CA2232310C - Stable compositions containing n-propargyl-1-aminoindan - Google Patents
Stable compositions containing n-propargyl-1-aminoindan Download PDFInfo
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- CA2232310C CA2232310C CA002232310A CA2232310A CA2232310C CA 2232310 C CA2232310 C CA 2232310C CA 002232310 A CA002232310 A CA 002232310A CA 2232310 A CA2232310 A CA 2232310A CA 2232310 C CA2232310 C CA 2232310C
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- Prior art keywords
- pharmaceutical composition
- composition
- aminoindan
- propargyl
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- 239000000203 mixture Substances 0.000 title claims abstract description 59
- RUOKEQAAGRXIBM-UHFFFAOYSA-N n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(NCC#C)CCC2=C1 RUOKEQAAGRXIBM-UHFFFAOYSA-N 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 40
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 12
- 229930195725 Mannitol Natural products 0.000 claims description 12
- 239000000594 mannitol Substances 0.000 claims description 12
- 235000010355 mannitol Nutrition 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 238000009472 formulation Methods 0.000 description 16
- 229920002472 Starch Polymers 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 239000008380 degradant Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- -1 glidants Substances 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Solid Fuels And Fuel-Associated Substances (AREA)
Abstract
A pharmaceutical composition comprising as active ingredient a racemic, S(-) , and R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least 60 % by weight of at least one pentahydric or hexahydric alcohol. Optionally the composition may contain citric acid and magnesium stearate.
Description
AMINOINDAN
FIELD OF THE INVENTION
The present invention concerns formulations of racemic, S(-) or R(+) enantiomers of N-propargyl-l-aminoindan, and especially formula-tions of the enantiomer R(+) of N-propargyl-l-aminoindan (referred to hereinafter as R(+) PAI) which is a selective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment of Parkinson's disease. In the following the enzyme monoamine oxidase will be referred to as MAO and the B-form thereof as MAO-B.
BACKGROUND OF THE INVENTION
GB 1 003 686 discloses a group of benzocycloalkane compounds in which the cycloalkane has from five to seven ring members and is substituted by an N-(alkynylalkyl)amino group, and their use as MAO
inhibitors. The patent further discloses the use of the subject compounds in admixture with a variety of substances including various alcohols such as a benzyl alcohol, stearyl alcohol, and methanol. The patent, however, does not teach how and by what criteria any of the many possible carriers and other ingredients are selected so as to overcome the stability problem of the product.
FIELD OF THE INVENTION
The present invention concerns formulations of racemic, S(-) or R(+) enantiomers of N-propargyl-l-aminoindan, and especially formula-tions of the enantiomer R(+) of N-propargyl-l-aminoindan (referred to hereinafter as R(+) PAI) which is a selective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment of Parkinson's disease. In the following the enzyme monoamine oxidase will be referred to as MAO and the B-form thereof as MAO-B.
BACKGROUND OF THE INVENTION
GB 1 003 686 discloses a group of benzocycloalkane compounds in which the cycloalkane has from five to seven ring members and is substituted by an N-(alkynylalkyl)amino group, and their use as MAO
inhibitors. The patent further discloses the use of the subject compounds in admixture with a variety of substances including various alcohols such as a benzyl alcohol, stearyl alcohol, and methanol. The patent, however, does not teach how and by what criteria any of the many possible carriers and other ingredients are selected so as to overcome the stability problem of the product.
The object of the present invention is to provide stable formula-tions comprising an effective amount of racemic, S(-) or R(+)-N-proparg-y1-l-aminoindan. For the sake of simplicity, the abbreviation PAI, unless specified otherwise, will be used to denote the enantiomers of N-propargyl-1-aminoindan, as well as their racemic mixtures.
SUMMARY OF THE INVENTION
In accordance with the invention it was surprisingly found that the stability of formulations comprising PAI can be significantly improved by the incorporation of relatively large amounts of certain alcohols.
In accordance with the present invention there is provided a pharmaceutical composition comprising as an active ingredient a therapeuti-cally effective amount of a compound being a member selected from the group of racemic, S(-), and R(+)-N-propargyl-l-aminoindan or a pharmaceutically acceptable salt thereof, and at least 60% by weight of at least one alcohol being a member selected from the group of pentahydric and hexahydric alcohols.
In a preferred embodiment of the present invention the active ingredient is R(+)-N-propargyl-1-aminoindan.
Preferably the composition comprises at least 70% of said at least one alcohol.
Typically the alcohol used in accordance with of the invention, is a member selected from the group of mannitol, xylitol and sorbitol.
In accordance with the invention the PAI-comprising composition may further include citric acid, preferably in an amount of 0.5 to 2% by weight.
If desired, compositions according to the invention may further comprise magnesium stearate, preferably in an amount of 0.1 to 0.5% by weight. According to this embodiment, where the amount of said at least one alcohol is less than 70% by weight, the composition further comprises citric acid in an amount specified above. Where the amount of said at least one alcohol is at least 70% by weight, the inclusion of citric acid is optional.
SUMMARY OF THE INVENTION
In accordance with the invention it was surprisingly found that the stability of formulations comprising PAI can be significantly improved by the incorporation of relatively large amounts of certain alcohols.
In accordance with the present invention there is provided a pharmaceutical composition comprising as an active ingredient a therapeuti-cally effective amount of a compound being a member selected from the group of racemic, S(-), and R(+)-N-propargyl-l-aminoindan or a pharmaceutically acceptable salt thereof, and at least 60% by weight of at least one alcohol being a member selected from the group of pentahydric and hexahydric alcohols.
In a preferred embodiment of the present invention the active ingredient is R(+)-N-propargyl-1-aminoindan.
Preferably the composition comprises at least 70% of said at least one alcohol.
Typically the alcohol used in accordance with of the invention, is a member selected from the group of mannitol, xylitol and sorbitol.
In accordance with the invention the PAI-comprising composition may further include citric acid, preferably in an amount of 0.5 to 2% by weight.
If desired, compositions according to the invention may further comprise magnesium stearate, preferably in an amount of 0.1 to 0.5% by weight. According to this embodiment, where the amount of said at least one alcohol is less than 70% by weight, the composition further comprises citric acid in an amount specified above. Where the amount of said at least one alcohol is at least 70% by weight, the inclusion of citric acid is optional.
The composition of the present invention may optionally also include conventional additives such as fillers, lubricants, disintegrants, glidants, flavoring agents, sweeteners, coloring agents, and the like, all as known per se. Examples of fillers which may be used in accordance with the present invention are lactose, starch, microcrystalline cellulose, maltrin and the like.
The compositions of the present invention may be prepared by methods known per se, familiar to those skilled in the art. For example, PAI and all other ingredients (with the exception of the lubricant, when used) may be screened and mixed thoroughly in a suitable trranulating machine. The granulation may occur in the presence of purified water, following which the composition is dried. The dry granulate may then be milled, lubricated and compressed into tablets. R(+) PAI itself may be prepared, for example, according to the process described in Example 6B of W095/11016.
The following non-limiting examples are given by wav of illustration.
EXAMPLES
mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 62.5 Maltodextrin (Maltrin 150) 36.0 CroscarmeIlose sodium (Ac-Di-Sol) 2.1 Talc 1.5 * Trade-mark mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 1.56 Mannitol 79.14 Starch 10.0 Pregelatinized starch 10.0 Colloidal silicon dioxide 0.6 Talc 2.0 Stearic acid 2,0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 76.58 Starch 10.0 Pregelatinized starch 10.0 Colloidal silicon dioxide 0.6 Citric acid 1.0 Talc 2.0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 69.88 Lactose (hydrous) 14.0 Starch 14.0 Glyceryl Behenate (Compitrol 888 ATO) 2.0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 77.28 Starch 10.0 Starch STA-RX 1500 10.0 Colloidal silicon dioxide, AerosiI* 0.6 *
Hydrogenated vevetable type I(SteroteY Dritex) 2.0 In order to compare the compositions of the present invention with those known in the prior art, two of the above formulations were compared with a formulation described in W095/11016.
Formulation of W095/11016 (Example 20) mg/tablet R(+)-N-propargyl-l-aminoindan HCI 1.56 Lactose (hydrous) 50.0 Pregelatinized starch 36.0 Microcrystalline cellulose 14.0 Sodium starch glycolate 2.14 Talc 1.0 Magnesium stearate 0.5 This formulation, as well as those described under Examples 2 and 3 of the present application were subjected to 6 months at 40 C and 75% humidity. The percentage of degradants of the active material was assayed at the end of the six month period.
* Trade-mark The following procedure was adopted to determine the degrada-tion of the formulations prepared. The tablets were finely powdered and extracted with a diluent such as a mixture of water, acetonitrile and perchloric acid. An aliquot of the extraction product was injected into an HPLC and eluted using the same mixture as said diluent mixture. The area corresponding to the PAI compound was determined as was that of any other major peak. The calculations of degradation percent was made by comparing the areas of the measured peaks with those obtained from the standard preparation.
It was found that the 'formulation prepared according to the disclosure of Example 20 of W095/11016 contained after storage 3.08%
degradants whereas the formulations of Examples 2 and 3 contained 0.51%
and less than 0.1% degradants, respectively.
Formulations according to the present invention and others according to the description given in Example 20 of W095/11016 were prepared containing the ingredients shown in Table 1. The formulations described in this Table are designated "PCT" when prepared in accordance with the disclosure in W095/11016, or by a number which corresponds to the number of the Example in the present application, in which they are described. The qualifying symbols of A, B, C or D appearing next to some of these designations denote certain variations in said formulations. The percentage of degradation, presented in Table 2, was calculated for all the formulations of Table 1, after storing them for 1 month at 55 C or for 6 months at 40 C and 75% humidity. Those formulations stored according to the latter storing conditions are marked in the Table with an astrix (*). As can be seen from Table 2, the stabilities of all the compositions of the ' present invention was superior to those of the prior art.
The compositions of the present invention may be prepared by methods known per se, familiar to those skilled in the art. For example, PAI and all other ingredients (with the exception of the lubricant, when used) may be screened and mixed thoroughly in a suitable trranulating machine. The granulation may occur in the presence of purified water, following which the composition is dried. The dry granulate may then be milled, lubricated and compressed into tablets. R(+) PAI itself may be prepared, for example, according to the process described in Example 6B of W095/11016.
The following non-limiting examples are given by wav of illustration.
EXAMPLES
mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 62.5 Maltodextrin (Maltrin 150) 36.0 CroscarmeIlose sodium (Ac-Di-Sol) 2.1 Talc 1.5 * Trade-mark mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 1.56 Mannitol 79.14 Starch 10.0 Pregelatinized starch 10.0 Colloidal silicon dioxide 0.6 Talc 2.0 Stearic acid 2,0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 76.58 Starch 10.0 Pregelatinized starch 10.0 Colloidal silicon dioxide 0.6 Citric acid 1.0 Talc 2.0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 69.88 Lactose (hydrous) 14.0 Starch 14.0 Glyceryl Behenate (Compitrol 888 ATO) 2.0 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 77.28 Starch 10.0 Starch STA-RX 1500 10.0 Colloidal silicon dioxide, AerosiI* 0.6 *
Hydrogenated vevetable type I(SteroteY Dritex) 2.0 In order to compare the compositions of the present invention with those known in the prior art, two of the above formulations were compared with a formulation described in W095/11016.
Formulation of W095/11016 (Example 20) mg/tablet R(+)-N-propargyl-l-aminoindan HCI 1.56 Lactose (hydrous) 50.0 Pregelatinized starch 36.0 Microcrystalline cellulose 14.0 Sodium starch glycolate 2.14 Talc 1.0 Magnesium stearate 0.5 This formulation, as well as those described under Examples 2 and 3 of the present application were subjected to 6 months at 40 C and 75% humidity. The percentage of degradants of the active material was assayed at the end of the six month period.
* Trade-mark The following procedure was adopted to determine the degrada-tion of the formulations prepared. The tablets were finely powdered and extracted with a diluent such as a mixture of water, acetonitrile and perchloric acid. An aliquot of the extraction product was injected into an HPLC and eluted using the same mixture as said diluent mixture. The area corresponding to the PAI compound was determined as was that of any other major peak. The calculations of degradation percent was made by comparing the areas of the measured peaks with those obtained from the standard preparation.
It was found that the 'formulation prepared according to the disclosure of Example 20 of W095/11016 contained after storage 3.08%
degradants whereas the formulations of Examples 2 and 3 contained 0.51%
and less than 0.1% degradants, respectively.
Formulations according to the present invention and others according to the description given in Example 20 of W095/11016 were prepared containing the ingredients shown in Table 1. The formulations described in this Table are designated "PCT" when prepared in accordance with the disclosure in W095/11016, or by a number which corresponds to the number of the Example in the present application, in which they are described. The qualifying symbols of A, B, C or D appearing next to some of these designations denote certain variations in said formulations. The percentage of degradation, presented in Table 2, was calculated for all the formulations of Table 1, after storing them for 1 month at 55 C or for 6 months at 40 C and 75% humidity. Those formulations stored according to the latter storing conditions are marked in the Table with an astrix (*). As can be seen from Table 2, the stabilities of all the compositions of the ' present invention was superior to those of the prior art.
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SUBSTITUTE SHEET (RULE 26)
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SUBSTITUTE SHEET (RULE 26)
Claims (38)
1. A pharmaceutical composition in tablet form comprising an amount of R (+) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least one alcohol selected from the group consisting of pentahydric and hexahydric alcohols.
2. The pharmaceutical composition of claim 1, wherein said at least one alcohol comprises at least 60% by weight of the total composition.
3. The pharmaceutical composition of claim 1, wherein the alcohol is selected from the group consisting of mannitol, xylitol and sorbitol.
4. The pharmaceutical composition of claim 1, further comprising citric acid.
5. The pharmaceutical composition of claim 4, wherein the amount of citric acid is 0.5 to 2% by weight of the total composition.
6. The pharmaceutical composition of claim 1, further comprising magnesium stearate.
7. The pharmaceutical composition of claim 6, wherein the amount of magnesium stearate is 0.1 to 0. 5% by weight of the total composition.
8. The pharmaceutical composition of claim 1, in which the amount of said at least one alcohol is between 60% and 70% of the total composition, and further comprising citric acid.
9. The pharmaceutical composition of claim 1, comprising an amount of R(+)-N-propargyl-1-aminoindan.
10. A pharmaceutical composition in tablet form comprising an amount of R (+ ) -N-propargyl-l-aminoindan or a pharmaceutically acceptable salt thereof, and at least 75% by weight of at least one alcohol selected from the group consisting of mannitol, xylitol and sorbitol.
11. The pharmaceutical composition of claim 10, wherein the amount of R(+)-N-propargyl-l-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% by weight of the composition, and wherein the alcohol is at least 75% by weight the composition.
12. The pharmaceutical composition of claim 10, wherein the composition comprises 3.12 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
13. The pharmaceutical composition of claim 10, wherein the composition comprises 1.56 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
14. The pharmaceutical composition of claim 11, wherein the alcohol is mannitol.
15. A pharmaceutical composition comprising an amount of R (+) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least one alcohol selected from the group consisting of pentahydric and hexahydric alcohols.
16. The pharmaceutical composition of claim 15, wherein said at least one alcohol comprises at least 60% by weight of the total composition.
17. The pharmaceutical composition of claim 15, wherein the alcohol is selected from the group consisting of mannitol, xylitol and sorbitol.
18. The pharmaceutical composition of claim 15, further comprising citric acid.
19. The pharmaceutical composition of claim 18, wherein the amount of citric acid is 0.5 to 2% by weight of the total composition.
20. The pharmaceutical composition of claim 15, further comprising magnesium stearate.
21. The pharmaceutical composition of claim 20, wherein the amount of magnesium stearate is 0.1 to 0.5% by weight of the total composition.
22. The pharmaceutical composition of claim 15, in which the amount of said at least one alcohol is between 60% and 70% of the total composition, and further comprising citric acid.
23. The pharmaceutical composition of claim 15, comprising an amount of R(+)-N-propargyl-1-aminoindan.
24. A pharmaceutical composition comprising an amount of R(+) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least 75% by weight of at least one alcohol selected from the group consisting of mannitol, xylitol and sorbitol.
25. The pharmaceutical composition of claim 24, wherein the amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% by weight of the composition, and wherein the alcohol is at least 75% by weight of the composition.
26. The pharmaceutical composition of claim 24, wherein the composition comprises 3.12 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
27. The pharmaceutical composition of claim 24, wherein the composition comprises 1.56 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
28. The pharmaceutical composition of claim 25, wherein the alcohol is mannitol.
29. The pharmaceutical composition of claim 2, wherein the amount of R (+) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% by weight of the composition.
30. The pharmaceutical composition of claim 2, wherein the composition comprises 3.12 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
31. The pharmaceutical composition of claim 2, wherein the composition comprises 1.56 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.
32. The pharmaceutical composition of claim 16, wherein the amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% by weight of the composition.
33. The pharmaceutical composition of claim 16, wherein the composition comprises 3.12 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, and wherein the alcohol is at least 75% by weight of the composition.
34. The pharmaceutical composition of claim 16, wherein the composition comprises 1.56 mg of the pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.
35. The pharmaceutical composition of claim 1, comprising an amount of a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.
36. The pharmaceutical composition of claim 35, wherein the pharmaceutically acceptable salt is the mesylate salt.
37. The pharmaceutical composition of claim 15, comprising an amount of a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.
38. The pharmaceutical composition of claim 37, wherein the pharmaceutically acceptable salt is the mesylate salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL115357 | 1995-09-20 | ||
| IL11535795A IL115357A (en) | 1995-09-20 | 1995-09-20 | Stable compositions containing N-propargyl-1-aminoindan and polyhydric alcohols |
| PCT/IL1996/000115 WO1997012583A2 (en) | 1995-09-20 | 1996-09-18 | Stable compositions containing n-propargyl-1-aminoindan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2232310A1 CA2232310A1 (en) | 1997-04-10 |
| CA2232310C true CA2232310C (en) | 2008-01-08 |
Family
ID=11068003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002232310A Expired - Lifetime CA2232310C (en) | 1995-09-20 | 1996-09-18 | Stable compositions containing n-propargyl-1-aminoindan |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US6126968A (en) |
| EP (1) | EP0858328B1 (en) |
| JP (1) | JP4108750B2 (en) |
| AT (1) | ATE362755T1 (en) |
| AU (1) | AU728524B2 (en) |
| CA (1) | CA2232310C (en) |
| DE (1) | DE69637096T2 (en) |
| DK (1) | DK0858328T3 (en) |
| ES (1) | ES2287940T3 (en) |
| HU (1) | HU225859B1 (en) |
| IL (1) | IL115357A (en) |
| PT (1) | PT858328E (en) |
| WO (1) | WO1997012583A2 (en) |
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| US5744500A (en) * | 1990-01-03 | 1998-04-28 | Teva Pharmaceutical Industries, Ltd. | Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof |
| IL118836A (en) | 1996-07-11 | 2001-01-11 | Teva Pharma | Pharmaceutical compositions comprising s-(-)-n-propargyl-1-aminoindan |
| IL149308A0 (en) | 1999-10-27 | 2002-11-10 | Teva Pharma | Use of 1-aminoindan derivatives for treatment of manic disorders |
| EP1567152B1 (en) | 2002-11-15 | 2013-08-14 | Teva Pharmaceutical Industries Limited | Use of rasagiline with riluzole to treat amyotrophic lateral sclerosis |
| GB2411355B (en) | 2004-02-27 | 2006-02-22 | Niche Generics Ltd | Pharmaceutical composition |
| WO2006014973A2 (en) * | 2004-07-26 | 2006-02-09 | Teva Pharmaceutical Industries, Ltd. | Pharmaceutical dosage forms including rasagiline |
| ATE365546T1 (en) * | 2004-11-10 | 2007-07-15 | Teva Pharma | METHOD FOR PRODUCING COMPRESSED SOLID DOSAGE FORMS SUITABLE FOR USE WITH POORLY WATER SOLUBLE DRUGS AND COMPRESSED SOLID DOSAGE FORMS PRODUCED THEREFROM |
| US8367105B2 (en) | 2004-11-10 | 2013-02-05 | Teva Pharmaceutical Industries, Ltd. | Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby |
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| EP1892233A1 (en) * | 2006-08-18 | 2008-02-27 | Ratiopharm GmbH | New salts of the active component rasagiline |
| HRP20130396T1 (en) * | 2006-12-14 | 2013-06-30 | Teva Pharmaceutical Industries Ltd. | Tannate salt of rasagiline |
| ES2375761T3 (en) * | 2006-12-14 | 2012-03-06 | Teva Pharmaceutical Industries Ltd. | SOLID CRYSTALLINE RASAGILINE BASE. |
| EP1987816A1 (en) * | 2007-04-30 | 2008-11-05 | Ratiopharm GmbH | Adsorbate of a rasagiline salt with a water-soluble inactive ingredient |
| WO2009032273A1 (en) * | 2007-09-05 | 2009-03-12 | Teva Pharmaceutical Industries, Ltd. | Method of treating glaucoma using rasagiline |
| US8188149B2 (en) * | 2007-09-17 | 2012-05-29 | Teva Pharmaceutical Industries, Ltd. | Use of R(+)-N-propargy1-1-aminoindan to treat or prevent hearing loss |
| WO2009089049A1 (en) * | 2008-01-11 | 2009-07-16 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations, their preparation and use |
| US20090247537A1 (en) * | 2008-03-25 | 2009-10-01 | William Dale Overfield | Methods for preventing or treating bruxism using dopaminergic agents |
| EP2271612B1 (en) * | 2008-03-31 | 2016-08-10 | Actavis Group PTC EHF | Rasagiline mesylate particles and process for the preparation thereof |
| JP2011522892A (en) * | 2008-06-13 | 2011-08-04 | テバ ファーマシューティカル インダストリーズ リミティド | Rasagiline for relieving Parkinson's disease |
| NZ589547A (en) | 2008-06-19 | 2013-03-28 | Teva Pharma | Dried rasagiline base having a water content less than 0.5 % by weight |
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| US20120122993A1 (en) | 2009-03-05 | 2012-05-17 | Sandoz Ag | Pharmaceutical composition containing 1h-inden-1-amine, 2,3-dihydro-n-2-propynyl-(1r)-, methanesulfonate |
| PL2451771T3 (en) | 2009-07-09 | 2014-12-31 | Ratiopharm Gmbh | Salts of rasagiline and pharmaceutical preparations thereof |
| CN102048717B (en) † | 2009-10-29 | 2014-02-19 | 重庆医药工业研究院有限责任公司 | Stable rasagiline composition |
| EP2515891A4 (en) | 2009-12-22 | 2013-06-05 | Teva Pharma | 3-keto-n-propargyl-1-aminoindan |
| CN108186611A (en) | 2010-04-30 | 2018-06-22 | 帝国制药美国公司 | Iodopropynylbutylcarbamate indane transdermal composition |
| EP2389927A1 (en) | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of rasagiline |
| JP2013533287A (en) | 2010-07-27 | 2013-08-22 | テバ ファーマシューティカル インダストリーズ リミティド | Use of rasagiline for the treatment of olfactory dysfunction |
| RU2013108256A (en) | 2010-07-27 | 2014-09-10 | Тева Фармасьютикал Индастриз Лтд. | DISPERSIONS OF Razagilin Citrate |
| JP5906302B2 (en) | 2011-03-24 | 2016-04-20 | テイコク ファーマ ユーエスエー インコーポレーテッド | Transdermal composition comprising an agent layer and an agent conversion layer |
| MX2014004308A (en) * | 2011-10-10 | 2014-07-24 | Teva Pharma | R(+)-n-formyl-propargyl-aminoindan. |
| AU2012323351A1 (en) | 2011-10-10 | 2014-05-22 | Teva Pharmaceutical Industries Ltd. | R(+)-N-methyl-propargyl-aminoindan |
| AU2012323346A1 (en) * | 2011-10-10 | 2014-05-15 | Teva Pharmaceutical Industries Ltd | Rasagiline citramide |
| EP2776020B1 (en) | 2011-11-09 | 2019-09-11 | Teikoku Seiyaku Co., Ltd. | Methods for the treatment of skin neoplasms |
| DE102012000786A1 (en) | 2012-01-18 | 2013-07-18 | Stada Arzneimittel Ag | Process for the preparation of a solid pharmaceutical composition containing the active substance rasagiline |
| EP2827848B1 (en) | 2012-03-21 | 2016-04-27 | Synthon BV | Stabilized pharmaceutical compositions comprising rasagiline salts |
| WO2013175493A1 (en) | 2012-04-09 | 2013-11-28 | Cadila Healthcare Limited | Stable oral pharmaceutical compositions |
| BR112015003451A2 (en) | 2012-08-17 | 2017-07-04 | Teva Pharma | parenteral formulation of rasagiline |
| MX366649B (en) | 2012-11-02 | 2019-07-17 | Teikoku Seiyaku Kk | Propynylaminoindan transdermal compositions. |
| ES2524865T1 (en) * | 2013-02-06 | 2014-12-15 | Galenicum Health S.L. | Stable pharmaceutical compositions in the form of immediate-release tablets |
| EP2764862A1 (en) * | 2013-02-06 | 2014-08-13 | Galenicum Health S.L. | Immediate release tablets of rasagiline hemitartrate |
| CN115400090A (en) * | 2022-10-09 | 2022-11-29 | 北京新领先医药科技发展有限公司 | Orally disintegrating tablet composition of rasagiline and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1187017A (en) * | 1966-07-16 | 1970-04-08 | Aspro Nicholas Ltd | Substituted 1-Amino Indanes and Tetrahydronaphthalens |
| GB8909793D0 (en) * | 1989-04-28 | 1989-06-14 | Beecham Group Plc | Pharmaceutical formulation |
| 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 |
| CA2039742A1 (en) * | 1990-04-23 | 1991-10-24 | Andrew B. Dennis | Tablet composition and method for problem pharmaceutical materials |
| IL112819A (en) * | 1991-10-16 | 2001-11-25 | Teva Pharma | Fluorinated 1-aminoindan compounds and a process for their preparation |
| IL111240A (en) * | 1993-10-18 | 2001-10-31 | Teva Pharma | Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them |
| IL112779A (en) * | 1994-03-01 | 1999-11-30 | Gergely Gerhard | Granular product or tablet containing an efferescent system and an active pharmaceutical substance and its preparation |
| JP3273141B2 (en) * | 1995-03-02 | 2002-04-08 | アール． ピー． シェーラー リミテッド | Pharmaceutical composition comprising monoamine oxidase B inhibitor |
-
1995
- 1995-09-20 IL IL11535795A patent/IL115357A/en not_active IP Right Cessation
-
1996
- 1996-09-18 WO PCT/IL1996/000115 patent/WO1997012583A2/en active IP Right Grant
- 1996-09-18 ES ES96930344T patent/ES2287940T3/en not_active Expired - Lifetime
- 1996-09-18 CA CA002232310A patent/CA2232310C/en not_active Expired - Lifetime
- 1996-09-18 EP EP96930344A patent/EP0858328B1/en not_active Expired - Lifetime
- 1996-09-18 DK DK96930344T patent/DK0858328T3/en active
- 1996-09-18 JP JP51411997A patent/JP4108750B2/en not_active Expired - Lifetime
- 1996-09-18 AU AU69427/96A patent/AU728524B2/en not_active Expired
- 1996-09-18 US US09/043,475 patent/US6126968A/en not_active Expired - Lifetime
- 1996-09-18 HU HU9802999A patent/HU225859B1/en unknown
- 1996-09-18 AT AT96930344T patent/ATE362755T1/en active
- 1996-09-18 DE DE69637096T patent/DE69637096T2/en not_active Expired - Lifetime
- 1996-09-18 PT PT96930344T patent/PT858328E/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2287940T3 (en) | 2007-12-16 |
| WO1997012583A2 (en) | 1997-04-10 |
| ATE362755T1 (en) | 2007-06-15 |
| EP0858328A4 (en) | 2001-07-11 |
| IL115357A (en) | 2000-01-31 |
| HUP9802999A2 (en) | 1999-04-28 |
| WO1997012583A3 (en) | 1997-06-05 |
| EP0858328A2 (en) | 1998-08-19 |
| US6126968A (en) | 2000-10-03 |
| DE69637096D1 (en) | 2007-07-05 |
| AU6942796A (en) | 1997-04-28 |
| JP4108750B2 (en) | 2008-06-25 |
| HUP9802999A3 (en) | 1999-05-28 |
| DK0858328T3 (en) | 2007-09-03 |
| EP0858328B1 (en) | 2007-05-23 |
| HU225859B1 (en) | 2007-11-28 |
| JPH11512736A (en) | 1999-11-02 |
| IL115357A0 (en) | 1995-12-31 |
| CA2232310A1 (en) | 1997-04-10 |
| DE69637096T2 (en) | 2008-01-31 |
| AU728524B2 (en) | 2001-01-11 |
| PT858328E (en) | 2007-08-20 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20160919 |