WO2013182625A1 - Formulation pharmaceutique avec un composé de propargylamine - Google Patents

Formulation pharmaceutique avec un composé de propargylamine Download PDF

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Publication number
WO2013182625A1
WO2013182625A1 PCT/EP2013/061646 EP2013061646W WO2013182625A1 WO 2013182625 A1 WO2013182625 A1 WO 2013182625A1 EP 2013061646 W EP2013061646 W EP 2013061646W WO 2013182625 A1 WO2013182625 A1 WO 2013182625A1
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WO
WIPO (PCT)
Prior art keywords
salt
rasagiline
formulation
calcium sulphate
tablet formulation
Prior art date
Application number
PCT/EP2013/061646
Other languages
English (en)
Inventor
Torfi Kristjansson
Original Assignee
Actavis Group Ptc Ehf
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 Actavis Group Ptc Ehf filed Critical Actavis Group Ptc Ehf
Publication of WO2013182625A1 publication Critical patent/WO2013182625A1/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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof

Definitions

  • the present invention relates to pharmaceutical compositions for solid dosage forms with propargylamine monoamine oxidase inhibitors, in particular rasagiline.
  • Rasagiline is an irreversible inhibitor of monoamine oxidase (MAO), which is used for treating symptoms of Parkinson's disease, alone or as adjunct therapy with other active agents. It is selective for MAO type B over type A and hence referred to as MAO-B inhibitor.
  • MAO-B inhibitor The chemical designation is (/?)-/V-(prop-2-ynyl)-2,3-dihydro-lr inden-l-amine (Formula I).
  • Other propargylamine type MAO-B inhibitors include ladostigil (Formula II).
  • Rasagiline was developed by Teva Neuroscience and has been marketed under the trade name Azilect, which is a once-daily tablet dosage form with doses of 0.5 or 1 mg.
  • the Azilect product contains rasagiline in the form of mesylate salt.
  • the commercially available rasagiline formulation further comprises inactive ingredients mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.
  • US 6126968 discloses a composition in tablet form comprising rasagiline or its pharmaceutically acceptable salt as active ingredient and at least one alcohol selected from group of pentahydric or hexahydric alcohols like mannitol, xylitol and sorbitol.
  • EP 814789 discloses formulations of MAO-B inhibitors which attempt to address some of the known problems. However, it carries out lyophilization of the MAO-B inhibitor formulations which introduces practical problems and results in high friability of the product.
  • EP 858328 discloses formulations with rasagiline and at least one alcohol which is a pentahydric or hexahydric alcohol, such as in particular mannitol.
  • US20080107729 & US20090111892 disclose solid pharmaceutical composition comprising rasagiline or its acceptable salt of rasagiline, and particles having a non- filamentous microstructure of at least two sugar alcohols.
  • WO 2011010324 attempts to provide formulations of rasagiline without pentahydric or hexahydric alcohols, using instead a carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or a mixture thereof, specifically proposing maltitol, sucrose, maltose or polydextrose.
  • a carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or a mixture thereof, specifically proposing maltitol, sucrose, maltose or polydextrose.
  • Discloses examples use maltitol, micro- crystalline cellulose or mixture of maltitol and microcrystalline cellulose, microcrystal- line cellulose and corn starch, with rasagiline mesylate.
  • WO 9511016 disclose the sulphate salt, phosphate salt, mesylate salt, maleate salt, esylate salt, acetate salt, fumarate salt, hy- drobromide salt, tosylate salt and benzoate salt. Yet further salts are disclosed in WO 2008019871 and WO 2008076315.
  • WO 2011003938 addresses problems of content uniformity by proposing a liquid salt of rasagiline, such as salts of small fatty acids, e.g.
  • WO 2009089049, WO 2006091836 and EP 2218444 disclose tablets of rasagiline mesylate, ladostigil tartrate and rasagiline citrate, respectively, which may comprise calcium sulphate as excipient. No amounts are provided for the excipient. Further, it is not disclosed that calcium sulphate could have a stabilizing effect. A tablet comprising rasagiline tartrate with calcium sulphate as excipient is also not disclosed.
  • Eyjolfsson, R, 'Calcium sulphate dihydrate: an useful excipient for tablets containing labile actives disclose the use of calcium sulphate to stabilize angiotensin-converting enzyme inhibitors called prils such as ramipril and quinapril. Such prils differ significantly from the propargylamine MAO-B compounds as referred to herein in their chemical structure and their action mechanism.
  • the inventors have surprisingly found that very stable homogeneous formulations of propargylamine MAO-B compounds such as rasagiline are obtained by using calcium sulphate as major excipient, which is preferably calcium sulphate dihydrate. Stability tests show excellent results.
  • the active ingredient can be in the form of a suitable pharmaceutically acceptable salt, such as the tartrate or mesylate salt. Particularly stable formulations are obtained when admixing citric acid or another weak acid in the formulation.
  • the invention provides in a first aspect a pharmaceutical formulation, suitable for tableting or in the form of tablets, comprising as an active ingredient a propargylamine monoamine oxidase inhibitor compound and calcium sulphate as excipient.
  • An active ingredient is a substance in a pharmaceutical drug that is biologically active, i.e. that has an effect on living matter.
  • the propargylamine monoamine oxidase inhibitor compound is preferably ( ?)-/ ⁇ A(prop-2-ynyl)-2,3-dihydro-l inden-l-amine, which can optionally be substituted at the benzene ring portion of the inden group.
  • Preferred compounds in the composition of the invention include rasagiline, ladostigil and pharmaceutically acceptable salt thereof.
  • Salts of the active compound in accordance with the present invention include tartrate salt, mesylate salt, succinate salt, maleate salt, esylate salt, acetate salt, sulphate salt, phosphate salt, hydrobromide salt, hydrochloride salt, tosylate salt, benzoate salt, hexanoate salt, octanoate salt, gluconate salt, aspartate salt, and citrate salt.
  • Useful salts of the active compound rasagiline according to the invention include but are not limited to highly soluble salts such as besylate, mesylate, succinate and tartrate salt of rasagiline.
  • tartrate salt of rasagiline provides surprisingly good stability, can accommodate a broad spectrum of excipients, and compares favourably with other salts such as e.g. the mesylate salt, which is used in the presently available commercial formulation.
  • the formulations of the invention comprise calcium sulphate as excipient, preferably at least about 50 wt%, such as in the range from about 50% to about 95 wt%, including the range from about 50-90 wt%, and more preferably in the range from about 55-85 wt%, such as in the range from about 60% to about 85 wt%, or in the range from about 65 wt% to about 80 wt%, including about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, or about 80 wt%.
  • the formulations comprise calcium sulphate in at least 50 wt%, such as in the range from 50% to 95 wt%, including the range from 50-90 wt%, and more preferably in the range from 55-85 wt%, such as in the range from 60% to 85 wt%, or in the range from 65 wt% to 80 wt%, including 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%.
  • the calcium sulphate can be in any pharmaceutically acceptable form, including hemihydrate form, including both alpha-hemihydrate form and beta-hemihydrate form, and dihydrate, which is the preferred form.
  • Calcium sulphate has many advantages as excipient, it has no caloric content, and has no laxative properties as sugar alcohols.
  • a suitable weak acid is added as non-active ingredient to the formulation in order to maintain an acidic environment in the formulation, which is beneficial for the com- pound salt.
  • a weak acid is preferably an acid with a pKa value of above 0, more preferably above 2.
  • Such added weak acid can in some embodiments be selected from citric acid, tartaric acid, acetic acid, aspartic acid and maleic acid. Citric acid is preferred.
  • the weak acid can be added in a suitable concentration in order to maintain a desired low pH, for citric acid a suitable range is from about 0.5% to about 3% by weight or from 0.5% to 3% by weight, such as in the range 0.5-2.5%, such as but not limited to 0.5%, 1.0%, 1.5% or 2.5% citric acid, or an equivalent amount of another weak acid that results in similar pH of the formulation.
  • the particle size, (DO.9 by volume) of the active ingredient which can be rasagiline (e.g. rasagiline mesylate, tartrate or other salt) or another propargyl amine MOA inhibitor compound as described herein is over 250 ⁇ , meaning that 10% by volume of the particles have a particle size of more than 250 pm (i.e. more than 10% by volume of the particles have a size larger than 250 pm), and in some embodiments 20% or more by volume of the particles have a particle size of more than 250 pm, or even 25% or more of the particles have a particle size of more than 250 pm.
  • rasagiline e.g. rasagiline mesylate, tartrate or other salt
  • another propargyl amine MOA inhibitor compound as described herein is over 250 ⁇ , meaning that 10% by volume of the particles have a particle size of more than 250 pm (i.e. more than 10% by volume of the particles have a size larger than 250 pm), and in some embodiments 20% or more by volume of the particles have a particle size of
  • the DO.9 (by volume) is 260 pm or more, such as 270 pm or more, such as 280 pm or 300 pm.
  • the upper limit of the particle size is typically 500 pm (D0.9).
  • Particle size can be measured using variety of techniques, however preferably the particle size is determined by laser diffraction technique. More preferably the laser diffraction technique is measured using Malvern Mastersizer (Malvern Instruments Ltd, Malvern, UK) equipment or equivalent.
  • the dispersion solvent is preferably hex- ane and the sample is optionally sonicated for up to 20 seconds.
  • the invention is not limited to particular crystal forms of the propargylamine monoamine oxidase inhibitor compound or salt thereof. Any suitable crystal forms may be used in accordance with the invention.
  • Any suitable crystal forms may be used in accordance with the invention.
  • acid addition salts of rasagiline such as rasagiline tartrate
  • several useful crystal forms exist.
  • the crystal form used in the formulation of the invention is the hemi pentahydrate form of rasagiline tartrate. This form and others have been described in WO 201007181.
  • the pharmaceutical formulations as defined herein are suitable for use in the treatment of Parkinson's disease.
  • the dosage form of the pharmaceutical tablets disclosed herein is typically a conventional tablet.
  • Conventional tablets, coated or uncoated are intended to be swallowed as a whole and are immediate release tablets. Immediate release tablets allow the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.
  • An uncoated conventional tablet as defined herein is typically a tablet which disintegrates within 5, more typically within 4, and even more typically within 3 minutes at 15 to 25 °C, typically at 20 to 25 °C, in water.
  • a coated conventional tablet as defined herein is typically a tablet which also disintegrates within 5, more typically within 4, and even more typically within 3 minutes at 15 to 25 °C, typically at 20 to 25 °C, in water.
  • a coated conventional tablet as defined herein may also be a tablet which disintegrates within 5, more typically within 4, and even more typically within 3 minutes at 15 to 25 °C, typically at 20 to 25 °C, in 0.1 M hydrochloric acid.
  • the invention further provides a process for the preparation for a pharmaceutical formulation as defined herein.
  • this process comprises
  • step c) granulating said mixture by spraying after step c), preferably in a high shear mixer.
  • this process comprises
  • step c) granulating said mixture by spraying after step c), preferably in a high shear mixer.
  • Step a) as defined herein is a step to mix the ingredients.
  • the mixture is further mixed after step b), therewith relating to a merging step to merge the material obtained after step b).
  • Example 1 Formulation A: 1 mg* tablets with rasagiline tartrate
  • Ingredients 1-5 added in listed order to mixer bowl, mixed, sieved and mixed again. The blend is wetted with ingredient 6 until granules have formed. The granules are dried and screened. Ingredients 7-9 are added to the granules, mixed, and the blend is ready for compression.
  • Example 2 Formulation B: 1 mg* tablets with rasagiline tartrate
  • Ingredients 1-6 added in listed order to mixer bowl, mixed, sieved and mixed again. The blend is wetted with ingredient 7 until granules have formed. The granules are dried and screened. Ingredients 8-10 are added to the granules, mixed, and the blend is ready for compression.
  • Example 3 Formulation C: 1 mg* tablets with rasagiline tartrate
  • Example 4 Comparative formulation D; 1 mg* tablets with rasagiline mesylate
  • Ingredients 1-5 added in listed order to mixer bowl, mixed, sieved and mixed again. The blend is wetted with ingredient 6 until granules have formed. The granules are dried and screened. Ingredients 7-9 are added to the granules, mixed, and the blend is ready for compression.
  • Example 5 Comparative formulation E: 1 mg* tablets with rasagiline tartrate
  • Ingredients 1-5 added in listed order to mixer bowl, mixed, sieved and mixed again. The blend is wetted with ingredient 6 until granules have formed. The granules are dried and screened. Ingredients 7-9 are added to the granules, mixed, and the blend is ready for compression.
  • formulations D and E which both have same inert excipients (mannitol as main filler) but formulation D comprises rasagiline mesylate whereas E comprises rasagiline tartrate, shows that the rasagiline mesylate formulation has more stability.
  • the active ingredient is however further stabilised. This shows a stabilising effect of calcium sulphate dihydrate in formulations with a propargylamine monoamine inhibitor compound such as rasagiline.
  • Tablets containing 1 mg of rasagiline are compressed in a Fette rotary tablet machine.
  • the manufacture should be done in areas of low humidity (30% +/- 10%).
  • Ingredient 6 is dissolved in 1400 g of ingredient 1 by stirring for 5 min.
  • the granules are wet screened through Comil 375-Q (9.5 mm) screen and then dried an Aeromatic T-2 fluid bed drier until loss in drying is less than 1.5% (measured with a Mettler HR 53, 5 g, 100°C, mode 2). Inlet temperature 60°C+/-5°C, outlet temperature target 36 - 38°C.
  • the dried granules are then sieved through a Comil-sieve R055R (1.4 mm) and put into a 28 litre BIN.
  • Ingredients 3 and 5 are hand - sieved through 0.710 mm screen and added to the 28 litre BIN.
  • Ingredient 2 is hand-screened through 0.250 mm screen and then added to ingredients 3 - 10.
  • the obtained mixture is further mixed in a Mini BIN Blender for 5 min at 10 rpm.
  • the final blend is kept in an airtight container together with a desiccant bag (0.5 kg).

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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)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques stables comprenant un composé inhibiteur de monoamine oxydase de propargylamine tel que la rasagiline ou un sel de celle-ci, par exemple, le tartrate, mésylate, succinate ou chlorhydrate de rasagiline. Les formulations contiennent du sulfate de calcium en tant qu'excipient inerte, de préférence sous la forme de sulfate de calcium dihydraté. Les formulations peuvent contenir en outre un acide faible tel que l'acide citrique, qui améliore plus avant la stabilité.
PCT/EP2013/061646 2012-06-08 2013-06-06 Formulation pharmaceutique avec un composé de propargylamine WO2013182625A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IS050034 2012-06-08
IS50034 2012-06-08

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WO2013182625A1 true WO2013182625A1 (fr) 2013-12-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2796130A3 (fr) * 2013-02-06 2015-02-25 Galenicum Health S.L. Comprimés à libération immédiate comprenant de l'hémitartrate de rasagiline
CN115400090A (zh) * 2022-10-09 2022-11-29 北京新领先医药科技发展有限公司 一种雷沙吉兰的口崩片组合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091836A1 (fr) * 2005-02-24 2006-08-31 Teva Pharmaceutical Industries, Ltd. Preparations de tartrate de ladostigil
EP2218444A2 (fr) * 2009-01-23 2010-08-18 Teva Pharmaceutical Industries, Ltd. Formulation de rasagiline à libération retardée
WO2010100219A2 (fr) * 2009-03-05 2010-09-10 Sandoz Ag Composition pharmaceutique contenant du (1r)-méthanesulfonate de 1h-indén-1-amine-2,3-dihydro-n-2-propynyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091836A1 (fr) * 2005-02-24 2006-08-31 Teva Pharmaceutical Industries, Ltd. Preparations de tartrate de ladostigil
EP2218444A2 (fr) * 2009-01-23 2010-08-18 Teva Pharmaceutical Industries, Ltd. Formulation de rasagiline à libération retardée
WO2010100219A2 (fr) * 2009-03-05 2010-09-10 Sandoz Ag Composition pharmaceutique contenant du (1r)-méthanesulfonate de 1h-indén-1-amine-2,3-dihydro-n-2-propynyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NICOLAUS B J R: "Symbiotic Approach to Drug Design", DECISION MAKING IN DRUG RESEARCH, XX, XX, 1 January 1983 (1983-01-01), pages 173 - 186, XP002197412 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2796130A3 (fr) * 2013-02-06 2015-02-25 Galenicum Health S.L. Comprimés à libération immédiate comprenant de l'hémitartrate de rasagiline
CN115400090A (zh) * 2022-10-09 2022-11-29 北京新领先医药科技发展有限公司 一种雷沙吉兰的口崩片组合物及其制备方法

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