DK169713B1 - Use of metformin in the manufacture of drugs - Google Patents

Abstract

The invention relates to the use of metformin and its salts in the preparation of medicaments. This derivative is used in the preparation of medicaments manifesting anti-ischaemic and antianoxic properties. It is also employed in the preparation of medicaments intended for the treatment or regression of neovascularisation.

Description

DK 169713 B1

The present invention relates to the use of metformin or its salts for the manufacture of medicaments for novel therapeutic use.

It is an object of the invention to provide the use of metformin 5 and its addition salts in the preparation of a medicament for a new therapeutic application, namely in the treatment of vascular and tumor neovascularizations.

The invention thus relates to a new use of metformin, namely to prepare a medicament for use in the treatment of various microangiopathies which are associated with the development of the hair core and new vessels.

The compound of the invention used is a base which can be converted to salts, especially in cases where a soluble or rapidly diffusible form is desired, with inorganic and organic, pharmaceutically acceptable acids. Particular mention should be made of hydrochlorides, sulfates, nitrates, phosphates, sulfites, dithionates, acetates, benzoates, citrates, glucolates, glyoxylates, mercaptoacetates, γ-hydroxybutyrates, powders, aspartates, glutamates, pyrrolidine carboxylates, methanesulfonates, methanesulfonates, methanesulfonates, methanesulfonates glucose-1-phosphates and chlorophenoxyacetates.

The compound metformin, N, N-dimethylimidodicarbonimide-diamide (Ν, Ν-dimethyldigluanide or N'-dimethylguanylgluadinine), is known for its anti-diabetic properties.

It has been found that metformin and its salts exert another effect which is completely different from the effects already known for these compounds. They counteract the phenomenon of new vascularizations of different origins by a yet unknown mechanism.

This effect has no relation whatsoever to the effects already established for these compounds. The now recognized property provides metformin and its salts with an ability to counteract or limit the progression of vascular lesions, especially in the retina where development of new vascular cortex leads to severe vitreoretinal complications. Phenomena of the same or similar nature also occur in cartilage changes as well as in certain tumor areas.

The use of metformin or its salts according to the invention thus indicates the possibility of a new therapeutic treatment to control the occurrence of new vascularization or to reduce the development of an already begun new vascularization (neovascularization). These disorders are found especially in retinopathies, in cases of gonarthrosis, in polyarthritis and in tumor pathology.

Drug preparations intended for treatment or regression of new vascularization contain an effective amount of the effective principle for said treatment, ie. considered the compound metformin itself.

Accordingly, in the use of the invention, an effective amount of metformin in the free form or in the form of a salt thereof can be incorporated into an excipient or inert carrier which is non-toxic and pharmaceutically acceptable.

The effective amount of metformin in this application is from 100 to 1000 mg per day. unit dose.

The total dose depends on the route of administration and the therapeutic indication. The daily number of doses is generally 1 to 4.

Pharmaceutical compositions for the treatment of new vasculature are those suitable for parenteral administration and in the form of, for example, injectable solutions or suspensions present in ampoules, glass for slow irradiation in veins; or for oral administration such as sachets, effervescent tablets, gel-like tablets, coated or uncoated tablets, dragees, ampoules or liquid oral preparations, microgranules or forms with prolonged or delayed delivery of the active substance.

The following examples serve to illustrate the invention.

Example 1

Shower tablets containing 0.500 g of metformin: metformin hydrochloride 641.5 g of lactose 105.0 g of mono-potassium phosphate 17.5 g of citric acid 16.0 g of sodium bicarbonate 8.4 g of magnesium stearate 2.1 g to 1000 finished tablets with an average weight of 0.790 g.

15

Example 2

Injection formulation with 250 mg metformin: metformin hydrochloride 321 mg 20 sorbitol 400 mg water for injection up to 10 mg

Example 3

Microgranules with 250 mg metformin: 25 metformin hydrochloride 321 mg corn starch 15 mg shellac 19 mg polyvidone excipient 9.5 mg polyoxyethylene glycol 4000 10 mg 30 sucrose 40 mg talc 19 mg gelatin until 1: 1 gelatin 433.5 mg 4 DK 169713 B1

Example 4

Pharmacological study on neovascularization

Neovascularization, i.e. new vascularization results from normal proliferation of endothelial abnormal cells, especially in a hypoxic environment.

This situation can be reproduced in vitro by examining such vascular or capillary proliferation on a culture of human endothelial cells brought into hypoxic state. Metformin at concentrations of 7 to 12 in the range of 10 to 10 M rapidly inhibits this propagation. Unlike the antimitotic agents, metformin does not exhibit any cytotoxicity on the cell cultures.

This antiangiogenic effect has been verified by 2 in vivo models of pathological angiogenesis. First, it was verified in the classical model of rabbit neovascularization in rabbits, (M.A. Gimbrone Jr., R.S. Cotran, S.B. Leafman, and A.J. Folkman, J. Natl Cancer Inst. 52). In-situ administration of metformin inhibits the occurrence of new vascularization.

In addition, the ability of metformin to counteract the formation of new vasculature has been particularly demonstrated in an experimental model for the study of new vessels or capillaries 25 (CJ Pournaras, J. Ilic, N. Gilodi. Clin. Mbl. Augenbeilk, 186 (1985) , 471-476). The experiments have been performed on miniature pigs. Irreversible vein occlusion was induced by photocoagulation by means of 5 DK 169713 B1 argon laser. Fluorescein angiography allows 4 weeks after occlusion, in the zones where there are not enough additional vessels and capillaries to ensure drainage function, to make visible the development of new vascularization 5 (neovascularization). In a comparison trial with 6 dwarf pigs treated with metformin, administered orally at a daily dose of 100 mg over 4 weeks, complete suppression of the incidence of neovascularization was found.

J 10 In the field of tumor pathology, and especially in metastasis formation, the effect on the vascular endothelium suggests that the extravascular colonization of circulating cancer cells may have been inhibited in vitro and in vivo by metformin.

Metformin at a concentration of 10.4-10 µM effectively inhibits in vitro penetration of cancer cells across the endothelium in culture into the extracellular matrix.

In a model of the study of lung metastases 20 in mice (Cancer chemother. Reports, 1972), metformin administered orally at doses of 25 and 12.5 mg causes a 50% decrease in the number of metastases.

Claims (8)

Use of metformin, N, N-dimethylimidodicarbonimide diamide, in the manufacture of a medicament for the treatment of vascular and tumor neovascularizations. Use according to claim 1, characterized in that an effective amount of metformin is incorporated in the pharmaceutical composition together with a non-toxic, pharmaceutically acceptable excipient or inert carrier. Use according to claim 2, characterized in that the metformin is in the form of a pharmaceutically acceptable organic or inorganic salt such as the hydrochloride, sulphate, nitrate, phosphate, sulphite, dithionate, acetate, benzoate, citrate, glycolate, glyoxylate, mercaptoacetate, the γ-hydroxybutyrate, pamoate, aspartate, glutamate, pyrrolidone carboxylate, methanesulfonate, naphthalene sulfonate, glucose-1-phosphate or chlorophenoxy acetate. Use according to claim 2, characterized in that the effective amount of metformin in the composition is between 100 and 1000 mg per day. unit dose. Use according to claim 2, characterized in that the composition is in the form of an injectable solution or suspension, uncoated or coated tablets, effervescent tablets, sachets, gel-like tablets, dragees, 25 ampoules or ingestible suspensions, microgranules or in an extended form. release. Use according to claim 1, characterized in that the composition is for the treatment of neovascularizations occurring in retinopathies. Use according to claim 1, characterized in that the composition is for the treatment of neovascularizations occurring in the case of gonarthrosis. Use according to claim 1, characterized in that the composition is for the treatment of neovascularisations occurring in polyarthritis.