WO1990003793A1

WO1990003793A1 - Compositions containing cyclosporins

Info

Publication number: WO1990003793A1
Application number: PCT/GB1989/001183
Authority: WO
Inventors: Rajan Madhok
Original assignee: Rajan Madhok
Priority date: 1988-10-07
Filing date: 1989-10-06
Publication date: 1990-04-19
Also published as: AU4346089A; GB8823621D0

Abstract

The immunosuppressive and anti-arthritic effects of cyclosporins are potentiated by formulation with gammalinoleic acid, a member of the n-6 series of unsaturated fatty acids, usually in weight proportions 5:1 to 1:30. Consequently, only reduced doses of cyclosporin are required, so that undesirable side effects such as renal vasoconstriction are alleviated.

Description

COMPOSITIONS CONTAINING CYC OSPORINS

Field of the Invention

The invention is concerned with improvements in or relating to compositions containing pharmacologically active peptides, that is a selected cyclosporin, together with a carrier. Prior Art

It has been proposed to provide such a composition in which a vegetable oil is used as a carrier component. Examples have usually been quoted as using olive oil although corn oil is a recognised alternative.

The administration of previously known cyclosporin compositions to patients who have, for example, received organ transplants or are suffering from immune system related diseases such as rheumatoid arthritis, has resulted in undesirable side effects, due mainly to renal vasoconstriction.

Cyclosporins are well known and are mentioned, for example, in GB 1491509 and GB 2015339. Cyclosporin -A and cyclosporin-G are commercially available.

It is an object of the present invention to avoid or minimise one or more of the above disadvantages.

Beneficial cardiovascular effects of fish oil (which contains amounts of n-3 unsaturated fatty acids) have been widely documented; see for example A. Leaf and P.c. Weber, The New England Journal of Medicine, 1988, 318, 549. The administration of cyclosporin with n-3 unsaturated fatty acids is reported in L.Elzinga et al. , Transplantation, 1987, _43_, 271 and T.S. Rogers et al. , Transplantation, 1988, _,45, 153-6. Summary of the Invention

The present invention provides a combination suitable for use in immunosuppression and/or the treatment of rheumatoid arthritis which combination comprises a pharmacologically active cyclosporin and gammalinoleic acid or a pharmaceutically acceptable functionally equivalent derivative thereof.

The gammalinoleic component may be used in a substantially pure form. Conveniently though it may be used in the form of a physiologically acceptable more or less readily obtainable oil mixture containing a substantial amount of gammalinoleic acid, such as evening primrose oil (EPO). Another suitable oil that may be mentioned is blackcurrant oil.

With a combination of the present invention it is possible significantly to reduce the amount of cyclosporin required for effective immunosuppression to a dosage level low enough for the risk of undesired side effects to be significantly reduced or avoided.

Whilst not wishing to restrict the scope of the invention in any way it appears that the EPO is able to modify the body's immune system such that the production of those compounds against which cyclosporin is targetted is significantly reduced thereby enhancing the effectiveness of the cyclosporin.

Moreover, the ability of the selected oil to change the metabolism of the body causes the production of substances which themselves are of benefit to the vascular system. This change is recognised as part of the function of essential fatty acids (EFA) in the human body. EFA are fats which cannot be synthesised by the body and therefore, like vitamins, must be obtained from dietary sources.

There are two known main series of EFA, the so-called n-6 series and n-3 series, being references to the position of the first double bond in the carbon chain. The parent molecule of the n-6 series is linoleic acid and of the n-3 series is alpha linoleic acid (or linolenic acid) .

Gammalinoleic acid ( 6,9,12-octadecatrienoic acid) has three double bonds and is a member of the n-6 series. Its abbreviation is 18:3,n-6.

Taking the n-6 series, linoleic acid (9,12- octadecadienoic acid 18:2,n-6) may be expected to be desaturated, by the appropriate enzyme, to gammalinoleic acid, but in many individuals this is an inefficient reaction and the required conversion rate may be inadequate. Thus, by providing an exogenous source of gammalinoleic acid, oils such as evening primrose oil can bypass any metabolic block and supply the EFA as needed. The EFA are the precursors for prostaglandins, specifically gammalinoleic acid is a precursor for the Series 1 (PGEi) series the presence of which act to reduce tissue impairment.

There is thus an appreciable advantage in the use of evening primrose oil as a carrier constituent of cyclosporin composition compared with the use of oils which do not contain gammalinoleic acid. Choice of EPO has the further advantage that it is readily available commercially.

As used herein, the expression "functionally equivalent derivative" indicates derivatives such as acids or esters which have been, or are converted in vivo into compounds, which have generally similar activity to that of gammalinoleic acid in the combination of the invention.

Where cyclosporin is conventionally used in the treatment of immune system related conditions, the dosages vary greatly according to purpose, to length of treatment period and to body weight of the recipient. It is suggested, however, that the highest acceptable dosage of cyclosporin has been considered to be in the region of 15mg/kg body weight and dosage at that level should continue for as short a time as possible. Nevertheless the risk of problems associated with renal vasoconstriction is high, and it may be that lOmg/kg is a more practical upper limit.

With the use of combinations according to the present invention, the level of the above mentioned practical doses may be reduced to 75% or 50% of the comparable figures giving similar effective desired beneficial results, but with correspondingly less risk.

The cyclosporin and gammalinoleic acid components may be used in a wide range of relative proportions in the combinations of the invention. In general they are used in relative proportions of cyclosporin to gammalinoleic acid of from 10:1 to 1:100, preferably from 5:1 to 1:30.

It will be understood by those skilled in the art that the combination of the present invention may be used on its own, especially where the components are present in ratios at which the cyclosporin component is substantially solubilised by the gammalinoleic acid component, and the combination is to be administered as an oral draught or intramuscular injection or the like. Conveniently though the combination is presented as a pharmaceutical composition including one or more other pharmaceutically acceptable carriers or excipients therefor.

In a further aspect of the invention there is provided a pharmaceutical formulation comprising the active combination together with a pharmaceutically acceptable carrier therefor. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Such carriers are solid, liquid or gaseous materials recommended for the purpose of administering the medicament.

These pharmaceutical compositions may be administered orally or parenterally (including subcutaneous, intra¬ muscular and intravenous injection) or as a suppository or pessary. It is preferred that the compositions are administered orally or parenterally. The terms formulation and composition are used synonomously.

For oral administration the pharmaceutical compositions may be presented as a draught in capsules, as an oleaginous solution or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. Where desirable or necessary flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation. Where the ratios of components permit, the combination may be presented in an aqueous solution, if necessary with the presence of a surfactant.

Capsules and cachets may contain the active compound alone or in admixture with one or more accessory ingredients. Capsules may also contain the active combination in oleaginous solution, suspension or emulsion, optionally in association with accessory ingredients.

For administration as a suppository or pessary the active combination may be presented in admixture with a suitable carrier such as cocoa butter and other material commonly used in the art, the formulation conveniently being shaped by moulding.

For administration in discrete dosage forms such as the tablets, capsules, suppositories and pessaries described above, the active combination is conveniently presented at 10 g to lOmg, desirably O.lmg to lOmg per tablet, capsule, suppository or pessary.

For parenteral administration the active combination may be presented in sterile solutions or suspensions in oleaginous vehicles, which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers.

For administration orally in liquid form the active compounds may preferably be presented in solution or suspension or emulsion at a concentration of from 0.1 to 10%, more preferably 0.2 to 5% w/v in unit multi-dose form. When presented in unit dose form, it may be preferred that each dose-unit contains O.lmg to lOOmg, preferably lmg to lOmg of active compound.

All the above formulations are produced by processes which comprise bringing into association the active compounds and one or more carriers.

According to the present invention there is therefore provided a process for producing a pharmaceutical formulation of a combination of the invention comprising bringing into association a combination of the invention and a pharmaceutically acceptable carrier therefor.

Combinations of the invention may be administered to human beings and to other animals for temporary immunosuppression. The dosage administered obviously depends on the activity of the combinations and also on the speed with which it is absorbed into the body and on other well known pharmaceutical considerations. The combination may be administered in the required dosages once or several times daily.

In a further aspect of the present invention provides in combination a pharmacologically active cyclosporin and gammalinoleic acid or a pharmaceutically acceptable functionally equivalent derivative thereof for use in the preparation of a medicament for immunosuppression and/or treatment or prophylaxis of rheumatoid arthritis.

In yet further aspects the present invention provides: a method of immunosuppression comprising the administration of an effective dosage of the combination of the invention to a mammal; and a method of treatment or prophylaxis of rheumatoid arthritis comprising the administration of an effective dosage 'of the combination of the invention to a mammal. Preferred Embodiments

There will now be given an example of a combination according to the invention. It will be understood that the description is given by way of example only and not by way of limitation.

Example I (draught)

A solution of cyclosporin is obtained by stirring 300mg thereof in 1.5ml of a mixture of 150mg a trans- esterification product of a vegetable oil triglyceride and a polyakylene polyol (LABRAFIL * M1944CS) and ethanol (in a ratio of 8:3 parts by weight). Evening primrose oil (0.6ml) was then added and the mixture filtered. The solution obtained contains for every 10 parts by weight of LABRAFIL, 3 parts by weight cyclosporin, 3 parts by weight ethanol and 5 parts by weight EPO.

Various modifications may be made within the scope of the invention. For example, other oils may be used in addition to EPO, for example certain fish oils rich in fatty acids.

*Trade Mark.

Claims

1. A pharmaceutical composition suitable for use in immunosuppression and/or the treatment of rheumatoid arthritis, which comprises an immunosuppressively - effective amount of a pharmacologically active cyclosporin, together with gammalinoleic acid or a pharmaceutically acceptable functionally equivalent derivative thereof.

2. A composition according to claim 1 which comprises evening primrose oil or blackcurrant oil as the source of gammalinoleic acid.

3. A composition according to claim 1 wherein the cyclosporin and the gammalinoleic acid are present in the relative weight proportions of from 5:1 to 1:30 respectively.

4. A composition according to claim 1 which further comprises a pharmaceutically acceptable excipient.

5. A composition according to claim 4 in discrete dosage form, wherein each dosage comprises from 0.1 mg to 10 mg of the combination of cyclosporin and gammalinoleic acid.

6. A method of immunosuppression which comprises the administration to a patient of an immunosuppressively - effective amount of the composition of any one of claims 1 to 5.

7. A method of treatment of rheumatoid arthritis which comprises the administration to a patient of an effective amount of the composition of any one of claims 1 to 5.

8. A method according to claim 6 wherein an amount of the composition is administered such as to provide a concentration of cyclosporin in the body of up to 10 mg/kg of body weight.

9. A method according to claim 7 wherein an amount of the composition is administered such as to provide a concentration of cyclosporin in the body of up to 10 mg/kg of body weight.

10. A pharmaceutical composition according to any of claims 1 to 5 for use in immunosuppression and/or the treatment of rheumatoid arthritis.

11. A pharmaceutical composition according to any of claims 1 to 5 for use in the preparation of a medicament for use in immunosuppression and/or the treatment of rheumatoid arthritis.

12. A method for the alleviation of renal vasoconstriction due to the effects of a cyclosporin, which comprises the administration to a patient being treated with a cyclosporin of an effective amount of gammalinoleic acid or a pharmaceutically acceptable functionally equivalent derivative thereof.

13. The use of gammalinoleic acid or a pharmaceutically acceptable functionally equivalent derivative thereof for the alleviation of renal vasoconstriction in a patient being treated with a cyclosporin.