycol.
  • step 3 Sift the blend of step 2 through a #20 mesh sieve and mix in a blender.
  • step 4 Compress the blend of step 4 into tablets.
  • step 6 Coat the tablets of step 5 with a dispersion of Opadry White in water, and dry.
  • EXAMPLE 7 Pharmaceutical formulations of rasagiline.
  • step 3 Sift the blend of step 2 through a #20 mesh sieve.
  • EXAMPLE 8 Pharmaceutical formulations of rasagiline.
  • step 3 Granulate the mixture of step 1 by spraying with the solution of 2 in the fluidized bed processor, and dry the granules.
  • samples are withdrawn from a double cone blender (after blending of granules with extra-granular excipients), from a stainless steel vessel (used for containing the blend immediately before tablet compression), and from the compressed 8A tablets.
  • the content uniformity is compared with that of commercial AZILECT tablets.
  • the content uniformity data are shown below, where the drug assay is expressed as a percentage of the label rasagiline content.
  • Samples of the 8A formulation are packaged in closed HDPE containers and stored at the accelerated stability testing conditions of 40 0 C and 75% RH.
  • the impurity content is analyzed by HPLC at intervals and results are shown below, where values are percentages of the label rasagiline content.
  • Tablets prepared in 8A are subjected to dissolution testing, using the USP procedure and the following dissolution conditions:
  • a randomized, two-way crossover, open-label, single-dose, fasting state and fed state clinical study involves administration of single doses of the product 8A ("T”) and the commercial product AZILECT 1 mg tablets ("R”) to 18 healthy human volunteers, and plasma rasagiline concentrations are determined at intervals after dosing.
  • AUCo- t the area under plasma concentration versus time curve, from the time of administration to the last measurable concentration, expressed in pg-hour/mL units.
  • Cmax maximum plasma concentration following administration, expressed in pg/mL units.

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Abstract

La présente invention concerne des préparations pharmaceutiques comprenant de la rasagiline ou des sels pharmaceutiquement acceptables de celle-ci. Certains aspects de la présente invention concernent des préparations fabriquées en utilisant de la rasagiline ou un sel ayant une répartition de la taille des particules selon laquelle environ 90 % des particules ont une taille inférieure à 1 000 μm, et ayant une uniformité de teneur telle que la préparation contient entre 90 % et 110 % de la teneur de l'étiquette en rasagiline ou en ses sels. Selon d'autres aspects, la présente invention concerne des préparations pharmaceutiquement stables comprenant de la rasagiline ou un sel pharmaceutiquement acceptable et au moins un excipient pharmaceutiquement acceptable, les formulations étant sensiblement dépourvues de polyol.
PCT/US2010/028314 2009-03-24 2010-03-23 Préparations de rasagiline WO2010111264A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN658CH2009 2009-03-24
IN658/CHE/2009 2009-03-24
US18651809P 2009-06-12 2009-06-12
US61/186,518 2009-06-12

Publications (2)

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WO2010111264A2 true WO2010111264A2 (fr) 2010-09-30
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Cited By (9)

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WO2011010324A1 (fr) * 2009-07-23 2011-01-27 Alkem Laboratories Ltd. Compositions pharmaceutiques orales stables comprenant de la rasagiline et procédé
EP2389927A1 (fr) * 2010-05-30 2011-11-30 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Formulations pharmaceutiques de rasagiline
WO2012153349A2 (fr) 2011-05-04 2012-11-15 Cadila Healthcare Limited Rasagiline et ses sels pharmaceutiquement acceptables
WO2013107441A1 (fr) * 2012-01-18 2013-07-25 Stada Arzneimittel Ag Procédé permettant de préparer une composition pharmaceutique solide contenant le principe actif rasagiline
WO2013175493A1 (fr) 2012-04-09 2013-11-28 Cadila Healthcare Limited Compositions pharmaceutiques orales stables
WO2014192022A1 (fr) * 2013-05-20 2014-12-04 Cadila Healthcare Limited Compositions pharmaceutiques de rasagiline
WO2016151466A1 (fr) * 2015-03-26 2016-09-29 Unichem Laboratories Limited Procédé de préparation de sel de potassium d'azilsartan médoxomil
WO2017168244A1 (fr) * 2016-03-26 2017-10-05 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques pour un dérivé de n-propargylamine
WO2022083063A1 (fr) 2020-10-23 2022-04-28 上海上药中西制药有限公司 Dose pour film sublingual de rasagiline ou d'un sel pharmaceutiquement acceptable associé et son procédé de préparation et utilisation associée

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WO2006014973A2 (fr) * 2004-07-26 2006-02-09 Teva Pharmaceutical Industries, Ltd. Dosages pharmaceutiques contenant de la rasagiline
EP1827409B1 (fr) * 2004-11-24 2011-08-24 Teva Pharmaceutical Industries, Ltd. Compositions de rasagiline delitantes oralement
CA2600011C (fr) * 2005-02-23 2015-11-10 Teva Pharmaceutical Industries Ltd. Preparations de rasagiline presentant une uniformite de teneur amelioree

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011010324A1 (fr) * 2009-07-23 2011-01-27 Alkem Laboratories Ltd. Compositions pharmaceutiques orales stables comprenant de la rasagiline et procédé
EP2389927A1 (fr) * 2010-05-30 2011-11-30 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Formulations pharmaceutiques de rasagiline
WO2012004691A3 (fr) * 2010-05-30 2012-04-12 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations pharmaceutiques de rasagiline
WO2012153349A2 (fr) 2011-05-04 2012-11-15 Cadila Healthcare Limited Rasagiline et ses sels pharmaceutiquement acceptables
WO2013107441A1 (fr) * 2012-01-18 2013-07-25 Stada Arzneimittel Ag Procédé permettant de préparer une composition pharmaceutique solide contenant le principe actif rasagiline
WO2013175493A1 (fr) 2012-04-09 2013-11-28 Cadila Healthcare Limited Compositions pharmaceutiques orales stables
WO2014192022A1 (fr) * 2013-05-20 2014-12-04 Cadila Healthcare Limited Compositions pharmaceutiques de rasagiline
WO2016151466A1 (fr) * 2015-03-26 2016-09-29 Unichem Laboratories Limited Procédé de préparation de sel de potassium d'azilsartan médoxomil
US9902717B2 (en) 2015-03-26 2018-02-27 Unichem Laboratories Limited Process of preparing potassium salt of Azilsartan medoxomil
WO2017168244A1 (fr) * 2016-03-26 2017-10-05 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques pour un dérivé de n-propargylamine
US10292947B2 (en) 2016-03-26 2019-05-21 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for N-propargylamine derivative
WO2022083063A1 (fr) 2020-10-23 2022-04-28 上海上药中西制药有限公司 Dose pour film sublingual de rasagiline ou d'un sel pharmaceutiquement acceptable associé et son procédé de préparation et utilisation associée
CN114469902A (zh) * 2020-10-23 2022-05-13 上海上药中西制药有限公司 雷沙吉兰或其药用盐舌下膜剂及其制备方法、应用

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