GB1596948A

GB1596948A - Stable solutions of hydrogenated ergopeptide alkaloids

Info

Publication number: GB1596948A
Application number: GB23758/78A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-08-06
Filing date: 1978-05-30
Publication date: 1981-09-03
Also published as: NO147901C; FR2399248A2; IE47791B1; ZA784435B; NO782605L; DK337678A; GR72791B; CS203199B2; NL7808122A; CA1111348A; SE7808210L; IT7826407A0; ATA567378A; DE2735587A1; SE444114B; AU3867678A; YU188378A; AT364463B; FR2399248B2; BE869560R

Abstract

The invention relates to stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives of the formula I <IMAGE> in which R represents hydrogen or alkyl having 1-4 carbon atoms with the exception of tert-butyl, R1 represents methyl, ethyl or isopropyl, R2 represents isopropyl, sec-butyl, isobutyl or benzyl and X represents hydrogen or methyl, and their pharmacologically acceptable salts in a mixture of pharmacologically acceptable alcohols or mixtures thereof and water having a dielectric constant of not more than 50, and process for the preparation of the stable solutions.

Description

(54) STABLE SOLUTIONS OF HYDROGENATED ERGOPEPTIDE ALKALOIDS (71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to stable solutions of hydrogenated ergopeptide alkaloids (ergot alkaloids) and salt forms thereof.

Solutions of such compounds in predominantly aqueous media have the disadvantage that the concentration of the active species decreases on storage, because of various decomposition reactions. For this reason it is normalpractice to pass inert gas through the solution during filling of the vessels in which the solution is to be sold, and to protect the contents from air, light and high temperatures.

It has now been found that the stability of hydrogenated ergot alkaloids in solution is a function of the dielectric constant of the solution, and that stable solutions can be obtained by the use of a solvent system comprising a mixture of water and one or more alcohols, said solutions having a dielectric constant of 50 or less.

The present invention provides a stable solution comprising a) a hydrogenated ergopeptide alkaloid of formula I,

in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl, R1 is methyl, ethyl or isopropyl, R2 is isopropyl, sec-butyl, isobutyl or benzyl, and X is hydrogen or methoxy or a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof, b) a pharmacologically acceptable alcohol or mixture thereof, and c) water, said solution having a dielectric constant of 50 or less.

Preferred compounds of formula I are those in which R is methyl, X is hydrogen and R1 is isopropyl or methyl, provided that R1 is methyl only when R2 is benzyl.

Particular preferred compounds in which R is methyl and X is hydrogen are dihydro - lz- - ergocryptine (R1=isopropyl, R2=isobutyl), dlhydro - ts - ergocryptine (R1=isopropyl, R2=sec - butyl), dihydroergocornine (R1=R2=isopropyl), dihydroergocristine (R,=isopropyl, R2=benzyl) and dihydroergotamine (R1=methyl, R2=benzyl), together with their salt forms.

Suitable salt forms are salts of pharmacologically acceptable acids, for example the methanesulfonate, maleate and tartrate salt forms.

Particularly preferred are dihydroergotamine (DHE) and a 1:1:1 molar mixture of dihydroergocryptine (2:1 a:P), dihydroergocornine and dihydroergocristine (dihydroergotoxin).

Pharmacologically acceptable alcohols include pharmacologically acceptable monofunctional alcohols having up to 18 carbon atoms, preferably up to 10 carbon atoms and most preferably up to 3 carbon atoms. An especially preferred alcohol of this type is ethanol. Further alcohols which may be used according to the invention include pharmacologically acceptable polyfunctional alcohols having up to 6, preferably 2 to 3 hydroxy groups, and up to 6, preferably 2 or 3 carbon atoms, especially glycerol and propylene glycol. Polyfunctional alcohols may also be used in polymeric form, for example polyalkylene glycols, especially polyethylene glycol, polypropylene glycol or their copolymers, having a molecular weight from 200 to 20,000, preferably from 200 to 600. A particular suitable polyalcohol is a polyethylene glycol with a molecular weight of approximately 400.

The above mono- and polyfunctional alcohols may be used according to the invention either alone or, advantageously, in the form of mixtures. If one of the mono- or polyfunctional alcohols should be a solid at room temperature, an alcohol which is liquid at room temperature may suitably be used as a co-solvent.

When a mixture of monofunctional and polyfunctional alcohols is used, the monofunctional and the polyfunctional alcohols should be present in a ratio of from 1:0.1 to 1:100 by weight, preferably in a ratio of from 1:1 to 1:10, more preferably of from 1:1 to 1:4 by weight. A particularly preferred range of ratios is from 1:1 to 1:2, preferably 1:2 by weight. Mixtures of ethanol and propylene glycol or ethanol, propylene glycol and glycerol, are particularly preferred.

The solutions according to the invention may further contain, as additional solvents, pharmacologically acceptable organic esters and ethers, particularly those formed from the above-mentioned mono- and polyfunctional alcohols and fatty acids having from 12-18 carbon atoms, for example stearic acid, palmitic acid and oleic acid; or fatty alcohols having from 12 to 18 carbon atoms, for example lauryl alcohol, cetyl alcohol and stearyl alcohol.

The dielectric constant of the solution may be measured by standard methods, for example with the help of a immersion condenser such as the model DFI 4 modified according to ASTM D 1531-595, sold by Wissenschaftlich - Technische Werkstatten GmbH of Weilheim, W. Germany. Preferably, the dielectric constant of the solution lies between 30 and 46, more preferably 34 and 46.

The water content is limited by the requirement that the dielectric constant of the solution shall not be greater than 50. Water has a dielectric constant of approximately 80 and alcohols generally in the range of approximately 25--40, and it is found that solutions having a mixture of water and one or more alcohols as solvent can generally contain not more than 40% by weight of water if the dielectric constant is to be less than 50. The preferred ranges of dielectric constant given above may be obtained by regulating the water content, generally within the range of 15400/, water by weight.

Although the concentration of the compound of formula I in the solutions is not critical, it is preferred to use solutions with a concentration of active species of from 0.01 to 1% wt./volume, preferably from 0.1 to 0.5% wt./volume. It is to be understood that the concentration to be used will depend upon the application for which the solution is intended.

The solutions may in addition contain further solubilising additives for example acids, particularly methanesulfonic acid, maleic acid and tartaric acid, but if such ionically dissociable additives are to be present, it is to be understood that the dielectric constant of the solution is to be measured in the absence of such additives.

The preparation of the compositions according to the invention is carried out by dissolving the compound of formula I in the solvent or solvent mixture by stirring at room temperature (15--25"C). This may be done under an atmosphere of inert gas and with exclusion of daylight, but these precautions are not essential in view of the improved slability of the solutions according to the invention. The solution may be filtered under pressure, preferably under inert gas pressure, and used to fill suitable vessels. It is not essential to carry out the filling operation under an inert gas atmosphere.

The preparation of solvent mixtures is carried out in conventional manner, and where one of the solvent components is solid at room temperature, mixing is suitably carried out at higher temperatures, e.g. at up to 800 C. Ethanol may advantageously be used as co-solvent.

Compositions according to the invention are useful as pharmaceuticals in the same way as corresponding aqueous solutions of the same active species. They may be administered orally, and may for this purpose be made up in vessels designed to dispense unit dosages, for example dropper bottles; or parenterally, in which case the solutions will normally be sterilized and may be sealed in ampoules of unit dosage. The compositions may also be administered in the form of nasal drops or nasal spray.

For oral administration, a preferred solvent mixture is an ethanol/propylene glycol or ethanol/propylene glycol/glycerol mixture as described above, containing up to 40%, preferably from 15 to 40%, by weight of water. Compositions containing at least 15% by weight of water have a more palatable taste for oral administration.

For parenteral administration, it is undesirable to use solvent mixtures containing more than 5% of ethanol, and a preferred solvent is propylene glycol containing up to 40%, preferably from 15 to 40%, by weight of water. The presence of at least 15% by weight of water lowers the viscosity of the solvent and thereby allows easier and less painful injection of the composition.

As is well known, dihydroergotoxin may, for example, be used in the treatment of conditions arising from cerebral vascular insufficiency and arteriosclerosis. A recommended oral dosage is 1.5 ml of a 0.1% wt./vol. solution, three times daily. As is also well known, dihydroergotamine is indicated, for example, in the treatment of orthostatic hypotension and the prophylaxis of migraine, suitable oral dosages being 0.5-1.5 ml of a 0.2% wt./vol. solution, 2 to 3 times daily. Dihydroergotamine may also be administered parenterally for the relief of acute migraine attacks, a suitable dose being one ampoule containing 1 ml of a 0.1% wt./vol. solution, administered 1--3 times as required at 30 minute intervals.

The following Examples illustrate the invention.

A) Preparation of Solvent Mixtures Solvent mixtures 14 were prepared by mixing together the quantities of solvents shown in the following table. The table also gives the water content in % by weight (taking into account the 6% water content of the 94% ethanol), and the measured dielectric constant. In all four mixtures, ethanol, glycerol and propylene glycol were present in 33:26:41 ratio by weight.

Mixture No. 1 2 3 4 Weights (g) ethanol (94%) 1183 1051 1992 1728 glycerol 869 773 1464 1272 propyleneglycol 1391 1236 2344 2040 distilled water 303. 686 2256 3056 Water content by wt. 10.0% 20.0% 29.5% 39.0% Dielectric constant 34.2 37.7 41.6 45.8 B) Preparation of Solutions EXAMPLE. 1 In 1 litre of solvent mixture 1 was dissolved 1.0 g of dihydroergotoxin methanesulfonate, by stirring at room temperature under a nitrogen atmosphere.

After filtration under nitrogen pressure, the solution was used to fill dropper bottles. The dielectric constant of the mixture remained unchanged.

EXAMPLE 2 In 1 litre of solvent mixture 1, prepared under sterile conditions, was dissolved 2.0 g of dihydroergotamine methanesulfonate, by stirring at room temperature.

After filtration under nitrogen pressure, the solution was used to fill dropper bottles.

EXAMPLES 3-8 Following the procedure of Examples 1 and 2, solutions were prepared using solvent mixtures 2--4 in place of solvent mixture 1.

EXAMPLE 9 In 100 ml of a mixture of 80 parts by wt. sterile propylene glycol and 20 parts by wt. water for injection was dissolved, by stirring at room temperature, 0. I g of dihydroergotamine methanesulfonate. After filtration under nitrogen pressure, the solution was sealed into sterile ampoules, each containing I ml of solution of dielectric constant 41.

EXAMPLE 10 10.0 g of polyethylene glycol of molecular weight 400 was dissolved in a mixture of 40.0 g 94% ethanol and 23.0 g propylene glycol. 20.0 g water was added, to give 100 ml of solvent mixture of dielectric constant 38, in which was dissolved 0.1 g dihydroergotoxin methanesulonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper bottles.

EXAMPLE 11 6.0 g of mixture of cetyl and stearyl alcohol was dissolved in 68.6 g 94% ethanol. 8.5 g water was added, to give 100 ml of solvent mixture of dielectric constant 30, in which was dissolved 0.1 g dihydroergotoxin methanesulfonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper bottles.

WHAT WE CLAIM IS: 1. A stable solution comprising a) a hydrogenated ergopeptide alkaloid of formula I,

in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl, R, is methyl, ethyl or isopropyl, R2 is isopropyl, sec - butyl, isobutyl or benzyl, and X is hydrogen or methoxy or a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof, b) a pharmacologically acceptable alcohol or mixture thereof, and c) water, said solution having a dielectric constant of 50 or less.

2. A solution as claimed in Claim I having a dielectric constant between 30 and 46.

3. A solution as claimed in Claim 2 having a dielectric constant between 34 and 46.

4. A solution as claimed in any one of claims 1--3 in which component a) is a compound of formula I stated in Claim 1, in which R is methyl X is hydrogen and R, is isopropyl or methyl, provided that R, is methyl only when R2 is benzyl.

5. A solution as claimed in Claim 4 in which component a) is dihydroergotamine.

6. A solution as claimed in Claim 4 in which component a) is dihydroergotoxin.

7. A solution as claimed in any one of Claims 4, 5 or 6 in which component a) is present in a concentration of from 0.01 to 1% weight/volume.

8. A solution as claimed in any one of the preceding claims in which component b) is propylene glycol.

9. A solution as claimed in any one of Claims 1--7 in which component b) is a mixture of

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 9 In 100 ml of a mixture of 80 parts by wt. sterile propylene glycol and 20 parts by wt. water for injection was dissolved, by stirring at room temperature, 0. I g of dihydroergotamine methanesulfonate. After filtration under nitrogen pressure, the solution was sealed into sterile ampoules, each containing I ml of solution of dielectric constant 41. EXAMPLE 10 10.0 g of polyethylene glycol of molecular weight 400 was dissolved in a mixture of 40.0 g 94% ethanol and 23.0 g propylene glycol. 20.0 g water was added, to give 100 ml of solvent mixture of dielectric constant 38, in which was dissolved 0.1 g dihydroergotoxin methanesulonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper bottles. EXAMPLE 11 6.0 g of mixture of cetyl and stearyl alcohol was dissolved in 68.6 g 94% ethanol. 8.5 g water was added, to give 100 ml of solvent mixture of dielectric constant 30, in which was dissolved 0.1 g dihydroergotoxin methanesulfonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper bottles. WHAT WE CLAIM IS:

1. A stable solution comprising a) a hydrogenated ergopeptide alkaloid of formula I,

5. A solution as claimed in Claim 4 in which component a) is dihydroergotamine.

6. A solution as claimed in Claim 4 in which component a) is dihydroergotoxin.

b1) a pharmacologically acceptable monofunctional alcohol having up to 18 carbon atoms, or mixtures thereof, and b2) a polyfunctional alcohol having up to 6 carbon atoms and 6 hydroxy groups or a polymeric polyfunctional alcohol having a molecular weight of from 200 to 20,000, or mixtures thereof, the weight ratio of component b1) to component b2) being from 1:0.1 to 1:100.

10. A solution as claimed in Claim 9 in which component b,) has up to 3 carbon atoms.

11. A solution as claimed in Claim 9 or Claim 10 in which component b2) is a polyfunctional alcohol of 2 to 3 carbon atoms and 2 to 3 hydroxyl groups.

12. A solution as claimed in Claim 9 or Claim 10 in which component b2) is a polymeric polyfunctional alcohol having a molecular weight of 200 to 600.

13. A solution as claimed in Claim 10 and Claim 11 in which component b,) is ethanol and component b2) is propylene glycol or glycerol or mixtures thereof.

14. A solution as claimed in any one of Claims 9-13 in which the ratio of component b,) to component b2) is from 1:1 to 1:10 by weight.

15. A solution as claimed in Claim 14 in which the said ratio is from 1:1 to 1:2 by weight.

16. A solution as claimed in any one of the preceding claims in which the concentration of water is from 15 to 40% by weight.

17. A stable solution of a hydrogenated ergopeptide alkaloid substantially as described in any one of the Examples.

18. A dropper bottle containing a solution as claimed in any one of the preceding claims.

19. A sterilised, sealed ampoule containing a solution as claimed in any one of Claims 1--17.

20. A method of preparing a stable hydrogenated ergopeptide alkaloid solution as claimed in Claim 1 which comprises dissolving a compound of formula I, stated in Claim 1, or a pharmaceutically acceptable acid addition salt thereof or a mixture thereof in a solvent consisting essentially of: a) a pharmacologically acceptable alcohol or a mixture thereof, and b) water, at a temperature of 15 to 250C.