FR2787330A1 - Compositions containing an immunosuppressant and an AT1 angiotensin II receptor antagonist, for prevention and treatment of vascular complications due to graft rejection - Google Patents

Abstract

Compositions containing an immunosuppressant and an AT1 angiotensin II receptor antagonist, together with a pharmaceutical excipient.

Description

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 The subject of the present invention is the use of a pharmaceutical composition containing in combination an AT receptor antagonist, angiotensin II and an immunosuppressant. This composition is particularly useful in the prevention or treatment of vascular complications of transplant rejection.

 Animal pharmacology studies on the effects of combining certain immunosuppressants with either an AT receptor antagonist, angiotensin II, or an ACE inhibitor are found in the literature.

 Thus, the association of cyclosporine A and DUP-753 (angiotensin II receptor antagonist) was studied in rats for its effect on the one hand on the thickness of the arterial walls and on the other hand on the angiotensin receptor density (M. Unkelbach et al., Eur. Heart J., 1993, 14, (Abstr. Suppl.), 353, and V.

Regltz-Zagrosek et al., J. Cardiovasc. Pharmacol., 1995, 26/1. 66-72).

 We have now surprisingly found that it is advantageous to combine an angiotensin II AT1 receptor antagonist and an immunosuppressant and that this association may be useful in the prevention or treatment of vascular complications of transplant rejection. .

 According to the present invention, by angiotensin II AT1 receptor antagonist is meant non-peptide compounds which exhibit a strong affinity for angiotensin II receptors of the AT subtype: (MI Steinberg et al., Cardiovascular Drug Reviews, 1993, 11 (3), 312-358). They are generally nitrogen heterocycles substituted by a biphenylmethyl group itself carrying an acid group. Mention may in particular be made, among nitrogen heterocycles, of imidazoles as well as other 5-membered rings such as pyrroles, pyrazoles, isoxazoles isothiazoles and triazoles. Such compounds are described in the following patents or patent applications: EP 28 834-A, EP 253 310-A, EP 324 377-A, EP 392 317-A, EP 403 159-A, EP 475 206-A, EP 503 785-A, EP 514 198-A, EP 573 271-A, EP 646 584-A, US 4 207 324, US 4 340 598, US 4 576 958, US 4 582 847, WO 91 14679, WO 91 - 17148, WO 92-20662, WO 93-341, WO 94-08989, WO 94-08990, WO 96-228, WO 96-40255, WO 96-40256, WO 96-40257, WO 96-40258.

 Other angiotensin II inhibitor compounds are described in patents or patent applications relating to derivatives formed on condensed heterocycles in particular benzimidazoles and imidazopyridines: 245 637-A, EP 399 731- A, EP 400 974- A, EP 392 317-A, EP 260 613-A, EP 412 848-A, EP 420 237-A, EP 426 021-A, EP 459 136-A, EP 502 314-A, EP 503 162-A, EP 504 888, EP 546 358A, EP 552 765-A, EP 595 151-A, EP 598 702-A, US 4 880 804, WO 93-190067, WO 94-01436, WO 94-204 498, DE 4 031 635.

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 In addition, other angiotensin II inhibitor compounds are formed from nitrogen heterocycles with 6 members, possibly condensed. Such compounds are described in particular in the following patents or patent applications: EP 412 848-A, EP 434 249-A,, EP 443 983-A, EP 475 206-A, EP 487 252-A, EP 487 745 -A, EP 500 409-A, EP 503 838-A, EP 514 198, EP 566 060-A, EP 569 013-A, EP 628 045A, GB 2 234 748-A, US 5 187 168, US 5 385 894, WO 91 07404, WO 93-3018, WO 93-20816, WO 94-03449, WO 94-07492, WO 94-11369, WO 94-11379, WO 95-002596.

 Finally, other types of structure have been described for angiotensin II inhibitor compounds, for example in the following patents or patent applications: EP 425 921-A, EP 488 532-A, EP 540 209-A, EP 586 513-A, EP 604 259-A, US 5 149 699, US 5 332 744, WO 94-00450, WO 94-17067.

CL-329 167 : 2-Butyl-6-(l-méthoxy-l-méthyléthyl)-3-[[2'-(lH-tétrazol-5-yl)[l,l'- biphényl]-4-yl]méthyl]-4(3H)-quinazolinone,
CS-866 : Ester 5-méthyl-2-oxo-l,3-dioxol-4-yl-méthylique de l'acide 4-(1-

hydroxy-l-méthyléthyl)-2-propyl-l-[2'-(lH-tétrazoI-5-yl)biphényl-4-ylméthyl] imidazole-5-carboxylique,
GA-0050 = GA-0056 : 2-(6-((2-Ethyl-5,7-diméthyl-3H-imidazo(4,5-b)pyridin-3yl) méthyl)quinolin-2-yl)benzoate de sodium,
KT3-671 : 2-Propyl-8-oxo-1-[[2'-(1H-tétrazol-5-yl)[1, l'-biphényl]-4-yI]méthyl]- 4,5,6,7-tétrahydrocycloheptimidazole,

L-159-282 ou MK-996 : N-[[ 4'-[(2-Ethyl-5,7-diméthyl-3H-imidazol[ 4,5-b]pyridin -3-yl)méthyl] [ 1, l'-biphényl]-2-yl] sulfonyl]-benzamide, Milfasartan ou tiénartan ou LR-B-081 : Méthyl 2-((4-butyl-2-méthyl-6-oxo-((2'- ( lH-tétrazol-5-yl)-( 1, l'-biphényl)-4-yl)méthyl)- I -(6H)-pyrimidinyl)méthyl)-3thiophèncarboxylate, ME-3221 : 3-Méthoxy-2,6-diméthyl-4-[[2'-(1H-tétrazol-5-yl)[ l'-biphényl]-4-yl] méthoxy]-pyridine, In particular and without limitation, mention may be made of the following compounds among the angiotensin II antagonists suitable for combinations according to the invention and in the pharmaceutical compositions according to the invention; these compounds are known by their international common name or by their code name, the chemical structure associated with each code being indicated below:
Irbesartan, losartan, pomisartan, saprisartan, valsartan, telmisartan, candesartan, eprosartan, tasosartan, embusartan,

CL-329 167: 2-Butyl-6- (1-methoxy-1-methylethyl) -3 - [[2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -4 (3H) -quinazolinone,
CS-866: 5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl ester of 4- (1-

hydroxy-1-methylethyl) -2-propyl-1- [2 '- (1H-tetrazoI-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylic,
GA-0050 = GA-0056: 2- (6 - ((2-Ethyl-5,7-dimethyl-3H-imidazo (4,5-b) pyridin-3yl) methyl) quinolin-2-yl) sodium benzoate ,
KT3-671: 2-Propyl-8-oxo-1 - [[2 '- (1H-tetrazol-5-yl) [1, l'-biphenyl] -4-yI] methyl] - 4,5,6, 7-tetrahydrocycloheptimidazole,

L-159-282 or MK-996: N - [[4 '- [(2-Ethyl-5,7-dimethyl-3H-imidazol [4,5-b] pyridin -3-yl) methyl] [1, l'-biphenyl] -2-yl] sulfonyl] -benzamide, Milfasartan or tienartan or LR-B-081: Methyl 2 - ((4-butyl-2-methyl-6-oxo - ((2'- (1H- tetrazol-5-yl) - (1, l'-biphenyl) -4-yl) methyl) - I - (6H) -pyrimidinyl) methyl) -3thiophencarboxylate, ME-3221: 3-Methoxy-2,6-dimethyl- 4 - [[2 '- (1H-tetrazol-5-yl) [l'-biphenyl] -4-yl] methoxy] -pyridine,

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SC-52458 ou forasartan : 5-[(3,5-dibutyl-IH-1,2,4-triazol-1-yl)méthyl]-2-[2-(IHtétrazol- 5-yl)phényl] -pyridine, SL-910-102 : 6-Butyl-(2-phényléthyl)-5-((2'-(lH-tétrazol-5-yl)(l,l'-biphényI)-4- yl)méthyl-4(l H)pyrimidinone,
TAK-536 : Acide 2-éthoxy-l-((2'-(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl)-

biphényl-4-yl)méthyl) I H-benzimidozole-7-carboxylique, Ripisartan ou UP-269-6 : S-Méthyl-7-propyl-8-((2'-(1H-tétrazol-5-yl)biphényl-4- yl)méthyl)-1,2,4-triazolo (1,5-c)pyrimidin-2(3H)-one,
KRH-594 = WK-1492 : Sel dipotassique de l'acide 2-(5-éthyl-3-(2-(lH-tétrazol-5-

yl)biphényl-4-yl)méthyl- I ,3,4-thiadiazoline-2-ylidène)aminocarbonyl-1-cyclopenten carboxylique, YM-358 : 2,7-Diéthyl-5-[[2'-( 1 H-tétrazol-5-yI) 1,1 l'-biphényl]-4-yl] méthyl]-SH- pyrazolo[l,5-b][l,2,4]-triazole,
606-A : Di sel de sodium de l'acide 5-acétyl-2-propyl-3-[2'-(lH-tétrazol-5yI)biphényl-4-ylméthyl]-4,5,6,7-tétrahydro-3H-imidazo[4,5-c]pyridine-4-carbo-xylique l'irbesartan étant particulièrement préféré, soit tel quel, soit sous forme polymorphe, soit sous forme d'un de ses sels ou solvats.

SC-52458 or forasartan: 5 - [(3,5-dibutyl-IH-1,2,4-triazol-1-yl) methyl] -2- [2- (IHtetrazol-5-yl) phenyl] -pyridine, SL-910-102: 6-Butyl- (2-phenylethyl) -5 - ((2 '- (1H-tetrazol-5-yl) (l, l'-biphenyI) -4- yl) methyl-4 (l H) pyrimidinone,
TAK-536: 2-Ethoxy-1 - acid ((2 '- (5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) -

biphenyl-4-yl) methyl) I H-benzimidozole-7-carboxylic, Ripisartan or UP-269-6: S-Methyl-7-propyl-8 - ((2 '- (1H-tetrazol-5-yl) biphenyl -4- yl) methyl) -1,2,4-triazolo (1,5-c) pyrimidin-2 (3H) -one,
KRH-594 = WK-1492: Dipotassium salt of 2- (5-ethyl-3- (2- (1H-tetrazol-5-) acid

yl) 4-biphenyl-yl) methyl- I, 3,4-thiadiazoline-2-ylidene) aminocarbonyl-1-cyclopenten carboxylic, YM-358: 2,7-Diethyl-5 - [[2 '- (1 H- tetrazol-5-yI) 1,1 l'-biphenyl] -4-yl] methyl] -SH- pyrazolo [1,5-b] [1,2,4] -triazole,
606-A: Di sodium salt of 5-acetyl-2-propyl-3- [2 '- (1H-tetrazol-5yI) biphenyl-4-ylmethyl] -4,5,6,7-tetrahydro- acid 3H-imidazo [4,5-c] pyridine-4-carbo-xylic, irbesartan being particularly preferred, either as it is, or in polymorphic form, or in the form of one of its salts or solvates.

 Several angiotensin II AT1 receptor antagonist compounds are now marketed for their cardiovascular action, especially in hypertension (Arie J. Man in't Veld, J. Hypertension, 1997, 15 (Suppl. 7), 527-533 ).

 By immunosuppressant is meant a product which suppresses or reduces the specific immunological reactions of the body against an antigen. As immunosuppressants, mention may in particular be made of antimetabolites, in particular methotrexate, alkylating agents, in particular cyclophosphamide, corticoids, such as prednisolone, cyclosporins, in particular cyclosporin A, as well as tacrolimus and azathioprine.

 It has now been found that the combination of an immunosuppressant with an angiotensin II AT1 receptor antagonist has unexpected efficacy and a particular advantage.

 Thus, such a combination can make it possible to observe effects greater than those observed when each of the compounds is used alone.

 The combination according to the present invention can be used in particular for the prevention or treatment of vascular complications of transplant rejection. By vascular complications of transplant rejection, we mean parietal vascular hypertrophy, vascular inflammation, vascular thrombotic processes,

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 hypertension, graft rejection, stroke, myocardial infarction, renal vascular thrombosis, renovascular hypertension.

 The association according to the invention comprising irbesartan and cyclosporin A has been studied in humans.

 Thus, it has been found that treatment with the combination of irbesartan and cyclosporine A makes it possible to reduce the vascular complications of transplant rejection.

 For its use as a medicament, the combination of an immunosuppressant and of an angiotensin II AT1 receptor antagonist compound according to the invention must be formulated in pharmaceutical composition. Said composition is generally formulated in dosage units.

 Thus according to another of its aspects, the present invention relates to pharmaceutical compositions comprising an immunosuppressant and an angiotensin II AT1 receptor antagonist in combination with at least one pharmaceutical excipient. More particularly, the present invention relates to pharmaceutical compositions comprising an immunosuppressant and irbesartan in combination with at least one pharmaceutical excipient and preferably the invention relates to pharmaceutical compositions containing cyclosporin A and irbesartan in combination with at least one pharmaceutical excipient. The compositions according to the invention are useful for the prevention or treatment of vascular complications of graft rejection.

 In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principles of the combination can be administered in unit administration forms , mixed with conventional pharmaceutical carriers, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.

 When a solid composition is prepared in the form of tablets, a pharmaceutical carrier can be added to the active principles of the combination, micronized or not, which can be composed of diluents such as, for example, lactose, microcrystalline cellulose, starch and formulation adjuvants such as binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), flow agents

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 like silica, lubricants like magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate.

 Wetting agents or surfactants such as sodium lauryl sulfate can be added to the formulation.

 The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation, hot melting.

 The tablets can be naked, coated (with sucrose for example) or coated with various polymers or other suitable materials.

 The tablets can have a flash, delayed or prolonged release by producing polymer matrices or by using specific polymers in the film coating.

 A capsule preparation is obtained by mixing the active ingredients with dry pharmaceutical vehicles (simple mixing or dry granulation, wet granulation, hot fusion), liquids or semi-solids.

 The capsules can be soft or hard, film-coated or not so as to have a flash, prolonged or delayed activity (for example by an enteric form).

 A preparation in the form of a syrup or elixir may contain the active ingredients together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.

 A preparation in the form of a syrup or elixir may contain the active ingredients together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.

 The water-dispersible powders or granules may contain the active ingredients in admixture with dispersing agents, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors .

 Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.

 For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol.

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 Thus, to prepare an aqueous solution for intravenous injection one can use a cosolvent such as for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween @ 80. To prepare an oily solution injectable intramuscularly, the active principles can be dissolved by a triglyceride or a glycerol ester.

 For local administration, creams, ointments, gels, eye drops can be used.

 For transdermal administration, it is possible to use patches in multilaminate or reservoir form in which the active ingredients can be in alcoholic solution.

 For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant is used; one can also use a system containing the active principles alone or associated with an excipient, in the form of powder.

 The active ingredients can also be presented in the form of a complex with a cyclodextrin, for example, a, ss. y-cyclodextrin, 2-hydroxypropyl-Pcyclodextrin, methyl-ss-cyclodextrin.

 The active ingredients can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.

 Among the sustained-release forms useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

 In each dosing unit the active ingredients of the combination are present in the quantities adapted to the daily doses envisaged. In general each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 1 to 200 mg of immunosuppressant, preferably 2 to 100 mg, and 0.5 to 500 mg of angiotensin II AT1 receptor antagonist, preferably 1 to 300 mg, said dosage unit to be administered one to four times a day. Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is

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 determined by the doctor according to the method of administration, the age, the weight and the response of said patient.

 According to another of its aspects, the present invention relates to the use of the combination according to the invention for the preparation of medicaments intended for the prevention or treatment of vascular complications of graft rejection, in humans and in animal.

 In particular, the pharmaceutical composition according to the invention is useful for the manufacture of a medicament for the prevention or treatment of vascular complications of transplant rejection.

 The present invention also relates to a method of treatment and a method of preventing vascular complications of transplant rejection comprising the administration of a pharmaceutical composition according to the invention.

 The compositions of the present invention may contain, in addition to the combination according to the invention, other active ingredients which may be useful in the treatment of the disorders or diseases indicated above.

 Thus, according to the present invention, it is possible to prepare pharmaceutical compositions containing the combination according to the invention associated with another compound acting on the renin-angiotensin system such as an inhibitor of the converting enzyme or a renin inhibitor . One can also associate the association according to the invention, for example, with a peripheral vasodilator, a calcium channel blocker, a beta-blocker or an alpha-1-blocker.

 These associations will strengthen the therapeutic activities of the association according to the invention.

EXAMPLE 1 Capsule
Cyclosporine A 50.00 mg
Irbesartan 150.00 mg
Lactose monohydrate 252.35 mg
Modified corn starch 57.77 mg
Colloidal anhydrous silica 2.13 mg
Magnesium stearate 4.25 mg
Talc 8.50 mg
For an opaque white capsule No. 0 filled to 425 mg
EXAMPLE 2 Capsule
Cyclosporine A 100.00 mg
Irbesartan 300.00 mg
Lactose monohydrate 138.60 mg

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 Modified corn starch 46.52 mg Colloidal anhydrous silica 2.13 mg Magnesium stearate 4.25 mg Talc 8.50 mg For an opaque white capsule No. 0 filled to 600 mg EXAMPLE 3 Tacrolimus capsule 5.00 mg Irbesartan 300.00 mg Lactose monohydrate 233.60 mg Modified corn starch 46.52 mg Anhydrous colloidal silica 2.13 mg Magnesium stearate 4.25 mg Talc 8.50 mg For an opaque white capsule No. 0 filled to 600 mg EXAMPLE 4 Azathioprine tablet 50 0.00 mg Irbesartan 150.00 mg Lactose monohydrate 30.75 mg Microcrystalline cellulose 39.00 mg Pregelatinized starch 45.00 mg Sodium croscramellose 15.00 mg Poloxamer 188 9.00 mg Silica 8.25 mg Magnesium stearate 3.00 mg Purified water qs

For one 350 mg tablet

Claims (13)

 CLAIMS 1. Pharmaceutical composition containing in combination an immunosuppressant and an AT receptor antagonist, angiotensin II mixed with at least one pharmaceutical excipient. 2. Pharmaceutical composition according to claim 1, in which the angiotensin II AT1 receptor antagonist is chosen from irbesartan, losartan, pomisartan, saprisartan, valsartan, telmisartan, candesartan, eprosartan, tasosartan, embusartan. 3. A pharmaceutical composition according to claim 2 wherein the angiotensin II AT1 receptor antagonist is irbesartan. 4. Pharmaceutical composition according to any one of claims 1 to 3 in which the immunosuppressant is chosen from: an antimetabolite, an alkylating agent, a corticosteroid, a cyclosporine, tacrolimus or azathioprine. 5. Pharmaceutical composition according to claim 4, in which the immunosuppressant is chosen from: methotrexate, cyclophosphamide, prednisolone, cyclosporine A, tacrolimus or azathioprine. 6. Composition according to claim 4, in which the immunosuppressant is cyclosporin A. 7. Pharmaceutical composition according to any one of claims 1 to 6 in the form of a dosage unit. 8. Pharmaceutical composition according to claim 7 containing 1 to 200 mg of immunosuppressant and 0.5 to 500 mg of an AT receptor antagonist, angiotensin II. 9. Pharmaceutical composition according to claim 8 containing from 2 to 100 mg of immunosuppressant and 1 to 300 mg of an angiotensin II AT1 receptor antagonist. 10. Pharmaceutical composition according to any one of claims 1 to 9 for the prevention of vascular complications of transplant rejection. 11. Pharmaceutical composition according to any one of claims 1 to 9 for the treatment of vascular complications of transplant rejection. 12. Use of a pharmaceutical composition according to any one of claims 1 to 9 for the manufacture of medicaments useful for treating vascular complications of transplant rejection. <Desc / Clms Page number 10> 13. Use of a pharmaceutical composition according to any one of claims 1 to 9 for the manufacture of medicaments useful for the prevention of vascular complications of transplant rejection.