GB2062468A

GB2062468A - Stable solutions of hydrogenated ergotalkaloids and heparin

Info

Publication number: GB2062468A
Application number: GB8036009A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1979-11-12
Filing date: 1980-11-10
Publication date: 1981-05-28
Also published as: ZA807005B; CH650930A5; AT371997B; ATA550480A; HU183244B; PT72041A; IE50372B1; DK155144B; DE2945636A1; IE802340L; FI72045B; IL61447A0; GR72128B; IL61447A; DK477880A; JPS5686116A; PH22800A; AU535357B2; FI803456L; AU6426580A

Description

1 GB 2 062 468 A 1

SPECIFICATION

Stable solutions of hydrogenated ergotalkaloids The present invention relates to pharmaceutical compositions in the form of stable solutions and comprising as active ingredients a combination of a) a compound of formula 1, 0 R1 OH 0 C-NH- N X 0 0 2 H dNI H wherein R is hydrogen orCI-4alkyl, R, is methyl, ethyl or isopropyl, R2 is isopropyl, sec.-butyl, isobutyl or benzyi, and X is hydrogen or methoxy, 1 50 1 80 or a pharmaceutically acceptable acid addition salt 90 thereof; and b) heparin ora pharmaceutically acceptable salt thereof.

Previous attempts to prepare pharmaceutical compositions in solution form comprising mixtures 95 of active i n g red ie nts a) a n d b) as affo resa id (fo r example of d ihydroergota mine and dihydroer govaline ortheir salts, e.g. the methane sulfonate, or of 6 - nor - 6 - isopropyl - 9,10 dihydro - 2',8 - methyl - 5'a - benzy] - ergopeptine or its salts, e.g. the male ate, and of heparin or its salts, e.g. the sodium salt) have not met with success. First the individual ingredients are themselves unstable in solution.

Secondly when combined in solution, the ingre dients a) and b) react to form difficultly soluble salts which precipitate out of the solution. The obtained solutions accordingly possess very low stability.

They cannot be kept in reserve for periods of more than a few hours and are thus of little practical value.

Various proposals have been made to surmount this problem. Thus it has been suggested to use e.g the methane sulfonate salt of dihydroergotamine in the form of a solid solution employing polyvinylpyrrolidone. Salt formation can be delayed in this manner, but only for a relatively limited period of time. More recently Iyophilised preparations have been developed for use in the preparation of injectable solutions.

As an alternative, individually stabilized solutions comprising components a) and b) separately, have been developed. The individually stabilized solutions are then brought into admixture shortly before administration.

Clearly none of these proposals provides a satis- factory, practical answer to the problem. The development of stabilized solution forms comprising ingredients a) and b) in combination, having a prolonged shelf-life, capable of transport and storage and re-cly for use as and when required has remahied a major objective.

In accordance with the present invention it has now surprisingly been found that the above problems may be overcome and clear solutions of component a) and b) in combination obtained, which are stable over prolonged periods of time, e.g. for two years and more, employing a carrier medium comprising.

c) water; d) a pharmaceutically acceptable mono- or poly-alcohol; e) an acetanilide anaesthetic or a pharmaceuti- cally acceptable acid addition salt thereof; and f) urea andlor the calcium salt of ethylenediaminetetraacetic azid.

Accordingly the present invention provides, in a first aspect a pharmaceutical composition in stable solution form comprising as active ingredients a combination of a component a) and a component b) as hereinbefore defined and a carrier medium com- prising c), d), e) and f) as hereinbefore defined.

Preferalilythe compositions according to the invention have a pH of from 4 to 6.

Suitabe pharmaceatically acceptable acid addition salt forms of the compounds of formula 1, include e.g. the methane sulfonates, maleates and tartrates. Suitable pharmaceutically acceptable salts of heparin include e.g. the sodium, potassium and calcium salt.

Preferred ingredients a) are dihydroergotamine or a pharmaceuticaily acceptable acid addition salt thereof, in particu[arthe methane sulfonate, dihydroerge!aline or a pharmaceutically acceptable acid addition salt thereof, in particular the methane sulfonate and 6 - nor - 6 - isopropyl 9,10 - 2'p - methyl - 5'a - benzyl - ergotpeptine and the pharmaceutically acceptable acid salts thereof, in particularthe maleate. When b) is present in pharmaceutically acceptable salt form this is preferably the sodium salt.

The ingredients a) and b) are preferably present in a ratio of 1 mg compound of formula 1: 500 to 70,000 I.U., more preferably 2,000 to 20,000 I.U. heparin. When ingredient a) andlor b) is present in pharmaceutically acceptable salt form the equivalent amount of salt form giving the stated ratios forthe free compound is employed.

Components c) and d) are preferably present in an amount of 45 to 72% and 28 to 55% respectively based on the total volume of the composition.

Preferred components d) are ethanol, propylene glycol, polyethylene glycol having an average molecularweight of 400, diethylene glycol and glycerol, as well as mixtures thereof. More preferably component d) comprises a mixture of (i) ethanol and (ii) triethylene glycol or of (iii) glycerol and (iv) propylene glycol. In such mixtures (i) and (ii) are preferably present in a ratio of from 1:6 to 10, more preferably 1:8 parts by weight and (iii) and (iv) are preferably present in a ratio of from 1:8 to 12, more preferably 1:10 parts by weight.

BY the term "acetanilide anaesthetic" as used in respect of component e) is meant any member of the class of physiologically acceptable acetanilide derivatives having anaesthetic activity, including the various known anaesthetically active 2 - amino - N - phenyl - acetanilide derivatives. Preferred 2 GB 2 062 468 A 2 acetanilide anaesthetics are 2 (diethylamino) - N - (2,6 - dimethyl - phenyl) - acetamide (also known as Lidocaine), 2 - (butylamino) - N - (2 - chloro - 6 - methyl - phenyl) acetamide (also known as Hosta cain) and 2 - (2 - diethylaminoacetamido) m - toluic 70 acid methyl ester (also known as Baycain). Apart from their clearly advantageous anaesthetic proper ties e.g. when the compositions are administered by injection, it has surprisingly been found that the pre sence of ingredient e) is essential in contributing to the long-term stability properties of the inventive compositions.

Preferably ingredient e) is present in an amount of 1 to 2% by weight based on the total weight of the composition. Ingredient f) is preferably present in an 80 amount of 2 to 5 mg based on an amount of 5,000 I.U. to 2,500 I.U. heparin, or an amount of 5 to 10 mg based on an amount of 2,500 I.U. heparin.

The compositions according to the invention may contain further additives, e.g. stabilizing agents, pre serving agents, colouring agents and surfactants, as known in the art. Suitable preserving agents include e.g. chlorocresol ortrichloro-tert.-butanol, suitably present in an amount of from 0.2 to 1% based on the total weight of the composition.

The compositions of the invention are suitably put up in unit dosage form, e.g. in the form of ampoules for injection, including e.g. throw-away syringes containing a predetermined amount of the composi tion. Such unit dosage forms preferably contain 0.5 mg of the compound of formula 1 andlor 2,500 or 5,000 I.U. heparin per unit dosage.

In addition to the foregoing the present invention also provides a process for the preparation of phar maceutical compositions in accordance with the invention, which process comprises bringing an active ingredient a) and an active ingredient b) as hereinbefore defined into solution in a carrier medium comprising components c), d), e) and f) as hereinbefore defined.

Preferably the process is carried out step-wise in a procedure comprising preparing a solution of an active ingredient a) in 4) a solvent medium comprising components d) and e); 2) preparing a solution of an active ingredient b) in a solvent medium comprising components c) and f); 3) combining the solutions obtained via steps 1) and 2); and 4) optionally adding additional component c) andlor d).

The process of the invention is preferably carried out with protective gassing, e.g. C02-gassing, of the solutions. If the pH of the obtained solution is outside the range pH 4 to 6, it is preferably adjusted to within this range e.g. by the addition of an appropriate quantity of a pharmaceutically acceptable acid e.g. an organic acid. When an acid addition salt of a compound of formula 1 is employed as ingredient a), the added acid will preferably correspond to the salt form employed. Thus when ingredient a) is in methane sulfonate salt form, any adjustment of the pH necessary will preferably be effected by addition of methane sulphonic acid.

The obtained composition may be put-up in unit dosage form as hereinbefore described, e.g. by filling into ampoules after filtration, preferably with protective, e.g. CO,, gassing.

The solutions according to the invention may be used fortherapeutic treatment or prophylaxis as known in the art; for example as antithrombolic agents particularly in the prophylaxis of postoperative thrombosis as described in e.g. U.K. Patent Specification No. 1,557,331 (- NZ Patent Specification No. 182797).

The following examples are illustrative of the present invention: Example 1 Preparation of a 5,000 L U. heparin 10.5mg Dihydroergotamine injectable solution:

1)18.4 kg of propylene glycol and 1.84 kg of anhydrous glycerol are poured into a 50 litre stirring vessel, and the mixture stirred for 10 minutes with C02-gassing. 0.0286 kg of dihydroergotamine methane sulphonate and 0.426 kg of lidocain hydrochloride are dissolved in the mixture with stirring and C02-gassing over a period of a further 30 minutes.

2) 18.4 kg of water (suitable for injection) are poured into a 30 litre stirring vessel and stirred for 10 minutes with C02-gassing. 1.896 kg of heparin sodium salt (= circa 285.7 million I.U.) and 0.114 kg of the calcium salt of ethylenediaminetetraacetic acid (commercially available underthe name calciumtriplex) are then dissolved in thewaterwith stirring and C02-gassing over a further 30 minutes.

(3) The solution obtained via step 2) above is added with stirring and C02-gassing to the solution obtained via step 1). The vessel in which solu tion 2) is obtained isthen washed out with 1 kg of water (suitable for injection) and is also added to the step 1) solution. The combined solutions are stirred for a further 10 minutes with C02-gassing. The pH of the solution is ca.

5.7.

The solution is made up to a weight of 42.810 kg = 40 litres by the addition (suitable for injection).

5) The obtained solution is pre-filtered using a membrane-filter (0.2 gm: Ultipor nm. Pall) and then passed via a sterilized pressure-filtration apparatus having a membrane filter (0.2 gm: Ultipor nm. Pall) at 1.7 bar with C02 directly into an ampoule-filling machine. The solution is filled in 0.7 mi dosages into 1 mi ampoules under sterile conditions. Example 11 Steps 1) - 4) of example 1 are repeatedly precisely using the following quantities of ingredients:

Step 1) Propylene glycol Anhydrous glycerol Dihydroergotamine- methane sulphonate Lidocain-I-ICM20 15.30 kg 1.53 kg 0.03 kg 0.32 kg 3 GB 2 062 468 A 3 Step 2) Water (for injection) Heparin-Na salt Ethylenediaminetetraacetic acid-Ca salt (hexahydrate) Step 3) 10 No change 12.00 kg 0.997 kg million L1J.) 0.12 kg Step 4) The solution is made up to a weight of 32.040 kg litres by the addition (for injection).

Step 5) The resultant solution is filled into 1 m] ampoules in 0.5 m] dosages.

Example 111 i) The method of example 1 is repeated using an equivalent quantity of a 1:10 (parts by weight) mixture of ethanol and triethylene glycol in place of propylene glycol and glycerol in step 1).

ii) The method of example 1 is repeated using an equivalent quantity of hostacain in place of lidocain in step 2).

iii) The method of example 1 is repeated using an equivalent quantity of Baycain in place of lidocain in step 2).

Claims

1. A pharmaceutical composition instable solu- tion form comprising as active ingredient a combina- tion of a) a compound of formula 1, X H o HN 0 RI OH 11 0 15 C-NH- N 0 R 2 wherein R is hydrogen orC,,alkyl, IR, is methyl, ethyl or isopropyl, R2 is isopropyl, sec.-butyl, isobutyi or benzyi, and 50 X is hydrogen or methoxy, or a pharmaceutically acceptable acid addition salt thereof; and b) heparin or a pharmaceutically acceptable salt thereof, and a carrier medium comprising c) water; d) a pharmaceutical ly acceptable mono- or polyalcohol; e) an acetanilide anaesthetic ora pharmaceutically acceptable acid addition saitthereof; and f) urea and/o r the calcium salt of ethyl ened ia m i netetraacetic acid.

2. Composition according to Claim 1, having a pH of from 4 to 6.

3. Composition according to Claim 1 or2, wherein the compound of formula 1 is dihydroer- gotamine.

4. Composition according to Claim 1 or2, wherein the compound of formula 1 is dihydroergovaline. 70

5. Composition according to Claim 3 or4, wherein the compound of formula 1 is in the form of the methane sulphonate.

6. Composition according to Claim 1 or2 wherein the compound of formula 1 is 6 - nor - 6 - isopropyl - 9,10 - dihydro 2'jS - methyl - Ta - benzyl - ergopeptine.

7. Composition according to Claim 6, wherein the compound of formula 1 is in the form of the maleate. 80

8. Composition according to anyone of Claims 1 to 7 wherein the heparin is in the form of the sodium salt.

9. Composition according to anyone of Claims 1 to 8 wherein the compound of formula 1 and heparin 85 are present in a ratio of 1 mg:500 to 70,000 I.U.

10. Composition according to Claim 9 wherein the ratio is 1 mg:2,000 to 20,000 I.U.

11. Composition according to anyone of Claims 1 to 10 wherein component c) is present in an amount of from 45 to 72% based on the total volume of the composition.

12. Composition according to anyone of Claims 1 to 11 wherein component cl) is present in an amount of from 28% to 55% based on the total vol- ume of the composition.

13. Composition according to anyone of Claims 1 to 12 wherein component cl) is selected from the group consisting of ethanol, propylene glycol, polyethylene glycol of average mol. wt. ca. 400, diethyleneglycol, glycerol and mixtures thereof.

14. Composition according to Claim 13 wherein component d) comprises either (i) ethanol and (ii) triethylene glycol or (iii) glycerol and (iv) propylene glycol.

15. Composition according to Claim 14 wherein (i) and (ii) are present in a ratio of from 1:6to 10 parts by weight or (H) and (iv) are present in a ratio of from 1:8 to 12 parts by weight.

16. Composition according to Claim 15 wherein (i) and (ii) are present in a ratio of from 1:8 parts by weight or (iii) and (iv) are present in a ratio of from 1:10 parts by weight.

17. Composition according to anyone of Claims 1 to 16 wherein the acetanilide anaesthetic is selected from the group consisting of Lidocain, Hostacain and Baycain.

18. Composition according to anyone of Claims 1 to 17 wherein the acetanilide anaesthetic is present in an amount of from 1 to 2% based on the total weight of the composition.

19. Composition according to anyone of Claims 1 to 18 wherein component f) is present in an amount of 2 to 5 mg based on an amount of 5,000 I.U. to 2,500 I.U. heparin or in an amount of 5 to 10 mg based on an amount of 2,500 I.U. heparin.

20. Composition according to anyone of Claims 1 to 19 in unit dosage form.

21. Composition according to anyone of Claims 1 to 19 in ampoule form for injection and containing 0.5 mg of compound of formula] and/or2,500 or 4 GB 2 062 468 A 4 5,000 LU. heparin.

22. Process for the preparation of a pharmaceutical composition according to any one of Claims 1 to 21 which process comprises bringing an active ingredient a) and an active ingredient b) into solution in a carrier medium comprising components c), d), e) and f).

23. Process according to Claim 22, which comprises the individual steps of 1) preparing a solution of an active ingredient a) in a solvent medium comprising components d) and e); 2) preparing a solution of an active ingredient b) in a solvent medium comprising components c) and f); 3) combining the solutions obtained via steps 1) and 2); and 4) optionally adding additional component c) andlor d).

24. Process according to Claim 22 or23 con ducted with inert gassing during solution.

25. Process according to anyone of Claims 22 to 24 wherein the obtained solution is adjusted to pH 4 to 6.

26. Process according to Claim 22, substantially as herein before described with reference to the accompanying examples.

27. A pharmaceutical composition whenever prepared by a process as claimed in any one of Claims 22 to 26.

Printed for Her Majesty's Stationery Office by The Tweeddale Press Ltd., Berwick-upon-Tweed, 1981. Published at the Patent Office, 25Southampton Buildings, London, WC2A lAY, from which copies may be obtained.

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