MXPA01005747A - Pharmaceutical compositions comprising quinapril magnesium - Google Patents

Abstract

Stable solid compositions comprising quinapril magnesium can be made using quinapril or an acid addition salt thereof, by reacting the quinapril or acid addition salt with an alkaline magnesium compound in the presence of a solvent, so as to convert all or substantially all of the quinapril or acid addition salt to quinapril magnesium.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING QUINAPRILMAGNESIUM FIELD OF THE INVENTION This invention relates to solid pharmaceutical compositions comprising a stable salt of quinapril, specifically the magnesium salt, quinaprilmagnesium. BACKGROUND Some inhibitors of ACE (Angiotensin converting enzyme), which are useful as antihypertensive agents, are susceptible to degradation by cyclization, hydrolysis or oxidation. Such ACE inhibitors include enalapril, quinapril and moexipril, and acid addition salts thereof. Enalapril and its acid addition salts and their use as ACE inhibitors are described in U.S. Patent No. 4,374,829. Quinapril and moexipril and their acid addition salts are disclosed in U.S. Patent No. 4,344,949. Several methods for improving the stability of these compounds are described in the prior art. Enalapril and its acid addition salts are stabilized more easily than quinapril and its acid addition salts. In this way there are some methods in the Ref: 130457 prior art which are satisfactory for the stabilization of enalapril and its acid addition salts, but not for quinapril and its acid addition salts. U.S. Patent No. 5,562,921 discloses that stable tablets comprising enalapril maleate can be prepared by restricting the inactive ingredients used in the tablets to certain discovered ingredients that do not cause degradation. However, since quinapril and its acid addition salts are less stable than enalapril maleate, this process does not work with quinapril and its acid addition salts. Both U.S. Patent No. 5,350,582 and U.S. Patent No. 5,573,780 disclose that stable tablets can be made by reacting the enalapril maleate with an alkaline sodium compound to convert the enalapril maleate to enalaprilsodium maleate. It was found that enaprilsodium is much more stable than enalapril maleate. U.S. Patent No. 4,830,853 discloses that certain ACE inhibitors, and in particular quinapril, can be stabilized against oxidation and discoloration by including ascorbic acid or sodium ascorbate in the composition. However, it appears that this process does not stabilize quinapril or its addition salts sufficiently to be commercially useful, since the products currently on the market do not use this process. Finally, the Patent of the United States No.

No. 4,743,450 discloses that certain ACE inhibitors can be stabilized, and in particular, quinapril and its acid addition salts when preparing solid compositions including an alkaline compound as a stabilizer. Magnesium, calcium and sodium compounds are preferred, and magnesium is more preferred. All examples of this patent relate to the solid dosage forms comprising quinapril hydrochloride as the active drug and magnesium carbonate as the stabilizer. There is also a publication of Gu et al., "Drug-Excipient Incompatibility Studies of the Dipeptide Angiotensin Converting Enzyme Inhibitor, Moexipril Hydrochloride: Dry Powder vs. Wet Granulation", Phar Res. 7 (4): 370-383. This publication discloses that moexipril hydrochloride can be stabilized by preparing compositions comprising moexipril hydrochloride and an alkaline stabilizing agent selected from sodium bicarbonate, sodium carbonate and calcium carbonate. It is stated that stabilization is carried out only when the compositions are prepared by a wet granulation process. At the conclusion of the publication, it is postulated that the stabilization results from the neutralization of the acidic drug by the basic excipient on the external surface of the granulated material. It is also established that it is possible for a portion of the moexipril to be converted to alkaline salts by means of granulation. It seems in this way that Gu et al teaches that only a portion (if any) of the drug can be converted, and only that portion on the external surface of the granules, to the alkaline salt, and that in this way the stable product is totally or mainly not from the conversion to alkaline salts, but from the stabilization of the moexipril hydrochloride by the presence of the alkaline stabilizing compound in the final product. Gu et al is consistent in this way with the teaching of U.S. Patent No. 4,743,450, which, as mentioned hereinbefore, teaches stable compositions comprising the unstable drug, stabilized by the presence of an alkaline compound in the final composition. Tablets containing quinapril hydrochloride are sold in the United States and elsewhere under the brand name Accupril® by Warner-Lambert Company. The label on these tablets indicates that the tablets contain quinapril hydrochloride and magnesium carbonate. This indicates that these tablets are compositions according to the teaching of U.S. Patent No. 4,743,450. There are certain problems inherent in the teaching of U.S. Patent No. 4,743,450. In particular: 1. Examples of U.S. Patent No. 4,743,450 indicate a ratio of magnesium carbonate to quinapril hydrochloride from about 5.8 to about 16.5 by weight, so that it appears that the required amount of the magnesium compound it is large and substantially exceeds the amount of quinapril hydrochloride. 2. By using the method of U.S. Patent No. 4,743,450, it is difficult to accurately control the exact final ingredients in the composition. Quinapril hydrochloride and magnesium carbonate are capable of forming an acid-base reaction. It is difficult to control the process to completely avoid the acid-base reaction in the preparation of the composition. Thus, if the teaching of U.S. Patent No. 4,743,450 is followed, the exact composition of the final product is uncertain and probably variable. In the light of the prior art, the object of the present invention is to allow a stable composition comprising a quinapril salt which solves these limitations of the prior art. DESCRIPTION OF THE INVENTION It has been found that the msagnesium salt of quinapril (ie, quinaprilmagnesium) is sufficiently stable to allow stable solid compositions, without the presence of an alkaline stabilizing compound in the final composition. It has also been discovered that stable solid compositions comprising quinaprilmagnesium can be prepared by using quinapril or an acid addition salt thereof, by reacting quinapril or the acid addition salt with an alkaline magnesium compound, to thereby convert all or substantially all quinapril or acid addition salt to quinaprilmagnesium. Since the purpose of the present invention is to remove unstable quinapril or acid addition salt thereof and replace it with stable quinaprilmagnesium, it will be understood that "all or substantially all" in the preceding paragraph means that the remaining amount of quinapril or salt of acid addition, if any, will be sufficiently small that any degradation thereof will not be significant for the stability of the final product. It will therefore be understood that "all or substantially all" means that at least about 80% of the quinapril or the addition salt thereof is converted to quinaprilmagnesium, preferably at least 90%, more preferably at least 95%, and more preferably 100% or virtually 100%. The quinapril or the acid addition salt thereof used in the process will preferably be quinapril hydrochloride. The alkaline magnesium compound will preferably be magnesium hydroxide or the magnesium salt of a weak acid such as, for example, magnesium carbonate. Magnesium oxide can be used instead of magnesium hydroxide, since the magnesium oxide will be converted to magnesium hydroxide in the presence of water. The molecular formula for quinapril hydrochloride is C25H30N2O5. HCl and the molecular weight is 475.0 g. The molecular equations, to convert quinapril hydrochloride to quinaprilmagnesio plus magnesium chloride, to react with magnesium hydroxide and magnesium carbonate are as follows: 1) When using magnesium hydroxide: 2C25H30N2O5.HCI + 2Mg (OH) 2? g (C25H29N20s) 2 + MgCl2 + 4H20 2) When using magnesium carbonate: 2C25H3oN205.HCl + 2MgC03? Mg (C25H29N205) 2 + MgCl2 + 2H20 + 2C02 It can be seen that a complete conversion of the quinapril hydrochloride to quinaprilmagnesium plus magnesium chloride requires for each mole (475 g) of quinapril hydrochloride, the following amount of the alkaline magnesium compound: ) if magnesium hydroxide is used, one mole, which is 58. 3 g. ii) If magnesium carbonate is used, one mole, which is 84.3 g. If only the minimum amount of the alkaline magnesium compound, calculated in this way, is used, it is possible that the reaction may not reach completion, leaving some of the quinapril or acid addition salt without converting to quinaprilmagnesium. In this way it is preferable to use an excess amount of the alkaline magnesium compound, to help ensure that the reaction is complete or substantially complete. A reaction for converting quinapril or acid addition salt thereof to quinaprilmagnesium can not be accomplished simply by mixing the quinapril or the acid addition salt together with the alkaline magnesium compound in dry form. It is necessary in this way to mix and react the quinapril or the acid addition salt and the alkaline magnesium compound with the aid of a solvent, which may be water or an organic solvent or a mixture of water and an organic solvent, and then evaporate the solvent to obtain a dry substance. The solvent will preferably be a mixture of water and an organic solvent, and a preferred organic solvent is acetone. After the solvent is evaporated, the dried material obtained will be further processed in a dosage form, such as a tablet or capsule. This process can be carried out in any of several ways, as follows: i) The quinapril or the acid addition salt and the alkaline magnesium compound can be reacted by adding them to the solvent and mixing in the liquid state until the reaction is complete . As mentioned hereinabove, the solvent may be water or an organic solvent, or a mixture of water and one or more organic solvents. The solvent will preferably be a mixture of water and an organic solvent, and more preferably a mixture of water and acetone. Preferably the amount of the solvent will be sufficient to completely dissolve the resulting quinaprilmagnesium, but not necessarily the excess of the alkaline magnesium compound, assuming that it is used in excess. After the reaction is completed, it is necessary to evaporate the solvent. This can be done, for example, by filtering the liquid to remove the extra alkaline magnesium compound, if any, and then spray drying. The resulting dry powder will be a mixture of quinaprilmagnesium and the magnesium salt of the acid used in the acid addition salt of quinapril (ie, magnesium chloride if quinapril hydrochloride is used). This dry powder can then be mixed with other suitable excipients (i.e., inactive ingredients such as, for example, lactose), and that mixture can be further processed into solid compositions; that is, compressed into tablets or used to fill two-piece hard gelatin capsules. The quinapril or the acid addition salt and the alkaline magnesium compound can be reacted in a liquid state as described in item i) above. However, instead of evaporating the solvent then, the resulting slurry or suspension can be used to wet granulate other excipients, and the wet mass can then be dried, for example, in an oven or a fluid bed dryer. The dry mass can then be compressed into tablets or used as a filler for the capsules, with or without the addition of other excipients. iii) Quinapril or acid addition salt can be mixed with one or more excipients, for example lactose, in a dry state, and then the dry mixture can be wet granulated with a solution or suspension of the alkaline magnesium compound in a adequate solvent, so a moist mass is formed. A sufficient amount of the appropriate solvent should be used and the mass should be allowed to sufficiently moisten for a sufficient time to allow the reaction between the quinapril or the acid addition salt and the alkaline magnesium compound to be completed or substantially completed, before Remove the solvent by drying the wet mass. The wet mass is then dried, and the dried material can then be compressed into tablets or used as a filler for the capsules, with or without the addition of other excipients. iv) The magnesium compound can be mixed with other excipients, for example lactose, in a dry state, and then the dry mixture can be wet granulated with a solution or suspension of quinapril or the acid addition salt in a suitable solvent , so a moist mass is formed. Again, a sufficient amount of suitable solvent should be used and the mass should be allowed to sufficiently moisten for a sufficient time to allow the reaction between the quinapril or the acid addition salt and the alkaline magnesium compound to be completed or substantially completed, before the solvent is removed by drying the wet mass. The wet mass is then dried, and the dried material can then be compressed into tablets or used as a filler for the capsules, with or without the addition of other excipients. v) Both the quinapril or the acid addition salt thereof and the alkaline magnesium compound can be mixed with other excipients, for example lactose, in a dry state and then the dry mixture can be wet granulated with a solvent to form a wet mass. Again, a sufficient amount of suitable solvent should be used and the mass should be allowed to sufficiently moisten for a sufficient time to allow the reaction between the quinapril or the acid addition salt and the alkaline magnesium compound to be completed or substantially completed, before the solvent is removed on drying. The wet mass is then dried, and the dried material can then be compressed into tablets or used as a filler for the capsules, with or without the addition of other excipients. The invention will be further understood from the following examples which are proposed to be illustrative but not to limit the invention. EXAMPLE 1 The following examples are mixed together for 30 minutes: Quinapril Hydrochloride 10.0 g Magnesium Hydroxide 10.0 g Povidone 28.77 g Water 480 g Acetone 240 g 760 g In the liquid mixture, 10.0 g of quinapril hydrochloride are reacted with 1.23 g of magnesium hydroxide to yield 9.47 g of quinaprilmagnesium plus 1.00 g of magnesium chloride, plus 0.76 g of water. The liquid is then filtered to remove the excess magnesium hydroxide. Therefore the material dissolved in water and acetone after filtration is: Quinaprilmagnesium 9.47 g Magnesium chloride 1.00 g Povidone 28.77 g TOTAL 39.24 g The spray-dried powder thus contains quinaprilmagnesium in a concentration of 9.47 g of 39.24 g. Due to the relative molecular weights of quinaprilmagnesium versus quinapril, 9.47 g of quinaprilmagnesium is equivalent in activity to 9.24 g of quinapril. Therefore the power of the spray-dried powder expressed as equivalent to quinapril is 9.24 g per 39.4 g. A portion of the spray-dried powder is mixed with other ingredients as follows: Spray dried powder 11.0 g Lactose monohydrate 13.0 g Magnesium stearate 0.25 g Red ferric oxide 0.7 g Colloidal silicon dioxide 0.05 g 25.0 g This sample is compressed into tablets each weighing 50 mg. In this way each tablet contains 22 mg of the spray-dried powder, which in turn contains 5.3 mg of quinaprilmagnesium, equivalent to approximately 5.2 mg of quinapril. EXAMPLES 2 TO 4 The ingredients are used as follows: Example 2 Example 3 Example 4 Quinapril Hydrochloride 5.42 g 5.42 g 5.42 g Magnesium hydroxide 5.42 g 5.42 g 5.42 g Anhydrous lactose 37.16 g 37.16 g 37.16 g Water 12.0 g 6.0 g 0 g Acetone 0 g 6.0 g 12.0 g TOTAL 60.0 g 60.0 g 60.0 g Total without solvent 48.0 g 48.0 g 48.0 g The procedure followed is to mix the first three ingredients together, and then add the solvent (ie, water and / or acetone as shown) and mix well again. The wet mass is allowed to stand for 30 minutes and then mixed again before drying, to ensure that the mixture is sufficiently wetted for a sufficient time to allow the completion or substantially complete reaction between quinapril hydrochloride and hydroxyl. magnesium. The wet mass is then dried in an oven at 60 ° C for four hours and then the dried material is passed through a # 20 screen to produce small granules. For the resulting fine granules of each of these examples, 1.0 g of magnesium stearate is mixed with 24 g of the granules, and this mixture is compressed into 50 mg tablets of weight each. Due to the relative amounts of the various ingredients used and the relative molecular weights, it is concluded that each tablet of each of examples 2, 3 and 4 contains about 5.1 mg of quinaprilmagnesium equivalent to about 5.0 mg of quinapril. STABILITY All the tablets of Examples 1, 2, 3 and 4 are tested for stability by storing the samples at an elevated temperature of 40 ° C and a high relative humidity of 75% for four days and then testing the samples for the degradation products. that result from hydrolysis and cyclization. The results are as follows: Example No. 1 2 3 4 Product of cyclization 0.80% 0.46% 0.50% 1.62% Product of hydrolysis 1.48% 6.02% 4.49% 4.67% These levels of the degradation products, and in particular the levels of the cyclization product are substantially lower than those obtained with the tablets comprising quinapril hydrochloride which has neither been converted to quinaprilmagnesium nor stabilized by the addition of a stabilizer. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (21)

1. CLAIMS Having described the invention as above, it is claimed as property contained in the following claims: 1. A process for preparing a solid pharmaceutical composition comprising quinaprilmagnesio, the process is characterized in that it comprises the step of reacting a quinapril or a salt of acid addition thereof with an alkaline magnesium compound in the presence of a solvent to thereby convert all or substantially all of the quinapril or the acid addition salt of quinapril to quinaprilmagnesium.
2. 2. A process according to claim 1, characterized in that it comprises the steps of: i) Adding the quinapril or the acid addition salt thereof and the alkaline magnesium compound to the solvent and mixing in the liquid state; ii) Evaporate the solvent to obtain a dry material; and iii) Further process the dried material towards the solid pharmaceutical composition.
3. 3. A process according to claim 2, characterized in that before the solvent is evaporated, the liquid is filtered to remove the unreacted alkaline magnesium compound.
4. 4. A process according to claim 2 or 3, characterized in that the solvent is evaporated by spray drying.
5. 5. A process according to claim 1, characterized in that it comprises the steps of: i) Adding the quinapril or the acid addition salt thereof and the alkaline magnesium compound to the solvent; i) Use the resulting solution or suspension to wet granulate other excipients to obtain a moist mass; iii) Dry the wet mass to obtain a dry mass; and iv) Further process the dry mass towards the solid pharmaceutical composition.
6. 6. A process according to claim 1, characterized in that it comprises the steps of: i) Adding the alkaline magnesium compound to the solvent; ii) Using the resulting solution or suspension to wet granulate a mixture of quinapril or the acid addition salt thereof and one or more excipients to obtain a wet mass; iii) Dry the wet mass to obtain a dry mass; and iv) Further process the dry mass towards the solid pharmaceutical composition.
7. 7. A process according to claim 1, characterized in that it comprises the steps of: i) Adding the quinapril or the acid addition salt thereof to the solvent; ii) Using the resulting solution or suspension to wet granulate a mixture of the alkaline magnesium compound and one or more excipients to obtain a wet mass; iii) Dry the wet mass to obtain a dry mass; and iv) Further process the dry mass towards the solid pharmaceutical composition.
8. A process according to claim 1, characterized in that it comprises the steps of: i) Mixing the quinapril or the acid addition salt thereof and the alkaline magnesium compound with 1 or more different excipients; ii) Add a solvent and mix to obtain a moist mass; iii) Dry the wet mass to obtain a dry mass; and iv) Further process the dry mass towards the solid pharmaceutical composition.
9. 9. A process according to any of claims 1 to 8, characterized in that the solvent comprises water.
10. 10. A process according to any of claims 1 to 8, characterized in that the solvent comprises an organic solvent.
11. 11. A process according to any of claims 1 to 8, characterized in that the solvent comprises water and an organic solvent.
12. 12. A process according to claim 10 or 11, characterized in that the organic solvent is acetone.
13. 13. A process according to any of claims 1 to 12, characterized in that the quinapril or the acid addition salt thereof is quinapril hydrochloride.
14. 14. A process according to any of claims 1 to 13, is characterized in that the alkaline magnesium compound is magnesium hydroxide, magnesium oxide or the magnesium salt of a weak acid.
15. 15. A process according to claim 14, characterized in that the alkaline magnesium compound is magnesium hydroxide.
16. 16. A process according to claim 14, characterized in that the alkaline magnesium compound is magnesium carbonate.
17. 17. A process according to any of claims 1 to 16, characterized in that the percentage of quinapril or the acid addition salt converted to quinaprilmagnesium is at least about 80%.
18. 18. A process according to any of claims 1 to 16, characterized in that the percentage of the quinapril or the acid addition salt thereof converted to quinaprilmagnesium exceeds 80%.
19. 19. A process according to any of claims 1 to 16, characterized in that the percentage of the quinapril or the acid addition salt thereof converted to quinaprilmagnesium exceeds 90%.
20. 20. A process according to any of claims 1 to 16 is characterized in that the percentage of quinapril or acid addition salt thereof converted to quinaprilmagnesium exceeds 95%.
21. 21. A solid pharmaceutical composition is characterized in that it comprises quinaprilmagnesium when prepared by a process according to any of claims 1 to 20.