AU610134B2 - Use of metformin in the preparation of medicines - 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

1.4 1.6 I 1.4

AUSTRALIA

Patents Act c7 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: p. 4')j and is LL ijr 04 a b APPLICANT'S REFERENCE: 2908/750/22 Name(s) of Applicant(s): Lipha, Lyonnaise Industrielle Pharmaceutique Address(es) of Applicant(s): 34, rue Saint Romain, Lyon,

FRANCE.

Address for Service is: PHILLIPS ORMONDE FITZPATRICK SPatent and Trade Mark Attorneys C 367 Collins Street Melbourne 3000 AUSTRALIA Complete Specification for the invention entitled: USE OF METFORMIN IN THE PREPARATION OF MEDICINES Our Ref 86297 POF Code: 1290/57762 The following statement is a full description of this invention, including the best method of perf'-ming it known to applicant(s): 6003q/1 1 o r ou B B.P. 8481 69369 LYON Cedex 08 requirer i'sj' PHIL LIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia P17/2/83 1 USE OF METFORMIN IN THE PREPARATION OF MEDICINES 00 o o 0 0 0 o0 0 0 0 0 0 0 0 0 o oo S000 0 0 0 0 00 o oo oo 0 0 0 0s 0 00 0 00 00 0 o G a 0 ¢0 S 15 FIELD OF THE ILV'ENTION This invention relates to the use of metformin and its salts in the preparation of medicines for new therapeutic applications. It has as its object the use of metformin and its addition salts in the preparation of a medicine for a new therapeutic application arising from the treatment of troubles of ischemic origin causing hypoxia, even anoxia, in cardiovascular therapy.

BACKGROUND OF THE INVENTION It is known that vasomotricity problems of microvessels, of microcirculation and capillary permeability are a major cause of serious and disabling pathologies.

Few substances have proven capable of successfully correcting metabolic and circulatory troubles linked to ischemia and anoxia.

The compound of the inventio ~i a base that can be salified, particul rv---Een a soluble or rapidly diffusible -r s desired, by a pharmaceutically ee-p-taa-ae-m--ne-i--e-r-c.!-i-a-ae4^1-.--T I- P18/178 PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia 12 7 -Ib- SUMMARY OF THE INVENTION According to the present invention there is provided a method for the treatment of a pathology at the microvascular level comprising administering to a patient in need thereof a composition comprising an amount of metformin sufficient for treating said pathology he suffers from, the metformin being incorporated in an excepient or pharmaceutically acceptable nontoxic inert vehicle.

The compound of the invention is a base that can be salified, particularly when a soluble or rapidly diffusible form is desired, by a pharmaceutically acceptable mineral or organic acid. There will be cited 00 0 oo oO 00 0 0 0 o O 0 00 0 0 0 0 o ooo o0 0 000 0 0 00 0 0 0 0 0 0 000000 0 0 0 C0

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DMW/2179U "n~olmr~ i Yin particular the hydrochlorides, sulfates, nitrates, phosphates, sulfites, dithionates, acetates, benzoates, citrates, glycolates, glyoxylates, mercaptoacetates, gamma-hydroxybutyrates, pamoates, aspartates, glutamates, pyrrolidone carboxylates, methane sulfonates, naphthalene sulfonates, glucose-l-phosphate, chlorophenoxy acetates.

Metformin N,N-dimethylimidodicarbonimidic diamide is known for it antidiabetic properties.

It has just been found that metformin and its addition salts have an effect completely different from the actions already known for these products. They o a stimulate spontaneous microarteriole vasomotricity, oo microcirculation and correct pathologic capillary S0 °o15 permeability.

oo o These effects have no relation to the already 0 0O o established effects of these products. These new .00 0 properties give these compounds anti-ischemic and antioanoxic properties. Therefore it has been found that in the case of ischemia or capillary lesions, as in 0 the case of retinopathies, the compounds according to "ooo the invention are able to assure a redistribution of the 0 00 o ,o blood flow, to reestablish a normal oxygenation and to o avoid phenomena of extravasion and edema due to a 0 0 a 25 hyperpermeability.

Therefore, the compounds according to the invention find a new use in therapy to antagonize or correct metabolic or circulatory troubles linked to S.ischemia and anoxia of tissues. These troubles are found particularly in retinopathies, acute or chronic ischemic accidents, in the sequelae of cerebral infract, in arterites, Raynoud's disease, and coronarites.

The medicines made in view of this new therapeutic application contain an effective amount of active principle in the treatment of ischemia and tissular anoxia. According to the process of the 2 invention an effective amount of metformin, in free or salified form, is incorporated in an excipient or pharmaceutically acceptable nontoxic inert vehicle.

The medicines can be present in various pharmaceutical forms. It is possible to cite for this purpose the forms destined for parenteral administration such as injectable solutions or suspensions packaged in ampules, auto-injectable syringes, in multidose bottles or in bags for venous perfusions. The forms for oral administration as, for example, uncoated or coated tablets, effervescent tablets, bags, capsules, dragees, powders or granules, drinkable solutions or suspensions, microgranules, extended-release forms.

For treatment of ischemia, tissular anoxia and capillary hyperpermeability, the usual dosage varies from 1 to 4 daily administrations, and the unit concentration varies from 100 to 1000 mg of active principle per dose taken.

The invention also has as its object another new application arising from the treatment of various microangiopathies linked to the development of neovascular networks.

It has been discovered that metformin and its salts have an effect completely different from the actions already known for these products. They oppose the phenomenon of neovascularization of various origins by a mechanism that is now unknown. This effect has no relation to the effects already established for these products. This new property gives these compounds an aptitude for opposing or limiting the progress of vascular lesions in particular at the level of the retina where the development of neovascular networks causes serious vitreoretinal complications. Phenomena of the same nature also appear during alterations of cartilage and in certain tumoral regions.

0 25 S. 0 3 The compounds of the invention find a new use in therapy to combat the appearance of neovessels or to reduce the development of an installed neovascularization. These troubles are found particularly in retinopathies, cases of gonarthrosis, polyarthrites and tumoral pathology.

The medicines intended for treatment or regression of a neovascularization contain a therapeutically effective amount of the active ingredient in said treatment.

According to the process of the invention an effective amount of metformin, in free or salified form, is incorporated in an excipient or pharmaceutically acceptable nontoxic inert vehicle.

The effective amount of metformin according to the invention is between 100 and 1000 mg per unit dose.

The dosage varies according to the manner of administration and the therapeutic indication. The daily dosage will generally be 1 to 4 administrations.

The pharmaceutical compositions intended for treatment of neovascularization are those which are suitable for parenteral administration in the form of oa, injectable solutions or suspensions packaged in ampules, Snbottles for slow venous perfusion, or for oral 25 administration (bags, effervescent tablets, capsules, uncoated or coated tablets, dragees, ampules or drinkable solutions, microgranules, extended-release o0 forms).

DETAILED DESCRIPTION OF THE INVENTION The following examples illustrate the invention without, however, limiting it.

4 Example I Effervescent tablets of 0.500 g of metformin: metformin hydrochloride............641.5 g 105.0 g monopotassium phosphate 17.5 g citric 16.0 g sodium bicarbonate 8.4 g magnesium 2.1 g finished tablets with an average weight of for 1000 0.790 g.

Example II 250-mg injectable form of metformin hydrochloride.............321 mg 400 mg water q.s.p. 10 ml Example III 250-mg microgranules of metformin hydrochloride.............321 mg corn 15 mg mg polyvidone mg polyoxyethylene glycol mg mg talc 19 mq capsule size 1 1 433.5 mg Example IV Pharmacological study on anti-ischemic properties.

The capacity of promoting spontaneous microvascular vasomotricity, microcirculation and reduction of pathological capillary permeability which is shown by metformin has been brought out by various 5 tests, in partici.ar that of the cutaneous window in the awake hamster Colantuoni, S. Bertuglia and M.

Intaglietta, Microvascular Research 28,143.158 (1984).

The window was illumined by transmission, the capillary bed was observed with a triocular microscope.

The image was transformed in a video signal by a camera.

Recording of the diameter of the microvessels was performed continuously.

The product to be studied was administered intravenously. An increase was observed of the frequency of contractions and dilatations of the terminal arterioles which went from one per minute in the controls to 10 per minute in the animals treated 0 with metformin in a dose of 2 mg/100 g intravenously.

00 15 On the hamster cheek model Colantuoni, o P.G. Berardi, G. Orefice, The Journal of Nuclear "o o Medicine and Allied Sciences, 23, No. 1-2, 49, 54 (1979), study of the microcirculation, by observation with a transmission microscope, revealed in the animal anesthetized with pentobarbital a disappearance of rhythmic contractions of the precapillary smooth muscle cells. After treatment with metformin, intravenously, 0 in doses of 1-2 mg/100 g, reappearance of the rhythmic contractions and relaxations of the precapillary smooth muscle cells was seen. This effect was seen along the terminal arterioles. It reestablished a pulsed flow in the ramifications of the capillaries and assured a redistribution of the blood in the microvessels.

SOn the same experimental model, adaptation of S 30 a microfluorimetric observation system (A.

Colantuoni...(1979), Lay and K.E. Arfors, Microvascular Research 31 84-99 (1986)) made it possible to study the passage of fluorescent macromolecules from the inside of the microvessels of the capillary bed to the interstitial milieu.

6 The marker used was fluorescein isothiocyanate dextran with a molecular weight of 150,000.

On the increased capillary permeability model, Table I shows that a treatment with metformin, orally at a rate of 3 mg/100 g per day, reduced in considerable proportions the percentages of cases of increased permeability observed at the end of 60 and 90 days in untreated animals.

TABLE I of cases of increased permeability at day 60 at day Without treatment 60 100 Metformin orally 0 33 3 mg/100 g/day i* 4 15 In a peripheral ischemia model in a rat, injection of microspheres in the femoral artery caused the appearance of an edema of the paw and a lowering of the motor capacities of the animal. A treatment with metformin intraperitoneally at a rate of 20 mg/kg reduced the edema 60% and made possible total recovery of motivi.ty.

Example V Pharmacological study in the field of neovascularization.

The neovascularization is the result of an abnormal proliferation of endothelial cells, particularly in a hypoxic environment.

This situation can be reproduced in vitro by studying such a proliferation on a culture of human endothelial cells placed in hypoxia. Metformin in concentrations on the order of 10 7 to 10-12 M greatly 7 IL -e :-I i"C inhibits this proliferation. Contrary to antimitotics, metformin does not exhibit cytotoxicity on these cell cultures.

This antiangiogenic effect was verified by two models of pathologic angiongenesis in vivo. First in the standard model of neovascularization of the rabbit cornea Gimbrone Jr., R.S. Cotran, S.B.

Leafman and A.J. Folkman, J. Natl. Cancer Inst. 52).

In situ administration of metformin inhibits the appearance of neovessels.

Further, the capacity of opposing the formation of neovessels shown by metformin was brought out in particular on an experimental model for studying the formation of neovessels Pournaras, J. Ilic, N. Gilodi, Klin. Mbl. Augenheilk., 186 (1985) 471-476).

The experiments were performed on a miniature pig. An irreversible venous occlusion was obtained by photocoagulation by argon laser. Fluorescein angiography made it possible to visualize, four weeks after the occlusion in the zones where the supply vessels were insufficient to assure the draining function, the development of a neovascularization In a comparable experiment on 6 miniature pigs treated with metformin orally with a daily dose of 100 mg for four weeks, the complete elimination of a neovascularization was noted.

In the field of tumoral pathology, in particular in regard to the metastatic process, the effect on the vascular endothelium led to the thought that extravascular colonization by circulating cancer cells could be braked in vitro and in vivo by metformin.

Actually, in vitro, metformin in a concentration of 10 4 to 10 5 M inhibits the penetration of cancer cells through the endothelium in culture on its extracellular matrix.

8 In vivo, in a model of pulmondry metastases in mice (Cancer Chemother. Reports, 1972), metformin in and 12.5 mg orally caused a 50% reduction in the number of metastases.

While the invention is described above in relation to certain specific embodiments, it will be understood that many variations are possible, and that alternative materials and reagents can be used without departing from the invention. In some cases such variations and substitutions may require some experimentation, but such will only involve routine testing.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and therefore such adaptations and modifications are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to'be understood that the 0 phraseology or terminology herein is for the purpose of description and not of limitation.

0 0 9 c'

Claims (12)

1. A method for the treatment of a pathology at the microvascular level comprising administering to a patient in need thereof a composition comprising an amount of metformin sufficient for treating said pathology he suffers from, the metformin being incorporated in an excepient or pharmaceutically acceptable nontoxic inert vehicle.

2. A method according to claim 1 for the treatment at the microvascular level of a pathology associated with spontaneous vasomotion disorders.

3. A method according to claim 2 for the treatment of tissue hypoxia or anoxia, rethinopathies, acute or chronic occlusive diseases, sequelea of cerebral infarct, arteritis, Reynaud's disease and coronaritis.

4. A method according to claim 1 for the treatment of a pathology at the microvascular level associated with capillary permeability troubles.

A method according to claim 4 for the treatment of S capillary permeability troubles associated with extravasation and edema, retinopathy, acute or chronic vascular occlusive diseases. 00 S

6. A method according to claim 1 for the treatment at the microvascular level of a pathology associated with neovascularization due in particular to an abnormal proliferation of endothelial cells.

7. A method according to claim 6 for the treatment at S the microvascular level of neovascularization with vitroretinal complications resulting from the development of neovascular network at the level of the retinal, polyarthritis or tumoral angiogenesis. 0 co o

8. A method according to any one of claims 1 to 7 o o° wherein the metformin is in the form of a pharmaceutically °a o acceptable organic or mineral acid salt.

9. A method according to claim 8 wherein the salt is selected from the group consisting of hydrochlorides, sulfates, nitrates, phosphates, sulfites, dithionates, acetates, benzoates, citrates, glycolates, glyoxylates, mercaptoacetates, gamma-hydroxybutyrates, pamoates, Saspartates, glutamates, pyrrolidone carboxylates, methane k-I 1/2179U I C I c T YII- i- -11- sulfonates, naphthalene sulfonates, glucose-l-phosphate, and chlorophenoxy actetates.

A method according to claim 1, wherein the effective amount of metformin is between 100 and 1000 mg per unit dose.

11. A method according to any one of claims 1 to 9 wherein the composition is in the form of injectable solutions or suspensions, uncoated, coated or effervescent tablets, bags, capsules, dragees, powders, granules, drinkable solutions or suspensions, microgranules and extended-release forms.

12. A method according to claim 1 substantially as hereinbefore described with reference to any one of the examples. DTED: 17 January 1991 PHILLIPS ORMONDE FITZPATRICK Patent Attorneys for: LIPHA, LYONNAISE INDUSTRIELLE PHARMACEUTIQUE DlvW/2179U