EP2600841A2 - Formulations pharmaceutiques de rasagiline - Google Patents

Formulations pharmaceutiques de rasagiline

Info

Publication number
EP2600841A2
EP2600841A2 EP11729170.8A EP11729170A EP2600841A2 EP 2600841 A2 EP2600841 A2 EP 2600841A2 EP 11729170 A EP11729170 A EP 11729170A EP 2600841 A2 EP2600841 A2 EP 2600841A2
Authority
EP
European Patent Office
Prior art keywords
rasagiline
pharmaceutical composition
pharmaceutically acceptable
binder
glidant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11729170.8A
Other languages
German (de)
English (en)
Inventor
Farhad Farshi
Recep Avci
Serdar Soylemez
Udaya Dude
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Original Assignee
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
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 Abdi Ibrahim Ilac Sanayi Ve Ticaret AS filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Priority to EP11729170.8A priority Critical patent/EP2600841A2/fr
Publication of EP2600841A2 publication Critical patent/EP2600841A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • This invention is related to dissolving of rasagiline or pharmaceutically acceptable salts thereof in a solvent or mixtures thereof, and treating the drug solution onto pharmaceutical material to provide the content uniformity.
  • a movement disorder is a neurological disturbance that involves one or more muscle or muscle groups. Movement disorder affects a significant portion of population, causing disability as well as stress. Movement disorders include Parkinson's disease, Huntington's chorea, progressive supranuclear palsy, Wilson's disease, Tourrette's syndrome, epilepsy, tardive dyskinesia, and various chronic tremor's, ties and dystonias.
  • Parkinson's disease also known as Parkinson disease or PD
  • Neurodegenerative means the degeneration, or death, of cerebral neurons. It is clinically characterized by resting tremor, rigidity, postrural instability, and bradykinesia. It affects approximately 1 % of the population aged over 60 years worldwide. The incidence of parkinson's disease increase with age and the cumulative lifetime risk of an individual developing the disease is about 1 in 40.
  • Parkinson's disease can be treated by deep brain stimulation, and neurorehabilitation.
  • the medications will most likely be used to increase the amount of dopamine in the brain.
  • Levodopa is the primary treatment for Parkinson's disease; but, its long-term use at high dosages cause motor complications that can be difficult to manage.
  • dopamine agonist aren't preferred for treatment of early stage of Parkinson's disease.
  • dopamine agonists have more side effects and don't control symptoms as well as levodopa.
  • monoamine oxidase type B (MAO-B) inhibitors are used in the early stages of Parkinson's disease to treat very mild symptoms such as resting tremor and delay the need for levodopa. Also, they have minimal side effects when used alone, and better medications are available for this purpose.
  • Rasagiline may be added to levodopa treatment to reduce motor fluctuctions, increase the time of effect of the levodopa and decrease the amount of levodopa needed to control symptoms.
  • Selegiline is the first selective MAO-B inhibitor, has been marketed in United States since June 1989. Nevertheless, selegiline has toxic metabolites such as amphetamine and methamphetamine. Rasagiline is second-generation propargylamine pharmacophere that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease and various other conditions. Pharmacologically, rasagiline was found to be ⁇ 10 -fold more potent than selegiline and was not metabolized to amphetamine derivatives.
  • 3-dihydro-1 H-inden-1 -amine has the molecular formula C12H-13N and relative molecular mass of 171.238 g/mol.
  • Rasagiline hydrochloride was also disclosed in. Afterwards some stability problems were reported for rasagiline hydrochloride. Then the mesylate salt form of rasagiline was disclosed by EP 812190 B (TEVA).
  • Rasagiline mesylate is a highly soluble compound. Water solubility is 0.01 ml, at pH 7.4 and also soluble in ethanol. It is sparingly soluble in isopropanol .Rasagiline is marketed in many countries as its mesylate salt. It is approved under trademark Azilet® by the US Food and Drug
  • compositions comprising rasagiline or pharmaceutically acceptable salt thereof and at least one alcohol selected from a group consists of pentahydric and hexahydric alcohols.
  • PHARMACEUTICAL INDUSTRIES LTD. 31.08.2006 discloses solid pharmaceutical formulation of rasagiline comprising an amount of the mixture of particles of a pharmaceutically acceptable salt of rasagiline, wherein more than 90% of the total amount by volume of rasagiline salt particles have a size of less than 250 microns. According to our invention, content uniformity of dosage form which can be independently ensured from particule size distribution of rasagiline.
  • EHT. 08.10.2009 discloses a process for the preparation of Rasagiline mesylate having a D90 particle size of about 600 microns to about 1500 microns, wherein; a) providing a solution of Rasagiline mesylate in a solvent medium comprising an ester solvent and an alcoholic solvent; b) subjecting the solution of step (a) to gradual cooling to produce a cooled solution; c) optionally, seeding the solution obtained in step (b); and (d) crystallizing Rasagiline mesylate particles having a D90 particle size of about 600 microns to about 1500 microns from the cooled solution. The particles of step (d) were further milled to obtain Rasagiline mesylate having a D90 particle size of about 255 microns to about 1400 microns.
  • composition comprising rasagiline or pharmaceutically acceptable salt of rasagiline, and particles having a non-filamentous microstructure of at least two sugar alcohols such as mannitol, xylitol, sorbitol, maltitol and lactitol.
  • the said composition also comprises a supplemental sugar alcohol, a supplemental flow agent and a supplemental disintegrant.
  • composition includes active pharmaceutical ingredient, is treated onto a pharmaceutical material or mixtures of pharmaceutical materials. This treatment can be adhering, adsorbing , absorbing , coating, mixtures thereof and the like.
  • Pharmaceutical material means any kind of excipients, pellets, granules, active or non-active containing tablet cores or mixture thereof and the like.
  • Treating the drug solution with an excipient or mixtures of excipients are performed by intragranulation or extragranulation phases.
  • Intra-granular ingredient(s) comprising a dry mix containing filler/diluent, disintegrants, binders, glidants, surfactant and optionally stabilizers including suitable buffers or anti-oxidants or a mixture of thereof.
  • Intragranulation can be carried out either by spraying technology in a fluidization processor or in high mixture granulator to knead the mass to form granule.
  • a binder solution can be used for intragranulation.
  • Extragranular excipients may be comprised filler/diluent, disintegrant,
  • binder binder, glidants, lubricants and optionally stabilizers.
  • particle size is important to attain compressibility, proper content uniformity, bioavailability, compactness of the final dosage form.
  • Proper content uniformity and release profiles are major concerns in the process development. Proper blending and prevention of segregation, especially when other techniques are not feasible, are required for a successful processing.
  • active pharmaceutical ingredients' (API) particle size distribution is the most critical point impacting the uniformity of low dose solid dosage forms.
  • API particle size can be reduced to below a certain size.
  • WO 2006/091657 A TEVA PHARMACEUTICAL INDUSTRIES LTD. 31.08.2006 delineates reducing of particle size and less than 250 micron particle size. If API has greater particles, preparing of rasagiline dosage form becomes problematic so as to obtain content uniformity.
  • the purpose is to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet.
  • the formulation comprises an effective amount of rasagiline and/or pharmaceutically acceptable salt or solvate thereof.
  • any reference to the term "rasagiline” is intended to include the pharmaceutically acceptable salts or solvates thereof, and especially rasagiline mesylate.
  • average particle size of Rasagiline mesylate used in formulation can be greater or lower than 250 ⁇ .
  • average particle size refers to the volume mean diameter of particles.
  • the diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern-Mastersizer Apparatus MS 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogenous suspension of particles.
  • formulations can be prepared by
  • Intragranular ingredient(s) can be selected from the group consisting of diluents, binders, disintegrants, fillers, lubricants, glidants, antioxidants, surface active agents, chelating agents, mixtures thereof and the like.
  • Suitable filler/diluent includes, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose lactose (e.g. spray-dried lactose, a-lactose, ⁇ -lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®),
  • methylcellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®), hydroxyethylcellulose,
  • hydroxypropylcellulose L-hydroxypropylycellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol.
  • HPMC hydroxypropylcellulose
  • HPMC hydroxypropyl methyl
  • a binder is used to impart cohesive qualities to the solid dosage form and thus ensure that a tablet remains intact after compression.
  • binders include, but not limited to, microcrystalline cellulose,
  • hydroxymethyl cellulose hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum),and synthetic polymers such as polymetacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, polyethylene oxide, mixtures thereof and the like.
  • starch including corn starch and pregelatinized starch
  • gelatin sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum)
  • synthetic polymers such as polymetacrylates and
  • a disintegrant is a substance which helps the composition break up once ingested .Disintegrants are, but not limited to, cross linked
  • polyvinylpyrolidone crospovidone, polyplyplasdone XL®, kollidon CL®
  • starches such as maize starch and dried sodium starch glycolate
  • gums such as maize starch and dried sodium starch glycolate
  • gums such as alginic acid, sodium alginate, guar gum
  • croscarmellose sodium cellulose products
  • microcrystalline cellulose and its salts microfine cellulose, low-substituted hydroxypropylcellulose, mixtures thereof and the like.
  • An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Suitable antioxidants are, but not limited to, ascorbic acid, sodium metabisulphite, butylated hydroxy anisole, butylated hydroxytoluene, sodium ascorbate, propyl gallate, alpha tocopherol, mixtures thereof and the like.
  • the solid pharmaceutical compositions of the present invention can further comprise extragranular ingredient(s).
  • Extragranular ingredient(s) can be selected from filler/diluent, disintegrant, binder, glidants and lubricants. More preferably extragranular excipients are lubricant and glidant.
  • the presence of a lubricant is particularly preferred when the composition is a tablet as lubricants to improve the tabletting process. Lubricants prevent composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improve flowability of the composition mixture.
  • Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.
  • Glidants improve the flowability of the composition.
  • the composition may also comprise a glidant.
  • Glidants are, but not limited to, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof and the like.
  • each type of additive employed e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges
  • Suitable pharmaceutical compositions include, but are not limited to,
  • oral pharmaceutical formulation is tablet.
  • the tablet can be coated or non-coated.
  • Solution may include an aqueous solvent or a non-aqueous solvent of mixture thereof or the like.
  • compositions can be prepared by using the process
  • a process for preparing content uniformity of solid pharmaceutical composition comprising intra-granular ingredient(s), extra-granular ingredient(s) and comprise the steps of:
  • step (a) 1. dissolving Rasagiline in a solvent to form drug solution, 2. Loading particles of the intra-granular ingredients into granulator and treating the drug solution of step (a) with particles of the intra-granular ingredients either by spraying technology in a fluidization processor or in high shear granulator.
  • step (b) 3. kneading the mass of step (b) to form granules and optionally granulate with a suitable pharmaceutically binder solution,
  • step (c) Drying the granular mass of step (c) in fluidized bed dryer until proper moisture then sizing the dried granules by using suitable milling equipment.
  • step (d) 1. mixing extra-granular excipient(s)with the granules of step (d) and blending to form final blend,
  • pharmaceutically acceptable solvent selected from the group consisting of water, ethanol or Isopropyl alcohol or mixtures thereof and the like.
  • Solution may include other pharmaceutical material(s).
  • solvents used for granulation process may be selected from water, isopropyl alcohol, acetone, ethanol, methylene chloride or combination thereof.
  • Intragranulation comprising active ingredient is from about 0.1 % to about 5%, filler/diluents is from about 30% to about 90% by the weight of composition, disintegrant is from about 3% to about 50% by weight of the composition, and binder is from about 3% to about 50% by weight of intragranular phase's ingredients.
  • intragranulation comprising rasagiline mesylate is %0.78, filler/diluent is 79.30%, disintegrant is 9.96%, binder is 9.96% by total weight of intragranulation phase's ingredients. (Table 1 ).
  • Extragranulation comprising glidant is from about 10% to about 90%, lubricant is from about 10% to about 90%by total weight of extragranular phase's excipients.
  • extragranulation comprising glidant is 56.52%
  • lubricant is 43.48 % by total weight of extragranulation step's excipients (Table-2).
  • composition comprising intragranular and extragranular steps wherein intragranular total is from%15 to %99 , extragranular total is from%3 to % 85 by the weight of total composition.
  • intragranular total is 95.62%
  • extragranular total is 4.38 % by weight of pharmaceutical composition.
  • composition comprising rasagiline or
  • pharmaceutically acceptable salt thereof is from about 0.1 % to about 5%
  • filler/diluent is from about 30% to about 90%
  • disintegrant is from about 3 % to about 20%
  • binder is from about 3 % to about 20%
  • glidant is from about 0.1 % to about 10%
  • lubricant is from about 0.1 % to about 10 by weight of pharmaceutical composition.
  • composition preferably comprising rasagiline or pharmaceutically acceptable salt thereof is 0.74%
  • filler/diluent is 75.83 %
  • disintegrant is 9.53 %
  • binder is 9.53 %
  • glidant is 2.47%
  • lubricant is 1.90 % by weight of pharmaceutical composition (Table-4).
  • the purpose of this invention is to minimize the
  • a suitable dissolution method is used to reach dissolution profiles.
  • USP Type-2 apparatus is preferred and used.
  • the tablets prepared in accordance with the present invention should exhibit the following dissolution profile when tested in a USP Type 2 apparatus, at 50 rpm, and 37° C and in 0.1 N HCI medium.
  • the similarity factor ⁇ 2 is a measurement of the similarity through a point by point comparison as shown in equation 1.
  • n is the number of sampling time points
  • Rt is the amount drug released from a reference batch at time t
  • Tt is the amount drug released from a test batch at time t.
  • f2 values greater than 50 ensure sameness of the performance of the reference product and test product.
  • test product and the reference product's results show that the f2 is in the limits of 50- 100 as established by the US FDA for claiming similarity between the dissolution profiles of the test and reference product.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne la dissolution de la rasagiline dans un solvant ou des mélanges de solvants, et le traitement de la solution du médicament sur un matériau pharmaceutique pour obtenir une teneur uniforme.
EP11729170.8A 2010-05-30 2011-05-26 Formulations pharmaceutiques de rasagiline Withdrawn EP2600841A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11729170.8A EP2600841A2 (fr) 2010-05-30 2011-05-26 Formulations pharmaceutiques de rasagiline

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10164418A EP2389927A1 (fr) 2010-05-30 2010-05-30 Formulations pharmaceutiques de rasagiline
EP11729170.8A EP2600841A2 (fr) 2010-05-30 2011-05-26 Formulations pharmaceutiques de rasagiline
PCT/IB2011/052289 WO2012004691A2 (fr) 2010-05-30 2011-05-26 Formulations pharmaceutiques de rasagiline

Publications (1)

Publication Number Publication Date
EP2600841A2 true EP2600841A2 (fr) 2013-06-12

Family

ID=43127223

Family Applications (2)

Application Number Title Priority Date Filing Date
EP10164418A Withdrawn EP2389927A1 (fr) 2010-05-30 2010-05-30 Formulations pharmaceutiques de rasagiline
EP11729170.8A Withdrawn EP2600841A2 (fr) 2010-05-30 2011-05-26 Formulations pharmaceutiques de rasagiline

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP10164418A Withdrawn EP2389927A1 (fr) 2010-05-30 2010-05-30 Formulations pharmaceutiques de rasagiline

Country Status (2)

Country Link
EP (2) EP2389927A1 (fr)
WO (1) WO2012004691A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013175493A1 (fr) * 2012-04-09 2013-11-28 Cadila Healthcare Limited Compositions pharmaceutiques orales stables
IN2013MU01782A (fr) * 2013-05-20 2015-06-26 Cadila Healthcare Ltd
EP3024442B1 (fr) * 2013-07-22 2019-01-16 Sandoz AG Compositions comprenant dapagliflozin amorphe
CN105496979B (zh) * 2015-12-08 2018-06-05 重庆华森制药股份有限公司 一种雷沙吉兰片剂
CN107753446B (zh) * 2017-03-07 2021-02-19 常州市第四制药厂有限公司 一种雷沙吉兰片剂及其制备方法

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WO2006014973A2 (fr) * 2004-07-26 2006-02-09 Teva Pharmaceutical Industries, Ltd. Dosages pharmaceutiques contenant de la rasagiline
WO2006057912A2 (fr) * 2004-11-24 2006-06-01 Teva Pharmaceutical Industries, Ltd. Compositions de rasagiline delitantes oralement

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IL92952A (en) 1990-01-03 1994-06-24 Teva Pharma R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them
IL111240A (en) 1993-10-18 2001-10-31 Teva Pharma Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them
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BRPI0608209A2 (pt) 2005-02-23 2010-11-09 Teva Pharma mistura de partìculas, composição sólida, método para tratamento de um paciente com mal de parkinson, processo para preparação de uma composição, e, composição farmacêutica sólida
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WO2006014973A2 (fr) * 2004-07-26 2006-02-09 Teva Pharmaceutical Industries, Ltd. Dosages pharmaceutiques contenant de la rasagiline
WO2006057912A2 (fr) * 2004-11-24 2006-06-01 Teva Pharmaceutical Industries, Ltd. Compositions de rasagiline delitantes oralement

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Also Published As

Publication number Publication date
EP2389927A1 (fr) 2011-11-30
WO2012004691A3 (fr) 2012-04-12
WO2012004691A2 (fr) 2012-01-12

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