IL96995A - Pharmaceutical compositions containing pimobendan and their preparation - Google Patents

Abstract

Pimobendan dosage forms for oral administration contain citric acid, ensuring constantly good absorption even with large pH variations in the gastrointestinal tract.

Description

Pharmaceutical compositions containing pimobendan and their preparation Dr. KARL THOMAE GmbH C. 82273 56224.701 Pimobendan Compositions This invention relates to orally administrable pharmaceutical compositions comprising pimobendan and methods for their preparation. Pimobendan is 4,5-dihydro-6- [2- (4-methoxyphenyl) -lH-benzimidazol-5-yl] -5-methyl-3 (2H) -pyridazinone and is a substance having cardiotonic, hypotensive and antithrombotic activities.

Pimobendan and other structurally different substances are described in European Patent No. 8391. However, unlike other substances described in that patent, the resorption of pimobendan when administered orally is prone to considerable inter- and intra-individual fluctuations when incorporated in known or conventional oral pharmaceutical forms. The reason for this is that pimobendan is characterised by a low and very highly pH-dependent solubility in aqueous media.

Depending on the buffer system used, about 100 to 300 mg of pimobendan dissolve per litre at a pH between 1 and 3 (corresponding to a 0.01 to 0.03% solution), but at pH 5 only about 1 mg/1 will dissolve in water (corresponding to a 0.0001% solution or 1 ppm) .

In in vivo tests on humans in which pimobendan was packed into hard gelatin capsules, one test subject showed no detectable blood level of pimobendan, a second test subject showed a very low blood level and a third showed higher blood levels. Overall, the blood levels of pimobendan fluctuated very considerably from one individual to another and the levels were generally too low. These unsatisfactory resorption characteristics can be explained primarily by the high pH-dependency of the solubility of pimobendan in aqueous media and by the fluctuating pH conditions in the gastrointestinal tracts of the test subjects. It is known that the pH of the gastric juices, particularly in patients who have been fasting, can fluctuate between 1 and 6, whereas in patients who have not fasted it is more frequently between 3 and 5 than 1 and 2.

It therefore appeared to be clear that the solubility of pimobendan could be increased by the simultaneous administration of an acid. In vitro tests showed, however, that pimobendan in 0.1 N hydrochloric acid (pH 1.1) dissolved in a quantity of only 100 mg/1 (corresponding to a 0.01% solution). In a fumaric acid solution (pH 2.27) only 50 mg/1 dissolve (corresponding to a 0.005% solution), in a 20% (by weight) tartaric acid solution (pH 1.2) 960 mg/1 dissolve (corresponding to a 0.096% solution), and in a 40% (by weight) tartaric acid solution (pH 0.7) only 3.9 g/1 dissolve (corresponding to a 0.39% solution). None of these levels is sufficient, or the quantity of acid required is no longer practicable for dissolving a sufficient quantity of the active substance and thereby ensuring reliable resorption, even if such quantities of these acids are administered orally simultaneously with the active substance.

Surprisingly, we have now succeeded in overcoming the low solubility and high pH-dependency of the solubility of pimobendan thereby ensuring a very satisfactory and more constant resorption, even when there are considerable pH fluctuations in the gastrointestinal tracts. This is achieved by formulating pimobendan together with citric acid in an acid: pimobendan ratio by weight of at least 5:1.

Thus viewed from one aspect the invention provides an orally administrable pimobendan-containing pharmaceutial composition comprising an intimate mixture of citric acid and pimobendan in a weight ratio of at least 5:1, optionally together with one or more pharmaceutical carriers or excipients.

The compositions of the invention may be produced by intimately mixing pimobendan with citric acid in a ratio of up to 1 part by weight of pimobendan per 5 parts by weight of citric acid, and subsequently processing it with conventional excipients to form a powder, pellets or granules for oral administration. The granules, powder or pellets may also be compressed with suitable excipients to form tablets which may, if desired, be covered with a flavour-masking coating.

Citric acid is a safe and well tolerated excipient which increases the solubility of pimobendan by a factor of 100, compared with artificial gastric juice (pH 1.2). Thus, 7.6g of pimobendan will dissolve per litre in an aqueous solution containing 20% by weight of citric acid (pH 1.4), whilst in an aqueous solution containing 40% by weight of citric acid (pH 1.0) as much as 12.1 g of pimobendan will dissolve per litre. These quantities of dissolved pimobendan are sufficient to ensure adequate resorption of the active substance even in patients who, when given conventional pimobendan preparations by oral route, showed either no detectable blood level or a very low and sharply fluctuating blood level of pimobendan.

Citric acid is difficult to process into solid preparations. To avoid the formation of salts of pimobendan with citric acid, which would increase the hygroscopicity of the formulation, it would appear that one should process the active substance and acid in two separate granulates. However, it has been found (see Examples lb to Id and 2a below) that when separated in this way the citric acid is unable to develop its full solubilising activity. However, it has been found that by intimately mixing pimobendan with citric acid to form a powder mixture which may subsequently be processed into granules, pellets or tablets, it is possible to obtain preparations with small amounts of citric acid which ensure adequate dissolution and sufficiently high blood levels of pimobendan.

Thus viewed from a further aspect the invention also provides a process for preparing compositions according to the invention in which citric acid and pimobendan in a weight ratio of at least 5:1 are brought into an intimately mixed form by granulation.

Technically, this can be achieved, for example, by aqueous or non-aqueous granulation, e.g. by granulation with alcohol or by the use of suitable granulating methods which make it possible to add the granulating fluid in accurately metered amounts, with simultaneous drying. Another possibility is the preparation of granules by dry granulation, these granules containing the active substance and citric acid intimately mixed. Owing to the hygroscopic properties of the citric acid, care must be taken to ensure that the compositions disintegrate rapidly in the release medium; in the case of tablets, this may be achieved for example by the addition of disintegrants, e.g. Amberlite IRP 88 (methacrylic resin with exchangeable protons) , Crospovidone (crosslinked polyvinylpyrrolidone) and microcrystalline cellulose, which simultaneously improve the compression properties of citric acid.

A weight ratio of pimobendan to citric acid of between 1:10 and 1:20 is preferred, the upper limit being defined by the ability of the preparations to be swallowed.

Viewed from a still further aspect the invention also provides a method of treatment of the 'human ■ OJC non-human animal body to combat cardiotonic, hypotensive and anti-thrombotic conditions, said method comprising orally administering to said body a pharmaceutical composition according to the invention.

The prevention of sharply fluctuating blood levels (both inter- and intra-individually) by the addition of citric acid can prehaps be explained as follows: when the intimate mixture of active substance and citric acid comes into contact with gastric juices, an acidic microsphere is formed around the particles due to the high rate of dissolution of the citric acid. This microsphere is always acidic, irrespective of the pH of the gastrointestinal juices, and ensures that the finely divided active substance reliably dissolves and is therefore freely available for resorption.

Solubility tests have shown, for pH values between 1 and 6, that the active substance dissolves out of this intimate mixture virtually irrespective of the pH. In addition, the active substance also forms supersaturated solutions with the citric acid which remain stable for hours. This ensures a high level of resorption in any case, even in patients with gastrointestinal juices of abnormally high pH. Of the many acids tested for this purpose, citric acid has unexpectedly proved to be outstanding; not only does it act as an acid, but it also serves as a solubilising agent and a stabiliser for the solution of active substance obtained. An important prerequisite for the dissolving of the active substance independently of the local physiological pH value is the intimate mixing of the pimobendan with the citric acid. For this, both substances should be present in powder form or as very small crystals, thereby ensuring contact with each other over a large surface area.

A comparison of the results from tests on dogs after oral administration of a composition according to Example la containing 5 mg of pimobendan, with those from a composition according to Example lb containing 5 mg of pimobendan and 50 mg of citric acid, showed that the pimobendan plasma level was approximately trebled by the form containing the citric acid compared with the form containing no citric acid. Each test was carried out on 5 experimental animals. The mean curves for the plasma levels of pimobendan found are shown in Figures 1 and 2 , in which the plasma level values are given in nanograms per millilitre as a function. of time.

Human trials using oral pimobendan compositions according to Examples 3b and 3c (capsules) on 11 test subjects gave the mean curves for the plasma levels of pimobendan shown in Figure 3. The maxima occurred at 1 to 1.5 hours after administration. In addition to the capsule formulations according to Examples 3b and 3c, the plasma level curves of pimobendan for the tablet according to Example 2b and the capsule according to Example 4 were each tested on 11 test subjects. It was found that the tablet containing only 50 mg of citric acid according to Example 2b is bioequivalent to the capsule formulation containing 209 mg of citric acid according to Example 4. The plasma levels of pimobendan were obtained by high pressure liquid chromatographic methods, resulting in the mean curves shown in Figure 4 (mean values ± standard deviations) .

By way of a comparison, a tablet formulation according to Example 3a, i.e. a formulation with no citric acid, was administered orally. This resulted in the curves for the plasma levels of pimobendan in three test subjects as shown in Figures 5a to 5c. If Figures 5a to 5c are compared with Figure 4, the superiority of the citric acid containing composition over a composition without citric acid becomes very clear.

This is made apparent by the reduced fluctuations in plasma levels of pimobendan.

It goes without saying, that instead of using pimobendan, one of its possible enantiomers can also be used with equal success.

The following non-limiting Examples are provided to illustrate the preparation of some oral pharmaceutical compositions of pimobendan. All percentages given are by weight. In these Examples : Amberlite IRP 88 = methacrylic resin with exchangeable H+ Collidone 25 = polyvinylpyrrolidone, average molecular weight 29,000 Avicel = macrocrystalline cellulose Polyplasdone XL = crosslinked polyvinylpyrrolidone = polyvinylpolypyrrolidone Compritol 888 = glyceryl monobehenate Tween 80 polyoxyethylene- (20) -sorbitan mono- oleate Explotab sodium carboxymethyl starch Aerosil 1 highly dispersed, X-ray amorphous silicon dioxide.

All measurements of rates of dissolution of pimobendan were carried out according to USP XXIII, paddle method, 150 rpm, in Mcllvaine buffer, pH 5.5 and in each case mean values were calculated from 3 individual measurements. r Example 1 Tablets containing 5 mq of pimobendan a) Tablets without citric acid Each tablet comprises (1) Pimobendan 5. 0 mg (2) Microcrystalline cellulose 58. 0 mg (3) Sec. calcium phosphate 72. 0 mg (4) Corn starch 54. 0 mg (5) Amberlite IRP 88 10. 0 mg (6) Magnesium stearate 1. 0 mg Total weight 200. 0 mg Some of the corn starch is dissolved in water with heating and the mixture of ingredients (1) to (4) is granulated therewith. (5) and (6) are added to the dried granules. Tablets 8 mm in diameter and weighing 200 mg are compressed from the finished mixture.

Results: Time (min) % pimobendan dissolved 5 8.5 10 10.2 15 10.7 20 10.8 30 10.8 b) Tablets containing 50 mg of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 50.0 mg (3) Microcrystalline cellulose 42.0 mg (4) Collidone 25 0.5 mg (5) Sec. calcium phosphate 52.0 mg (6) Corn starch 39.5 mg (7) Amberlite IRP 88 10.0 mg (8) Magnesium stearate 1.0 mg Total Weight 200.0 mg Some of the corn starch is dissolved in water with heating and ingredient (1), some of (3), (5) and some of (6) are granulated therewith. (2) and the remainder of (3) and (6) are granulated with the aqueous solution of (4) . The granules are dried and mixed together. (7) and (8) are added to the mixture of dried granules to form the final mixture. This is then compressed to form tablets 8 mm in diameter and weighing 200 mg.

The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.

Results; Time (min) % pimobendan dissolved 5 7.7 10 19.2 15 34.0 20 40.6 30 43.0 c) Tablets containing 103 ma of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 103.0 mg (3) Microcrystalline cellulose 35.0 mg (4) Collidone 25 1.0 mg (5) Sec. calcium phosphate 31.5 mg (6) Corn starch 81.5 mg Amberlite IRP 88 10.0 g Magnesium stearate 3.0 mg Total Weight 270.0 mg The tablets are produced analogously to those of Example lb.

The resulting tablets are 9 mm in diameter, and weigh 270 mg.

The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together. d) Tablets containing 206 mg of citric acid Each tablet comprises (1) Pimobendan 5. 0 mg (2) Citric acid 206. 0 mg (3) Avicel 50. 0 mg (4) Collidone 25 2. 0 mg (5) Sec. calcium phosphate 63. 0 mg (6) Corn starch 46. 0 mg (7) Amberlite IRP 88 20. 0 mg (8) Magnesium stearate 3. 0 mg Total Weight 395. 0 mg The tablets are produced analogously to those of Example lb.

The resulting tablets are 11 mm in diameter, and weigh 395 mg.

The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.

Results; Time (min) % pimobendan dissolved 5 23.8 10 59.0 15 67.0 30 69.0 Example 2 Tablets containing 2.5 ma of pimobendan a) Tablets containing 103 mg of citric acid Each tablet comprises (1) Pimobendan 2. 5 mg (2) Corn starch 23. 0 mg (3) Microcrystalline cellulose 26. 0 mg (4) Anhydrous calcium phosphate 31. 5 mg (5) Polyplasdone XL 59. 0 mg (6) Citric acid, fine particles (anhydrous) 103. 0 mg (7) Compritol 888 5. 0 mg Total weight 250. 0 mg (1) to (4) are granulated with aqueous starch solution. The other ingredients are added to the dry granules to make the final mixture. This is then compressed to form tablets measuring 9 mm in diameter and weighing 250 mg.

The active substance and acid initially are present separately, for ease of manufacture, but are subsequently mixed together.

Results: Time (min) % pimobendan dissolved 5 18.7 10 20.5 20 21.8 30 22.2 60 22.7 Tablets containing 50 ma of citric acid Each tablet comprises (1 Pimobendan 2.5 mg (2 Anhydrous powdered citric acid 50.0 mg (3 Avicel PH 101 13.0 mg (4 Anhydrous calcium hydrogen phosphate 15.0 mg (5 Undried corn starch 6.0 mg (6 Collidone 25 0.5 mg (V Insoluble polyvinylpyrrolidone 59.0 mg (8 Compritol 888 3.0 mg (9 Magnesium stearate 1.0 mg Total Weight 150.0 mg (6) is dissolved in ethanol and the mixture of ingredients (1) to (5) is granulated therewith. (7) to (9) are added to the dry granules to form the final mixture. This mixture is compressed to form tablets measuring 8 mm in diameter and weighing 150 mg.

The active substance and acid are present together in the same granulate.

Results: Time (min) % pimobendan dissolved 15 71.1 30 85.0 Example 3 Capsules containing 5 mg of pimobendan a) Capsules without citric acid Each capsule contains (1) Pimobendan 5.0 mg (2) Lactose 90.25 mg (3) Corn starch 36.0 mg (4) Tween 80 0.5 mg (5) Explotab 8.0 mg (6) Magnesium stearate 0.25 mg Total weight 140.0 mg The individual powders are intensively mixed together and packed, into size 4 hard gelatin capsules, the contents of each weighing 140 mg. b) Capsules containing 230 mg of citric acid Each capsule contains (1) Pimobendan 5.0 mg (2) Citric acid 230.45 mg (3) Collidone 25 3.78 mg (4) Magnesium stearate 0.77 mg Total Weight 240.00 mg (1) and (2) are intensively mixed together and granulated with an alcoholic solution of (3) . (4) is added to the dried granulate. The final mixture thus obtained is packed into size 1 hard gelatin capsules, the contents of each weighing 240 mg.

The active substance and acid are present together in the same granulate.

Results; Time ( in) % pimobendan dissolved 5 100 c) Capsules containinq 207 mq of citric acid Each capsule contains (1) Pimobendan, finely ground 5. 0 g (2) Citric acid 206. 5 mg (3) Microcrystalline cellulose 40. 0 mg (4) Aerosil 130 V 11. 0 mg (5) Collidone 25 4. 0 mg (6). Magnesium stearate 1. 5 mg Total Weight 268. 0 mg (1) is triturated with (2) . (3) and to the triturated material. The mixture is granulated with an alcoholic solution of (5) . (6) is mixed into the dry granulate. The finished mixture is packed into size 1 capsules, the contents of each weighing 268 mg.

The active substance and acid are present in one and the same granulate.

Results : Time (min) % pimobendan dissolved 84.1 90.2 91.7 92.5 Example 4 Capsules containinq 2.5 mq of pimobendan and 209 mq of citric acid Each capsule contains (1) Pimobendan 2.5 mg (2) Powdered citric acid 209.0 mg (3) Microcrystalline cellulose 40.0 mg (4) Silicon dioxide 11.0 mg (5) Polyvinylpyrrolidone 4.0 mg (6) Magnesium stearate 1.5 mg Total Weight 268.0 mg The tablets are produced analogously to those of Example 3c.

The active substance and acid are present in the same granulate.

Results; Time (min) % pimobendan dissolved 15 96.5 30 99.1 Example 5 Film coated tablet containing 2.5 mq of pimobendan and 50 mg of citric acid Each tablet comprises (1) Pimobendan 2. 5 mg (2) Powdered anhydrous citric acid 50. 0 mg (3) Avicel PH 101 13. 0 mg (4) Anhydrous calcium hydrogen phosphate 15. 0 mg (5) Undried corn starch 6. 0 mg (6) Collidone 25 0. 5 mg (7) Insoluble polyvinylpyrrolidone 59. 0 mg (8) Compritol 888 3. 0 mg (9) Magnesium stearate 1. 0 mg Total weight 150. 0 mg The preparation procedure is as described in Example 2b, but the finished mixture is compressed into biconvex tablets, which are each coated with 5 mg of hydroxypropyl-methylcellulose .

The active substance and acid are together in the same granulate.

Results: Time (min) % pimobendan dissolved 10 76.8 30 86.1

Claims (12)

Claims

1. An orally administrable pimobendan-containing pharmaceutial composition comprising an intimate mixture of citric acid and pimobendan in a weight ratio of at least 5:1, optionally together with one or more pharmaceutical carriers or excipients.

2. A composition as claimed in claim 1 in the form of a granulate, powder or pellets, optionally packed into capsules .

3. A composition as claimed in claim 1, in the form of the granulate, powder or pellets compressed with a suitable excipient into tablets which are optionally provided with a flavour-masking coating.

4. A composition as claimed in any of claims 1 to 3 , wherein the weight ratio of pimobendan to citric acid is between 1:10 and 1:20.

5. A composition as claimed in any of claims 1 to 4 containing a disintegrant .

6. A process for preparing a pharmaceutical composition as claimed in claim 1, wherein citric acid and pimobendan in a weight ratio of at least 5:1 are brought into an intimately mixed form by granulation.

7. A process as claimed in claim 6 wherein granulation is effected by dry granulation or in the presence of an optionally agueous granulating fluid with metered addition of granulating fluid and simultaneous drying.

8. A process as claimed in either of claims 6 and 7 wherein the resulting granulate is processed into pellets. 96995/2 - 18 -

9. A process as claimed in any one of claims 6 to 8 wherein the resulting granulate or pellets are compressed with suitable excipients into tablets which are optionally provided with a flavour-masking coating.

10. · A process as claimed in any one of claims 6 to 8 wherein the resulting granulate or pellets are packed into capsules.

11. A method of treatment of the non-human animal body to combat cardiotonic, hypotensive and antithrombotic conditions, said method comprising orally administering to said body a pharmaceutical composition as claimed in any one' of claims l to 5.

12. Pharmaceutical compositions as defined in claim 1 substantially as herein disclosed in any one of the Examples . For the Aopj icants, DR. REINHOLD, COHN AND PARTNERS BY : ■ Λ