MXPA00006504A - Compositions and treatment for diabetic complications - Google Patents

Abstract

This invention is directed to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective COX-2 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using those pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy.

Description

COMPOSITIONS AND TREATMENT FOR DIABETIC COMPLICATIONS FIELD OF THE INVENTION This invention relates to methods, pharmaceutical compositions and kits (kits) comprising an aldose-ruductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective inhibitor of cyclooxygenase- 2 (COX-2), a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy. Aldose reductase inhibitors act by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol. , in humans and others similar. In this way, the undesirable accumulations of galactitol in the lens of galactosemic individuals and of sorbitol in the lens, the peripheral nerve cord and the kidneys of various diabetic individuals are prevented or reduced. Accordingly, the aldose reductase inhibitors have therapeutic value for controlling certain diabetic complications, e.g., diabetic nuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy. It is known that there are two forms of cyclooxygenase (COX): COX-1 and COX-2, the former being a constitutive form and the latter being an inducible form. COX-1 exists in the stomach, intestines, kidneys and platelets, while COX-2 is expressed during inflammation. Both isoforms of the COX enzyme metabolize arachidonic acid by a similar mechanism, but each has different substrate specificities. Selective COX-2 inhibitors are advantageous in the treatment of pain and inflammation, while at the same time avoiding side effects such as gastric and renal toxicity.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to pharmaceutical compositions comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; a) a selective inhibitor of COX-2 of formula I, I in which R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; wherein R 4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbinyl, amido, N-monoalkylamido, N-monoaryl-amido, N, N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt thereof or said prodrug; or b) a COX-2 inhibitor of formula II, II wherein R5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl; R6 is selected from cycloalkyl, cycloalkenyl and aryl; where R6 is optionally substituted in a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl-amino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl , aminosulfonyl, halo, alkoxy, and alkylthio; and R7 is selected from lower alkyl, hydroxyl and amino; a prodrug thereof or a pharmaceutically acceptable salt thereof or said prodrug; and a pharmaceutically acceptable excipient, vehicle or diluent. This invention is also directed to methods of treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth hereinbefore. In particular, diabetic complications such as, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy can be treated by the methods of this invention. This invention is also directed to kits comprising: a) a first unit dosage form comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and an excipient, pharmaceutically acceptable carrier or diluent; b) a second unit dosage form comprising a selective COX-2 inhibitor of formula I, wherein R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; wherein R4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoaryl-amido, N, N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; or a COX-2 inhibitor of formula II, II wherein R5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkylaryloxyalkyl, arylthioalkyl, hydroxyl amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl; R6 is selected from cycloalkyl, cycloalkenyl and aryl; wherein R6 is optionally substituted in a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl-amino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl , aminosulfonyl, halo, alkoxy and alkylthio, and R7 is selected from lower alkyl, hydroxyl and amino; a prodrug thereof to a pharmaceutically acceptable salt of said compound or said prodrug; and c) a package. This invention is also directed to methods of treating a diabetic complication in a mammal, comprising administering to said mammal an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and a) a selective COX-2 inhibitor of formula I wherein R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; where R4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamino, N, N-dialkylamino, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, Nd alkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; or b) a COX-2 inhibitor of formula II, wherein R 5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl; R6 is selected from cycloalkyl, cycloalkenyl and aryl; wherein R6 is optionally substituted in a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl-amino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl , aminosulfonyl, halo, alkoxy and alkylthio, and R7 is selected from lower alkyl, hydroxyl and amino; a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. It is preferred that the ARI and the selective COX-2 inhibitor be administered together. It is also preferred that the ARI and the COX-2 inhibitor be administered separately in any order. In the compositions, methods and kits of this invention, it is preferred that said ARI be fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or of said prodrug. It is especially preferred that said ARI be zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug, and said COX-2 inhibitor be celecoxib or valdecoxib, a prodrug thereof or a pharmaceutically acceptable salt of said selective inhibitor. of COX-2 or of said prodrug.

When used in this specification and in the appended claims, the term "lower alkyl" refers to alkyl groups containing one to four straight or branched chain carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION The COX-2 inhibitors of formula I, including celecoxib, which are used in the compositions, methods and kits of this invention are prepared according to methods set forth in US Pat. No. 5,466,823, which is incorporated herein by reference. this memory by reference. Celecoxib is also known as 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] -benzenesulfonamide, and has the following chemical structure: The COX-2 inhibitors of formula II, including valdecoxib, which are used in the compositions, methods and kits of this invention are prepared according to methods set forth in U.S. 5,633,272, which is hereby incorporated herein by reference in its entirety. Valdecoxib is also known as 4- (5-methyl-3-phenyl-4-isoxazolyl) -benzenesulfonamide, and has the following chemical structure: The methods, compositions and kits of this invention are useful for treating diabetic complications including but not limiting character, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy. The term "treat", as used herein, refers to retarding, stopping or reversing the progress of, or alleviating or preventing the disorder or condition to which the term "treating" is applied, or one or more symptoms of said disorder or condition. The term "treatment", as used herein, refers to treating a disorder, symptom or condition, as the term "treating" is defined above. Any inhibitor of aldose reductase can be used in the compositions, methods and pharmaceutical kits of this invention. The expression "aldose reductase inhibitor" refers to a compound that inhibits the bioconversion of glucose in sorbitol catalyzed by the enzyme aldose reductase. Such inhibition is easily determined by those skilled in the art according to standard assays (J. Malone, Diabetes, 29: 861-864, 1980. "Red Cell Sorbitol, an Indicator of Diabetic Control"). The following patents and patent applications, each of which is hereby incorporated in its entirety herein by reference, illustrate aldose reductase inhibitors that can be used in the compositions, methods, and kits of this invention, and refer to methods of preparing such aldose reductase inhibitors: U.S. Patent 4,251,528 U.S. Patent 4,600,724; U.S. Patent 4,464,382 U.S. Patent 4,791,126; U.S. Patent 4,831,045 U.S. Patent 4,734,419; 4,883,800; U.S. Patent 4,883,410; U.S. Patent 4,771,050; U.S. 5,252,572; U.S. Patent 5,270,342; U.S. 5,430,060; U.S. Patent 4,130,714; U.S. Patent 4,540,704; U.S. Patent 4,438,272; U.S. Patent 4,436,745; U.S. Patent 4,438,272; U.S. Patent 4,436,745; U.S. Patent 4,438,272; U.S. Patent 4,436,745; U.S. Patent 4,438,272; U.S. Patent 4,980,357; U.S. Patent 5,066,659; U.S. Patent 5,447,946 and U.S. Patent 5,037,831. A variety of aldose reductase inhibitors are specifically described and referenced below; however, other aldose reductase inhibitors will be known to those skilled in the art. Likewise, common chemical names U.S. are given in parentheses, if applicable. AN or other designations together with reference to the appropriate patent literature describing the compound.

Accordingly, examples of aldose reductase inhibitors useful in the compositions and methods of this invention include: 1. 3- (4-bromo-2-fluorobenzyl) -3,4-dihydro-4- acid oxo-1-phthalazine-acetic (ponalrestat, US 4,251,528); 2. N [[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl]} -N-methylglycine (tolrestat, U.S. 4,600,724); 3. 5 - [(Z, E) -β-methylalcinamylidene] -4-oxo-2-thioxo-3-thiazolidine-acetic acid (epalrestat, US 4,464,382, US 4,791,126, US 4,831,045); 4. 3- (4-bromo-2-fluorobenzyl) -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazoyneacetic acid (zenarestat, US 4,734,419 and 4,883,800); 5. 2R, 4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. 4,883,410); 6. 2R, 4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. 4,483,410); 7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benz-oxazine-4-acetic acid (U.S. 4,771,050); 8. 3,4-dihydro-3-oxo-4 - [(4,5,7-trifluoro-2-benzo-thiazolyl) methy1] -2H-1,4-benzothiazine-2-acid acetic acid (documents SPR-210 and US 5,252,572); 9. N- [3,5-dimethyl-4 [(nitromethyl) sulfonyl] phenyl] -2-methyl-benzeneacetamide (documents ZD5522, U.S. 5,270,342 and U.S. 5,430,060); 10. (S) -6-fluorospiro [chroman-4,4 '] - imidazolidine] -2,5, -dione (sorbinyl, U.S. 4,130,714); 11. d-2-methyl-6-fluoro-spiro (chroman-4 ', 4, -midazolidine) -2', 5'-dione (U.S. 4,540,704); 12. 2-fluoro-spiro (9H-fIuoreno-9,4, -imidazolidine) -2 ', d'dione (U.S. 4,438,272); 13. 2,7-di-fluoro-spiro (9H-fluorene-9,4, -imidazolidine) -2, 5'-dione (U.S. 4,436,745 and U.S. 4,438,272); 14. 2,7-di-fluoro-5-methoxy-spiro (9H-fluorene-9,4'-imidazolidine) -2", 5'-dione (US 4,436,745 and US 4,438,272); 15. 7-fluoro-spiro (5H-indenol [1,2-b] pyridine-5,3'-pyrrolidine) -2,5'-dione (US 4,436,745 and US 4,438,272); 16. d-cis-6'-chloro-2 ', 3'-d and h -dro-2'-methylene-espyro- (imidazolidnan-4,4'- 4'H- pyran (2,3-b) pyridine) -2,5-dione (US 4,980,357); 17. spiro [midazolidine-4,5, (6H) -quinoline] -2,5- dione-3, -chloro-7 ', di-dihydro ^' -methyl-cis'- (US 5,066,659); 18. (2S, 4S) -6-fluoro-2 ', d- dioxospirotchroman ^^ '- imidazolidine) -2-carboxamide (fidarestat, US Pat. No. 5,447,946), and 19. 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluorospiro [isoquinoline-4 (11 -1), 3'-pyrrolidine] -1, 2,, 3,5, (2H) -tetrone (minalrestat, US 5,037,831).

All of the prior patents that describe ARI compounds are incorporated herein by reference in their entirety. Other inhibitors of aldose reductase include compounds of formula A, and their pharmaceutically acceptable salts, wherein Z in the compound of formula A is O or S; R1 in the compound of formula A is hydroxy or a group capable of being eliminated in vivo to produce a compound of formula A in which R1 is OH; and X and Y in the compound of formula A are the same or different and are selected from hydrogen, trifluoromethyl, fluoro and chloro. A preferred subgroup within the above group of aldose reductase inhibitors includes the compounds numbered 1, 2, 3, 4, 5, 6, 9, 10 and 17, and the following compounds of formula A: acid 3.4 -dihydro-3- (5-fluorobenzothiazol-2-ylmethyl) -4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = F; Y = H]; 21. 3- (d, 7-difiuorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hidoxyl; X = Y = F]; 22. 3- (d-chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = CI; Y = H]; 23. 3- (5,7-Dichlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = Y = CI]; 24. 3,4-Dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) phthalazin-1-ylacetic acid [R1 = hydroxy; X = CF3; Y = H]; 25. 3,4-Dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = F; Y = H]; 26. 3- (5,7-difluorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-acetic acid [R1 = hydroxy]; X = Y = F]; 27. 3- (D-Chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophtalazin-1-ylacetic acid [R1 = hydroxy; X = CI; Y = H]; 28. 3- (5,7-Dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophtalazin-1-acetic acid [R1 = hydroxy; X = Y = CI]; and 29. zopolrestat; 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-phthalazine-acetic acid, [R1 = hydroxy; X = trifluoromethyl; Y = H]. In compounds 20-23 and 29, Z is S. In compounds 24-28, Z is O. Of the above subgroup, compounds 22-29 are more preferred, with compound 29 being particularly preferred. Said compounds of formula A are prepare as described in the US document 4,939,140, which is incorporated herein by reference in its entirety.

The aldose reductase inhibitor compounds of this invention are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly in view of the pertinent patent specifications. The activity of the selective COX-2 inhibitors of the present invention can be demonstrated by the following tests. The activity of COX-1 is determined by methods well known to those skilled in the art. The COX-2 assay based on human cells is carried out as previously described (Moore et al., Inflam. Res 4d, 64, 1996). The in vivo study of rat foot edema induced by carrangenan is carried out as previously described in Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962. The selectivity for COX-2 can be determined by methods well known to those skilled in the art and particularly by the ratio in terms of the IC50 value of the inhibition of COX-1. to the inhibition of COX-2. In general, it can be said that a compound exhibiting a COX-1 / COX-2 inhibition ratio greater than 2 has a satisfactory selectivity for COX-2. This invention relates both to methods for treating diabetic complications in which the ARI, the prodrug thereof or the pharmaceutically acceptable salt of said ARI or said prodrug and said selective COX-2 inhibitor, the prodrug thereof or the pharmaceutically acceptable salt thereof of said selective COX-2 inhibitor or said prodrug are administered together, as part of the same pharmaceutical composition, as to methods in which these two active agents are administered separately, as part of an appropriate dosage regimen d designed for get the benefits of combination therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between the doses of the active agents will depend on the ARI and the selective COX-2 inhibitor that are used, the type of pharmaceutical formulations used, the characteristics of the individual to treat and the severity of complications. Generally, in the embodiment of the methods of this invention, an effective dose for the aldose reductase inhibitors of this invention is in the range of about 0.01 mg / kg / day to 100 mg / kg / day in single doses or divided, preferably 0.1 mg / kg / day at 20 mg / kg / day in single or divided doses, and the selective COX-2 inhibitor will be administered in single or divided doses. Selective COX-2 inhibitors will generally be administered in amounts ranging from about 0.01 mg / kg / day in single or divided doses, preferably 10 mg to about 300 mg per day for an average individual, depending on the selective COX inhibitor. -2 and 0 the route of administration. However, there will necessarily be some variation in the dosage depending on the condition of the individual to be treated. The person responsible for the administration will determine, in any case, the appropriate dose for the particular individual.

The administration of the pharmaceutical compositions of this invention can be done by any method that provides a composition of this invention preferably to the desired tissue (e.g., nerve, kidney, retina and / or cardiac tissues). These methods include oral, parenteral, intraduodenal, etc. Generally, the compositions of the present invention will be administered in single (e.g., once a day) or multiple doses, or by constant infusion. Pharmaceutical compositions comprising an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug and a selective inhibitor of COX-2, a prodrug thereof or a salt The pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug will be collectively referred to collectively as "the active compositions of this invention". The active compositions of this invention can be administered to an individual in need of treatment by a variety of conventional routes of administration, including oral, topical, parenteral, e.g., intravenous, subcutaneous or intramedullary routes. Additionally, the active compositions of this invention can be administered intranasally, as a rectal suppository or using an instant formulation ("flash"), that is, allowing the medication to dissolve in the mouth without the need for water.

The active compositions of this invention can be administered alone or in combination with pharmaceutically acceptable excipients, vehicles or diluents, in single or multiple doses. Suitable pharmaceutical excipients, carriers and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compositions of this invention and the pharmaceutically acceptable excipients, carriers or diluents are then easily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable and analogous solutions. These pharmaceutical compositions may contain, if desired, additional ingredients such as flavorings, binders, other excipients and the like. Thus, for oral administration purposes, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often used for tablet manufacturing purposes. Solid compositions of a similar type can also be used as fillers in filled soft and hard gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient of this memory may be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerin and their combinations. For parenteral administration, solutions of the active compositions of this invention may be employed in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should first be made isotonic with enough saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In relation to this, the sterile aqueous media used are all readily available by standard methods known to those skilled in the art. Generally, a composition of this invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, when the patient suffers from gastrointestinal disorders or as long as the medication is optimally applied to the surface of a tissue or organ as may be determined by the physician in charge of the treatment.

For buccal administration, the composition (two active agents administered together or separately) can take the form of tablets or lozenges formulated in a conventional manner. For intranasal administration or administration by inhalation, the active compounds of the invention (two active agents administered together or separately) are conventionally supplied in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol-type presentation for spraying from a pressurized container or a nebulizer, with the use of a suitable propellant, eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be easily determined by providing a valve that supplies a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, which contain a mixture of powders of a compound of the invention and a suitable powder base such as lactose or starch. For purposes of transdermal administration (e.g., topical), sterile aqueous or partially aqueous diluted solutions are prepared (usually in an approximate concentration of 0.1% to 5%), analogous to the above parenteral solutions.

Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent to those skilled in the art in view of this disclosure. For examples and methods of preparation of pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mac Publishing Company, Easton, Pa., Edition 19a (199d). The active compositions of this invention contain a certain amount of an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt thereof and of a selective COX-2 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt thereof. selective inhibitor of COX-2 or said prodrug. The amount of each of said ingredients can be independently, for example, 0.0001% -95% of the total amount of the composition, where the total amount of each can not, of course, exceed 100%. In any case, the composition or formulation to be administered will contain a proportion of each of the components of the composition according to the invention in an amount effective to treat the disease / condition of the individual to be treated. Since the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. . The kit comprises two separate pharmaceutical compositions: an aldose reductase inhibitor, a prodrug thereof or a salt of said aldose reductase inhibitor or prodrug, and a selective inhibitor of COX-2, a prodrug thereof or a salt of said selective COX-2 inhibitor or prodrug as described above. The kit comprises a package for containing the separate compositions such as a divided bottle or a divided metal foil pack. Typically, the kit comprises instructions for the administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), or are administered at different dosage intervals, or when titration of the individual components of the composition is desired. the prescribing doctor. An example of a case of this type is a so-called bubble pack ("blister pack"). Bubble containers are well known in the packaging industry and are being widely used for the packaging of unit dosage dosage forms (tablets), capsules, etc.). Bubble containers generally consist of a sheet of relatively rigid material covered with a thin sheet of a preferably transparent plastic material. During the packaging process, small depressions are formed in the thin sheet of plastic. The depressions have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are introduced into the depressions and the sheet of relatively rigid material is sealed against the thin sheet of plastic on the face of the thin sheet that is opposite to the direction in which the depressions were formed. As a result, the tablets or capsules are hermetically sealed in the depressions between the plastic sheet and the sheet. Preferably, the sturdiness of the sheet is such that tablets or capsules can be removed from the bubble pack by manual application of pressure in the depressions, whereby a sheet opening is formed at the depression site. The tablet or capsule can then be removed through said opening. It may be desirable to provide a memory aid in the kit, e.g., in the form of numbers next to the tablets or capsules, in which case the numbers correspond to the days of the regime in which the tablets or capsules so specified should be ingested. Another example of help of this kind for the memory is a calendar printed on the cardboard, eg, as follows "first week, Monday, Tuesday, ... etc ... second week, Monday, Tuesday, ..." etc . Other variations of memory aids will be readily apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules that must be taken on a given day. Also, a daily dose of the aldose reductase inhibitor can be constituted by a single tablet or capsule, while a daily dose of the COX-2 inhibitor can be constituted by several tablets or capsules, and vice versa. Help for memory should reflect this. In another specific embodiment of the invention, a dispenser designed to distribute the daily doses one at a time in the order of their proposed use is provided. Preferably, the dispenser is equipped with a memory aid, in order to further facilitate compliance with the scheme. An example of such an aid for memory is a mechanical counter that indicates the number of daily doses that have been distributed. Another example of a memory aid of this type is a battery-activated micro-chip memory, coupled with a liquid crystal indicator, or audible recall signal which, for example, reads the date on which the last one was taken. daily dose and / or remind the patient when the next dose should be taken. The compositions of this invention will generally be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. In the formulations that follow, "active ingredient" means a combination of the compounds of this invention.

Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.26-100 Starch, NF 0-660 Fluidizable starch powder 0-dO Fluid silicone of 3d0 centistokes 0-1 d Prepared with tablet formulation using the following ingredients: Formulation 2: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.26-100 Microcrystalline cellulose 200-660 Combustion silicon dioxide 10-650 Stearic acid 5-1 d The components are mixed and compressed to form tablets. Alternatively, tablets are prepared, each containing 0.26-100 mg of active ingredients, as follows: Formulation 3: Tablets Ingredient Amount (mg / tablet) Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 3d Polyvinylpyrrolidone (as a 10% solution in water 4 Sodium carboxymethyl cellulose 4.6 Magnesium stearate O.d Talc 1 The active ingredient, starch and cellulose are passed through a U.S. No. 46 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. No. 14. The granules thus produced are dried at dO ° -60 ° C and passed through a U.S. No. 18. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a U.S. sieve. No. 60 mesh, are then added to the granules which, after being mixed, are compressed in a tablet machine to produce tablets. Suspensions each containing 0.26-100 mg of active ingredient per dose of d ml are manufactured as follows: Formulation 4: Suspensions Ingredient Quantity (mg / d ml) Active ingredient 0.26-100 mg Sodium carboxymethyl cellulose 60 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavoring at will Color at will Purified water up to 5 ml The active ingredient is passed through a U.S. sieve. mesh No. 45, and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, the flavoring, and the dye are diluted with a part of the water, and added with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared that contains the following ingredients: Formulation d: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.2d Ethanol 2d.7d Propellant 22 (chlorodifluoromethane) 74.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, it is cooled to 30 ° C, and transferred to a filling device. The required amount is then fed to a stainless steel vessel and diluted with the rest of the propellant. The valve units are then adapted to the package. Suppositories are prepared as follows: Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Glycerides of saturated fatty acids 2,000 The active ingredient is passed through a U.S. sieve. of mesh No. 60 and suspended in glycerides of saturated fatty acids previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal capacity 2 g and allowed to cool.

An intravenous formulation is prepared as follows: Formulation 7: Intravenous solution Ingredient Quantity Active ingredient 2d mg-10,000 mg Isotonic saline 1,000 ml The solution of the above ingredients is administered intravenously to a patient.

Claims (4)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A pharmaceutical composition comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; a) a selective inhibitor of COX-2 of formula I, I in which R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; wherein R4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoaryl-amido, N, N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor of formula I or said prodrug; or b) a selective inhibitor of COX-2 of formula II, wherein R 5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamine, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl; R6 is selected from cycloalkyl, cycloalkenyl and aryl; where R6 is optionally substituted in a substitutable position with one or more radicals selected independently of alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl , halo, alkoxy and alkylthio; and R7 is selected from lower alkyl, hydroxyl and amino; a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor of formula II or said prodrug; and a pharmaceutically acceptable excipient, vehicle or diluent.
2. 2. A composition of claim 1, wherein said selective COX-2 inhibitor is celecoxib, a prodrug thereof or a pharmaceutically acceptable salt of celecoxib or said prodrug or valdecoxib, a prodrug thereof or a pharmaceutically acceptable salt. of valdecoxib or said prodrug.
3. 3. A composition of claim 2, wherein said ARI 0 is fidarestat, palrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug of said compound or a pharmaceutically acceptable salt of said ARI or said prodrug.
4. 4. A composition of claim 3, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug. d.- A composition of claim 4, wherein said selective COX-2 inhibitor is valdecoxib, a prodrug thereof or a pharmaceutically acceptable salt of valdecoxib or said prodrug. 6. A composition of claim 4, wherein said selective inhibitor of COX-2 is celecoxib, a prodrug thereof or a pharmaceutically acceptable salt of celecoxib or said prodrug. 7. - A method for treating a mammal suffering from a diabetic complication, comprising administering to said mammal a pharmaceutical composition of claim 1. 8. A method of claim 7, wherein said diabetic complication is diabetic neuropathy, diabetic nephropathy, Diabetic cardiomyopathy, diabetic retinopathy, cataracts or myocardial infarction. 9. A method for treating a mammal suffering from a diabetic complication, comprising administering to said mammal a pharmaceutical composition of claim 2. 10. A kit comprising: a) a first unit dosage form comprising an inhibitor of aldose reductase (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent;; b) a second unit dosage form that comprises a selective COX-2 inhibitor of formula I, in which R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; wherein R4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoaryl-amido, N, N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor of formula I or said prodrug; or a selective COX-2 inhibitor of formula II wherein R5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alcoxicarboniltioalquilo and alquilaminocarboniltioalquilo; R6 is selected from cycloalkyl, cycloalkenyl and aryl; where R6 is optionally substituted in a substitutable position with one or more radial independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl-amino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and R7 is selected from lower alkyl, hydroxyl and amino; a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug; and c) a package. 11. A method for treating a diabetic complication in a mammal, comprising administering to said mammal an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and a) a selective inhibitor of COX-2 of formula I, I in which R1 is sulfamyl; R2 is haloalkyl; R3 is selected from hydride and alkyl; and R 4 is selected from aryl, cycloalkyl and cycloalkenyl; where R4 is optionally substituted in a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoaryl-amido, N, N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino, N, N-dialkylamino, heterocyclic, nitro and acylamino; or a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor of formula I or said prodrug; or b) a COX-2 inhibitor of formula II, II wherein R5 is selected from alkyl, carboxyalkyl, alkoxycarbonyl, aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl, alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio, cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl, aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl, hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio, alkoxycarbonyloxylalkyl, alkylaminocarbonyloxyalkyl, alkoxycarbonylthioalkyl, and alkylaminocarbonylthioalkyl; R6 is selected from cycloalkyl, cycloalkenyl and aryl; wherein R6 is optionally substituted in a substitutable position with one or more radicals independently selected from alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkyl-amino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl , aminosulfonyl, halo, alkoxy and alkylthio; and R7 is selected from d lower alkyl, hydroxyl and amino; a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor of formula II or said prodrug. 12. A method of claim 11, wherein said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt thereof or said prodrug. 13. A method of claim 12, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug; and said COX-2 inhibitor is celecoxib, d a prodrug thereof or a pharmaceutically acceptable salt of celecoxib or said prodrug. 14. A method of claim 12, wherein said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or said prodrug; and said COX-2 inhibitor is valdecoxib, or a prodrug thereof or a pharmaceutically acceptable salt of valdecoxib or said prodrug.