Pharmaceutical composition containing n-propargyl-1-aminoindan

Description

The invention relates to a pharmaceutical composition containing R(+)N-propargyl-1-aminoindan [hereinafter referred to as R(+) PAI], which is a selective irreversible inhibitor of the B-form of the monoamine oxidase enzyme, which can be used, for example, for the treatment of Parkinson's disease. The monoamine oxidase enzyme is hereinafter abbreviated as "MAO", and its B-form is abbreviated as "MAO-B". British Patent No. GB ​​1 003 686 describes benzocycloalkane derivatives in which the cycloalkane ring of 5-7 carbon atoms is substituted with an N-(alkynylalkyl)amino group and which are useful as MAO inhibitors. The document covers the use of mixtures of the above compound and various substances, such as alcohols, such as benzyl alcohol, stearic alcohol and methanol. However, the document does not cover how and under what conditions the possible carriers and other components can be selected to help overcome the stability problem of the product. The object of the invention is to develop a stable pharmaceutical composition containing an effective amount of R(+)-N-propargyl-1-aminoindan. Surprisingly, we have found that the stability of formulations containing PAI as an active ingredient can be significantly increased by using large amounts of certain alcohols. Accordingly, the invention relates to a pharmaceutical composition comprising, as active ingredient, R(+)-N-propargyl-1-aminoindane or a pharmacologically acceptable salt thereof and at least 60% by weight of at least one pentahydroxyalcohol or hexahydroxyalcohol. The pharmaceutical composition according to the invention preferably contains at least 70% by weight of at least one alcohol. Mannitol, xylitol and / or sorbitol are preferably used as alcohols. According to the invention, the composition containing PAI may contain citric acid as an additional component, preferably 0.5-2% by weight of citric acid. If desired, the pharmaceutical composition according to the invention contains magnesium stearate as an additional component, preferably 0.1-0.5% by weight of magnesium stearate. When magnesium stearate and up to 70% by weight of alcohol are used, the composition contains citric acid as an additional component in the amount specified above. If the amount of alcohol exceeds 70% by weight, citric acid is used if desired. The pharmaceutical composition according to the invention optionally contains as additional components the usual excipients, such as fillers, lubricants, disintegrants, flavors, sweeteners and dyes. These excipients are known. Examples of excipients include lactose, starch, microcrystalline cellulose and maltrin. The composition according to the invention is prepared in a conventional and generally known manner. For example, the PAI and the other components (except for the optionally used lubricant) are sieved and thoroughly mixed in a suitable granulating device. Granulation can be carried out in the presence of distilled water, which is added followed by a drying step. The dry granulate is then ground, supplemented with the lubricant and tabletted. R(+) PAI can be prepared, for example, as described in WO 95 / 11016 (see Example 6B thereof). The invention is illustrated in more detail by the following examples, without the scope of protection being limited to the embodiments or implementations according to the examples. Example 1 We produce tablets that each contain the following amounts of components: R(+)-N-propargyl-1-amino-indane mesylate 3.12 mg Mannitol 62.5 mg Maltodextrin (maltrin 150) 36.0 mg Croscarmellose sodium (Ac-Di-Sol) 2.1 mg Talc 1.5 mg. Example 2 Tablets are prepared, each containing the following amounts of components: R(+)-N-propargyl-1-amino-indane mesylate 1.56 mg Mannitol 79.14 mg Starch 10.0 mg Pregelatinized starch 10.0 mg Colloidal silicon dioxide 0.6 mg Talc 2.0 mg Stearic acid 2.0 mg. Example 3 Tablets are prepared, each containing the following amounts of components: R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg Mannitol 76.58 mg Starch 10.0 mg Pregelatinized starch 10.0 mg Colloidal silicon dioxide 0.6 mg Citric acid 1.0 mg Talc 2.0 mg. Example 4 Tablets are prepared, each containing the following amounts of components: R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg Mannitol 69.88 mg Lactose (aqueous) 14.0 mg Starch 14.0 mg Glyceryl behenate (Compitrol 888 ATO) 2.0 mg. 5.Example 1 Tablets are prepared, each containing the following amounts of components: R(+)-N-propargyl-1-aminoindane mesylate 3.12 mg Mannitol 77.28 mg Starch 10.0 mg Starch STA-RX 1500 10.0 mg Colloidal silicon dioxide 0.6 mg Hydrogenated vegetable oil type I (Sterotex Dritex) 2.0 mg. HU 225 859 B1 Example 6 In order to compare the compositions of the invention with known compositions, two of the above compositions are compared with the composition disclosed in WO 95 / 11016. The composition described in Example 20 of WO 95 / 11016 contains the following components per tablet: R(+)-N-propargyl-1-aminoindane hydrochloride 1.56 mg Lactose (aqueous) 50.0 mg Pregelatinized starch 36.0 mg Microcrystalline cellulose 14.0 mg Sodium starch glycolate 2.14 mg Talc 1.0 mg Magnesium stearate 0.5 mg. The above composition and the compositions of Examples 2 and 3 of the invention are stored for six months at a temperature of 40°C and a humidity of 75%. The extent of degradation of the active ingredient is determined in % after six months of storage. The degradation of the preparations is measured by the following method: the tablets are finely ground and extracted with a solvent such as a mixture of water, acetonitrile and perchloric acid. An aliquot of the extract is injected onto an HPLC column and eluted with the solvent used for extraction. The area corresponding to the PAI compound and the other major peaks are determined. The % degradation is calculated relative to the area under the peak obtained with the standard preparation. We found that WO 95 / 11016, 20. The composition prepared according to Example 1 shows 3.08% decomposition after storage, while the compositions according to Examples 2 and 3 show 0.51% and less than 0.1% decomposition, respectively. Example 7 A composition according to the invention and a composition according to Example 20 of WO 95 / 11016 are prepared from the components given in Table 1. The compositions indicated in the table by the abbreviation “PCT” are prepared by According to WO 95 / 11016. The numbers given correspond to the example numbers according to the invention. The symbols A, B, C and D mean that the composition of the composition has been changed. The % degradation of the compositions according to Table 1 after storage for one month at 55 °C and for 6 months at 40 °C and 75% humidity is summarized in Table 2. The compositions stored under the latter storage conditions are marked with * in the table. It can be seen from Table 2 that the stability of the compositions according to the invention is better than that of the known compositions. Table 1 Example number PCT (mg) PCT-A (mg) PCT-B (mg) PCT-C (mg) 1. (mg) 1A. (mg) 1B. (mg) 1C. (mg) 1D. (mg) 2. (mg) N-Propargyl-1(R)-amino-indane mesylate 1.56 5.0 1.0 7.81 3.12 3.12 1.56 3.12 1.56 1.56 Mannitol (USP) 62.5 62.5 79.14 Starch STA-RX 1500 36.0 47.0 36.0 47.0 36.0 36.0 36.0 10.0 Starch NF (paste) 5.6 4.4 Colloidal silicon dioxide (Aerosil 200) 0.6 Citric acid 10 20 Talc (USP) 1.0 1.5 1.0 1.5 1.5 1.5 1.0 1.0 1.0 2.0 Microcrystalline cellulose (Avicel 102) 14.0 20.0 14.0 20.0 14.0 14.0 14.0 Stearic acid (NF) 2.0 2.0 Lactose (NF; aqueous) 50.0 66.0 50.0 66.0 50.0 47.44 46.44 Sodium starch glycolate 2.14 3.0 2.2 2.99 2.14 2.14 2.14 Magnesium stearate 0.5 0.7 0.5 0.7 0.52 0.1 0.5 0.5 AC-DI-SOL 2.1 2.1 Lactose (spray dried) Compritol 888 ATO Maltrin 36.0 36.0 Sorbitol Xylitol 300 HU 225 859 B1 Table 1 (continued) Példaszám PCT (mg) PCT-A (mg) PCT-B (mg) PCT-C (mg) 1. (mg) 1A. (mg) 1B. (mg) 1C. (mg) 1D. (mg) 2. (mg) Sterotex-Dritex Össztömeg (mg) 105,2 143,2 104,7 146,0 105,22 105,74 106,8 105,2 105,2 105,3 Példaszám 2A. (mg) 3. (mg) 3A. (mg) 4. (mg) 5. (mg) 5A. (mg) 5B. (mg) 5C. (mg) 8. (mg) 9.(mg) N-propargyl-1 (R)-amino-indane mesylate 1.56 3.12 1.56 3.12 3.12 1.56 1.56 1.56 1.56 1.56 Mannitol (USP) 78.44 76.58 77.44 69.88 77.28 78.87 78.87 78.87 Starch STA-RX 1500 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Starch NF (paste) 10.0 5.6 4.4 10.0 14.0 10.0 10.0 10.0 10.0 10.0 10.1 10.0 Colloidal Silicon dioxide (Aerosil 200) 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Citric acid 1.0 1.0 Talc (USP) 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Microcrystalline cellulose (Avicel 102) Stearic acid (NF) 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Lactose (NF; aqueous) 14.0 Sodium starch glycolate Magnesium stearate 0.1 0.5 0.5 AC-DI-SOL Lactose (spray dried) Compritol 888 ATO Maltrin 2.0 Sróit 78.84 Xylitol 300 78.84 Sterotex-Dritex 2.0 Total weight (mg) 104.6 105.3 104.6 103.0 103.0 105.13 103.53 105.53 105.0 105.0. Table 2 Example No. Degradation (%) Mannitol (wt%) Sorbitol (wt%) Xylitol (wt%) Magnesium stearate (wt%) Citric acid (wt%) PCT 2.26 0.5 PCT-A 2.76 0.49 PCT-B 1.46 0.49 PCT-C 2.59 0.5 1. 1.22 59.4 1A. 3.97 59.1 0.49 1B. 2.04 0.1 1C. 1.04 0.47 0.95 1D. 0.40 0.47 1.9 2. 0.29 75.1 2A. 0.27 75 HU 225 859 B1 Table 2 (continued) Example No. Degradation (%) Mannitol (wt%) Sorbitol (wt%) Xylitol (wt%) Magnesium stearate (wt%) Citric acid (wt%) 3. 0.02 72.7 0.95 3A. 0.02 74 0.95 4. 0.02 67.8 5. 0.21 75 5A. 0.32 75 0.1 5B. 0.65 76.2 0.47 5C. 0.52 74.7 0.47 6. 0.74 75.1 7. 1.01 75.1

Claims

PATENT CLAIMS 1. A pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmacologically acceptable salt thereof and at least 60% by weight of at least a pentahydroxy alcohol and / or a hexahydroxy alcohol.

2. The pharmaceutical composition of claim 1, wherein the alcohol is mannitol, xylitol or sorbitol.

3. A pharmaceutical composition according to claim 1 or 2, which comprises as active ingredient a pharmaceutically effective amount of racemic R(+)-N-propargyl-1-aminoindan or a pharmacologically acceptable salt thereof and at least 75% by weight of mannitol.

4. The pharmaceutical composition according to any one of claims 1-3, which is in the form of a tablet.

5. A pharmaceutical composition according to claim 3, wherein R(+)-N-propargyl-1-aminoindane or a pharmacologically acceptable salt thereof is present in an amount corresponding to up to 3.0% by weight of the pharmaceutical composition.

6. A pharmaceutical composition according to any one of claims 1-5, wherein the active ingredient is R(+)-N-propargyl-1-aminoindane.

7. A pharmaceutical composition according to any one of claims 1-5, wherein the active ingredient is a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindane.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable salt is mesylate.

9. A pharmaceutical composition according to any one of claims 1-8, wherein the alcohol is mannitol.

10. A pharmaceutical composition according to any one of claims 1-9, which further comprises citric acid.

11. A pharmaceutical composition according to claim 10, comprising 0.5-2% by weight of citric acid.

12. A pharmaceutical composition according to any one of claims 1-11, further comprising magnesium stearate.

13. A pharmaceutical composition according to claim 12, comprising 0.1-0.5% by weight of magnesium stearate.

14. A pharmaceutical composition according to claim 1 or 2, comprising less than 70% by weight of alcohol and 0.5-2% by weight of citric acid.

15. The pharmaceutical composition of claim 1, which is in the form of a tablet.

16. A pharmaceutical composition according to claim 1 or 15, which comprises R(+)-N-propargyl-1-aminoindane as the active ingredient.

17. A pharmaceutical composition according to claim 1 or 15, which comprises a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindane as the active ingredient.

18. A pharmaceutical composition according to claim 17, comprising the mesylate as a pharmaceutically acceptable salt.

19. A pharmaceutical composition according to any one of claims 1 or 15-18, which comprises mannitol as the alcohol.

20. A pharmaceutical composition according to any one of claims 1 or 15-19, further comprising citric acid.

21. The pharmaceutical composition according to claim 20, which comprises 0.5-2% by weight of citric acid.

22. A pharmaceutical composition according to any one of claims 1 or 15-21, further comprising magnesium stearate.

23. A pharmaceutical composition according to claim 22, comprising 0.1-0.5% by weight of magnesium stearate.