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Home , Ceronapril, Sorbinil, Spiraprilat, Zenarestat

USOO6337327B1 (12) United States Patent (10) Patent No.: US 6,337,327 B1 Tuffin et al. (45) Date of Patent: Jan. 8, 2002

(54) PHARMACEUTICAL COMPOSITIONS OTHER PUBLICATIONS COMPRISING ANALDOSE REDUCTASE INHIBITOR AND AN ACE INHIBITOR Goldfarb et al: “Effect of polyol pathway inhibition and dietary myo inositol on glomerular hemodynamic function (75) Inventors: David Patrick Tuffin; Frank Carey, in experimental diabetes mellitus in rats' Diabetes, vol. 40, both of Macclesfield; Mary Anne No. 4, 1991, pp. 465-471, XP02080592 see p. 467, col. 2, Cotter; Norman Eugene Cameron, paragraph 3, p. 468, col. 1, paragraph 1. both of Aberdeen, all of (GB) Scott, R.S.: “Prevention of diabetic complications' New Ethicals, vol. V32, Nov. 1995, p. 15–20 XP002080593 see (73) Assignee: Zeneca Limited, London (GB) p. 20, col. 1, paragraph 3–4. Cameron et al., “ converting enzyme inhibition (*) Notice: Subject to any disclaimer, the term of this prevents development of muscle and dysfunction and patent is extended or adjusted under 35 Stimulates angiogenesis in Streptozotocin-diabetic rats', U.S.C. 154(b) by 0 days. Diabetologia, vol. 35, 1992, pp. 12-18. (21) Appl. No.: 09/462,353 Cameron et al., “ inhibition, nerve perfu Sion, oxygenation and function in Streptozotocin-diabetic (22) PCT Filed: Jul. 2, 1998 rats: dose-response considerations and independence from a (86) PCT No.: PCT/GB98/01959 myo-inositol mechanism”; Diabetologia; Vol. 37, pp. 651-663. S371 Date: Jan. 7, 2000 Cameron et al.; :The Effect of Aldose Reductase Inhibition on the Pattern of Nerve Conduction Deficits in Diabetic S 102(e) Date: Jan. 7, 2000 Rats; Quarterly Journal of Experimental Physiology, 1989, (87) PCT Pub. No.: WO99/02189 pp. 917-926. Goldfarb et al., “Effects of Polyol-Pathway Inhibition and PCT Pub. Date:Jan. 21, 1999 Dietary myo-Inositol on Glomerular Hemodynamic Func (30) Foreign Application Priority Data tion in Expermental Diabetes Mellitus in Rats', Diabetes, vol. 40, 1991, pp. 465–471. Jul. 8, 1997 (GB) ...... 9714274 Scott; “Prevention of Diabetic Complications'; New Ethi (51) Int. Cl...... A61K 31154; A61K 31/50; cals, vol. 32, Nov. 1995; pp. 15–20. A61K 31/505; A61K 31/425; A61K 31/40 (52) U.S. Cl...... 514/226.5; 514/247; 514/259; * cited by examiner 514/367; 514/409; 514/431; 514/451; 514/474; 514/518 Primary Examiner Kevin E. Weddington (58) Field of Search ...... 514/474, 226.5, (74) Attorney, Agent, or Firm- Pillsbury Winthrop LLP 514/247, 259, 367, 409, 431, 451, 518 (57) ABSTRACT (56) References Cited The invention relates to pharmaceutical compositions com prising an aldose reductase inhibitor and an ACE inhibitor, U.S. PATENT DOCUMENTS and their use in the treatment of diabetic complications Such 6,069,168 A * 5/2000 Horrobin et al...... 514/474 as diabetic neuropathy, diabetic retinopathy and diabetic nephropathy. FOREIGN PATENT DOCUMENTS EP O 469 887 2/1996 11 Claims, No Drawings US 6,337,327 B1 1 2 PHARMACEUTICAL COMPOSITIONS Accordingly, further independent aspects of the present COMPRISING ANALDOSE REDUCTASE invention include the following: INHIBITOR AND AN ACE INHIBITOR (1) A pharmaceutical composition which comprises epal restat and , together with a pharmaceutically The present invention relates to pharmaceutical acceptable carrier and/or diluent, compositions, and in particular to pharmaceutical composi (2) A pharmaceutical composition which comprises tolr tions containing an aldose reductase inhibitor (ARI) and an estat and lisinopril, together with a pharmaceutically angiotensin converting enzyme (ACE) inhibitor, which are acceptable carrier and/or diluent, useful in the prevention and treatment of the complications (3) A pharmaceutical composition which comprises of diabetes mellitus. 1O ponolrestat and lisinopril, together with a pharmaceu Diabetes mellitus is a chronic disease characterised by hyperglycemia and by complications that include diabetic tically acceptable carrier and/or diluent; nephropathy, diabetic neuropathy, diabetic retinopathy, dia (4) A pharmaceutical composition which comprises betic cataract and the like. While various investigators have Zopolrestat and lisinopril, together with a pharmaceu studied the use of ACE inhibitors or aldose reductase 15 tically acceptable carrier and/or diluent; inhibitors independently in Such conditions, none have pro (5) A pharmaceutical composition which comprises posed the combination therapy provided by the present AD-5467 and lisinopril, together with a pharmaceuti invention. cally acceptable carrier and/or diluent; Prolonged administration of an ACE inhibitor at a thera (6) A pharmaceutical composition which comprises SNK peutically effective dose may be deleterious or give rise to 860 and lisinopril, together with a pharmaceutically Side effects in certain patients, for example it may lead to acceptable carrier and/or diluent, Significant deterioration of renal function, induce (7) A pharmaceutical composition which comprises ADN hyperkalemia, neutropenia, angioneurotic oedema, rash or 138 and lisinopril, together with a pharmaceutically diarrhoea or give rise to a dry cough. Administration of an acceptable carrier and/or diluent, ARI may also give rise to deleterious effects or Side effects 25 (8) A pharmaceutical composition which comprises at the dose required to inhibit the enzyme aldose reductase AS-3201 and lisinopril, together with a pharmaceuti Sufficiently to produce a Significant beneficial therapeutic cally acceptable carrier and/or diluent; effect. The present invention lessens the problems associated with administration of an ARI or an ACE inhibitor alone (9) A pharmaceutical composition which comprises Zenar and/or provides a means for obtaining a therapeutic effect estat and lisinopril, together with a pharmaceutically which is significantly greater than that otherwise obtainable acceptable carrier and/or diluent, with the Single agents when administered alone. (10) A pharmaceutical composition which comprises Sor Furthermore, diabetic complications involve a complex binil and lisinopril, together with a pharmaceutically mechanism or number of mechanisms, which initiate a acceptable carrier and/or diluent, cascade of biochemical alterations that in turn lead to 35 (11) A pharmaceutical composition which comprises Structural changes. These may result in a diverse patient methoSorbinil and lisinopril, together with a pharma population. The present invention therefore provides the ceutically acceptable carrier and/or diluent; additional advantage that it allows tailoring of treatment to (12) A pharmaceutical composition which comprises imi the needs of a particular patient population. restat and lisinopril, together with a pharmaceutically Accordingly the present invention provides a pharma 40 acceptable carrier and/or diluent, and ceutical composition which comprises an aldose reductase (13) A pharmaceutical composition which comprises inhibitor and an ACE inhibitor, together with a pharmaceu minalrestat and lisinopril, together with a pharmaceu tically acceptable carrier and/or diluent. tically acceptable carrier and/or diluent. Suitable aldose reductase inhibitors useful in the com A preferred pharmaceutical composition of the invention positions of the present invention include, for example, 45 comprises the aldose reductase inhibitor ZD5522, or a , , ponolrestat, Zopolrestat, AD-5467, pharmaceutically acceptable Salt thereof, and an ACE inhibi SNK-860, ADN-138, AS-3201, , , tor (including any of the ACE inhibitorS Specifically named methosorbinil, imirestat, minal restat (WAY-121509) and above), together with a pharmaceutically acceptable carrier ZD5522 (3',5'-dimethyl-4'-nitromethylsulfonyl-2-(2-tolyl) and/or diluent. acetanilide, prepared as described in European Patent 50 An especially preferred pharmaceutical composition of Application, Publication No. 469887, Examples 3 and 60), the invention comprises the aldose reductase inhibitor or a pharmaceutically acceptable Salt thereof. A preferred ZD5522, or a pharmaceutically acceptable Salt thereof, and aldose reductase inhibitor includes, for example, ZD5522. the ACE inhibitor lisinopril, or a pharmaceutically accept Suitable ACE inhibitors useful in the compositions of the able Salt thereof, together with a pharmaceutically accept present invention include, for example, , 55 able diluent and/or carrier. benazeprilat, , , fentiapril, , Pharmaceutically acceptable Salts of the aldose reductase libenzapril, , pentopril, , pivopril, inhibitors and of the ACE inhibitors, in accordance with the , , , , Spiraprilat, present invention, are the Salts with physiologically accept , ceronapril, , indolapril, lisinopril, able bases and/or acids well known to those skilled in the art , and , or a pharmaceutically acceptable 60 of pharmaceutical technique. Suitable Salts with physiologi salt thereof. A preferred ACE inhibitor includes, for cally acceptable bases include, for example, alkali metal and example, lisinopril. alkaline earth metal Salts, Such as Sodium, potassium, cal Independent aspects of the present invention include a cium and magnesium Salts, and ammonium Salts and Salts pharmaceutical composition which comprises any one of the with Suitable organic bases, Such as methylamine, named aldose reductase inhibitors identified above and any 65 dimethylamine, trimethylamine, piperidine, morpholine and one of the named ACE inhibitors identified above, together triethanolamine. Suitable Salts with physiologically accept with a pharmaceutically acceptable carrier and/or diluent. able acids include, for example, Salts with inorganic acids US 6,337,327 B1 3 4 Such as hydrohalides (especially hydrochlorides or A further aspect of the present invention comprises the hydrobromides), Sulphates and phosphates, and Salts with use of an aldose reductase inhibitor and an ACE inhibitor in organic acids. the preparation of a pharmaceutical composition for use in The pharmaceutical compositions of the present invention the treatment of diabetic complications. may be administered in Standard manner for example by oral A further aspect of the present invention is a method for or parenteral administration, using conventional Systemic treating diabetic complications (such is diabetic neuropathy, dosage forms, Such as a tablets, capsules, pills, powders, diabetic nephropathy or diabetic retinopathy) wherein a aqueous or oily Solutions or Suspensions, emulsions, Sterile therapeutically effective amount of an aldose reductase injectable aqueous or oily Solutions or Suspensions. These inhibitor in combination with an ACE inhibitor is adminis dosage forms will include the necessary carrier material, excipient, lubricant, buffer, bulking agent, anti-oxidant, dis tered Systemically, Such as orally or parenterally. Where the persant or the like. patient to be treated is normotensive, the ACE inhibitor will In particular, compositions for oral administration are preferably be administered in amounts below that required preferred. to cause a reduction in blood pressure. Where the patient to The doses of an aldose reductase inhibitor and an ACE 15 be treated is hypertensive, the ACE inhibitor will preferably inhibitor which can be administered in accordance with the be used in amounts usually employed to treat hypertension. present invention depends on Several factors, for example The present invention provides a novel method for treating the age, weight and the Severity of the condition under diabetic complications and the amounts of aldose reductase treatment, as well as the route of administration, dosage and ACE inhibitor required when administered in associa form and regimen and the desired result, and additionally the tion with the combined therapy are lower than would potency of the particular aldose reductase inhibitor and ACE normally be used, and thus any deleterious effects or Side inhibitor employed in the composition. In addition, account effects are minimised. should be taken of the recommended maximum daily doS The effect of a pharmaceutical composition of the present ages for the ACE inhibitors. invention may be examined by using one or more of the A unit dosage formulation Such as a tablet or capsule will 25 published models of diabetic complications well known in usually contain, for example, from 0.1 mg to 500 mg of an the art. The pharmaceutical compositions of the present aldose reductase inhibitor and from 0.1 mg to 500 mg of an invention are particularly useful for the prevention of, reduc ACE inhibitor. Preferably a unit dose formulation will ing the development of, or reversal of, deficits in nerve contain 0.1 to 100 mg of an aldose reductase inhibitor and function found in diabetic patients, and therefore particu 0.1 to 100 mg of an ACE inhibitor. The pharmaceutical compositions of the present invention larly useful in the treatment of diabetic neuropathy. This may be administered up to six times daily, conveniently 1 to may be demonstrated, for example, by measuring markers 4 times daily and preferably 1 to 2 times daily, So that a dose Such as nerve conduction Velocity, nerve amplitude, quan of the aldose reductase inhibitor in the general range of 0.01 titative Sensory testing, autonomic function testing and to 100 mg/kg, preferably 0.1 to 10 mg/kg, more preferably 35 morphometric changes. Experimentally, Studies analogous 0.1 to 5 mg/kg, is administered daily and a dose of ACE to those described in Diabetologia, 1992, Vol. 35, pages inhibitor in the general range 0.01 to 100 mg/kg, preferably 12-18 and 1994, Vol. 37, pages 651-663 may be carried out. 0.01 to 20 mg/kg, more preferably 0.01 to 1 mg/kg, is A further aspect of the present invention is a method of administered daily. treating or preventing the development of disease conditions The present invention covers the combination of (or 40 asSociated with impaired neuronal conduction Velocity in a product containing) an aldose reductase inhibitor and an warm-blooded animal (including a human being) requiring ACE inhibitor for Simultaneous, Separate or Sequential use Such treatment which comprises administering to Said ani in the treatment of diabetic complications. In one aspect of mal a therapeutically effective amount of a combination of the present invention, the aldose reductase inhibitor or a an aldose reductase inhibitor and an ACE inhibitor. A further pharmaceutically acceptable Salt thereof and an ACE inhibi 45 aspect of the present invention is the use of an aldose tor or a pharmaceutically acceptable Salt thereof are pre reductase inhibitor and an ACE inhibitor for the manufacture Sented in admixture in one pharmaceutical dosage form. In of a medicament for use in the treatment or prevention of the another aspect, the present invention covers the administra development of disease conditions associated with impaired tion of Separate unit dosages of the aldose reductase inhibi neuronal conduction Velocity. tor and the ACE inhibitor in order to achieve the desired 50 therapeutic effect. Such separate unit dosages may be admin A further aspect of the present invention is a method of istered concurrently or Sequentially as determined by the reversing impaired neuronal conduction Velocity in a warm clinician. Preferably the aldose reductase inhibitor and the blooded animal (including a human being) requiring Such ACE inhibitor are both administered orally. The present treatment which comprises administering to Said animal a invention also covers an agent for the treatment of diabetic 55 therapeutically effective amount of a combination of an complications comprising a pharmaceutically acceptable aldose reductase inhibitor and an ACE inhibitor. A further carrier and/or diluent and, as active agents, an aldose reduc aspect of the present invention is the use of an aldose tase inhibitor and an ACE inhibitor in quantities producing reductase inhibitor and an ACE inhibitor for the manufacture a Synergistic therapeutic effect. of a medicament for use in the reversal of impaired neuronal In another aspect of the invention there is provided a 60 conduction Velocity. combination of pharmaceutical compositions for combina The following non-limiting Examples Serve to illustrate tion therapy of diabetic complications, the combination the present invention. consisting of a pharmaceutical composition comprising an aldose reductase inhibitor and a pharmaceutical composition EXAMPLE 1. comprising an ACE inhibitor. Particular diabetic complica 65 tions include, for example, diabetic neuropathy, diabetic Suitable pharmaceutical compositions of an aldose reduc nephropathy and diabetic retinopathy. tase inhibitor (ARI), such as ZD5522, include the following: US 6,337,327 B1 6 EXAMPLE 5 Male Sprague-Dawley rats, 19 weeks old at the start of the Study, were divided into non-diabetic animals (normal con mg/tablet trol group) and animals rendered diabetic by intraperitoneal Tablet 1 administration of Streptozotocin, (40–45 mg/kg, freshly dis solved in sterile saline). Diabetes was verified 24 hours later ARI 1OO by estimating hyperglycemia and glucosuria (Visidex II and Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Diastix; Ames, Slough, UK). Diabetic rats were tested Maize starch paste (5% w/v paste) 2.25 weekly and weighed daily. Animals were rejected if the Magnesium stearate 3.0 plasma concentration was <20 mM of if body Tablet 2 weight consistently increased over 3 dayS. Samples were taken from the tail vein or carotid artery after final experi ARI 50 Lactose Ph. Eur. 223.75 ments for plasma glucose determination (GOD-Perid Croscarmellose sodium 6.O method; Boehringer Mannheim, Mannheim, Germany). Maize starch 15.O 15 After 6 weeks of untreated diabetes, groups of rats were Polyvinylpyrrolidone (5% w/v paste) 2.25 treated for a further 2 weeks with lisinopril (0.3 mg/kg/day) Magnesium stearate 3.0 or the aldose reductase inhibitor, ZD5522 (0.25 mg/kg/day) Tablet 3 or a combination of the two drugs, dissolved in the drinking Water. ARI 1.O Lactose Ph. Eur. 93.25 At the end of the treatment period, rats were anesthetized Croscarmellose sodium 4.0 with thiobutabarbitone by intraperitoneal injection (50-100 Maize starch paste (5% w/v paste) 0.75 mg/kg). The trachea was cannulated for artificial ventilation Magnesium stearate 1.O and a cartoid cannula was used to monitor mean Systemic Capsule 1 blood pressure. Motor nerve conduction Velocity was mea ARI 1O Sured (as previously described by Cameron et al., Lactose Ph. Eur. 488.5 25 Diabetologia, 1993, Vol. 36, pages 299-304) between sciatic Magnesium stearate 1.5 notch and knee in the nerve branch to tibialis anterior muscle, which is representative of the whole Sciatic nerve in terms of Susceptibility to diabetes and treatment effects. EXAMPLE 2 RESULTS Suitable pharmaceutical compositions of an ACE inhibi Nerve conduction velocity (meani-SEM) was 64.4+0.5 tor include the following: m/S in nondiabetic control rats and this was reduced to 50.9+0.5 m/s with untreated diabetes (p<0.001). Treatment with lisinopril or ZD5522 produced small (~20%) but sta Tablet 1 35 tistically significant increases in conduction Velocity to 53.9+0.6 (p<0.01) and 53.7+0.3 (p<0.001) m/s respectively. ACE Inhibitor 1OO Corn starch 50 With joint treatment, conduction velocity was within the Gelatin 7.5 nondiabetic range, 63.85+0.41 (p<0.001 vs the diabetic Microcrystalline cellulose 25 control group). This conduction velocity increment was Magnesium stearate 2.5 40 considerably greater than that predicted from Simple addi Tablet 2 tion of the effects of the two drugs (56.1 m/s, p<0.0001, one ACE inhibitor 2O Sample t-test). Pregelatinised starch 82 What we claim is: Microcrystalline cellulose 82 1. The pharmaceutical composition which comprises an Magnesium stearate 1. 45 aldose reductase inhibitor and an angiotensin converting enzyme inhibitor, together with a pharmaceutically accept able carrier and/or diluent. EXAMPLE 3 2. The pharmaceutical composition as claimed in claim 1 Suitable pharmaceutical compositions containing an ARI wherein the aldose reductase inhibitor is selected from and an ACE inhibitor in a Single dosage form include the 50 epalrestat, tolrestat, ponolrestat, Zopolrestat, AD-5467, following: SNK-860, ADN-138, AS-3201, Zenarestat, sorbinil, methosorbinil, imirestat, minalrestat and ZD5522, or a phar maceutically acceptable Salt thereof. 3. The pharmaceutical composition as claimed in claim 1 Tablet 55 wherein the angiotensin converting enzyme inhibitor is ARI 70 Selected from benazepril, benazeprilat, captopril, delapril, ACE inhibitor 1O fentiapril, foSinopril, libenzapril, moexipril, pentopril, Corn starch 40 perindopril, pivopril, quinapril, quinaprilat, ramipril, Gelatin 6 Spirapril, Spiraprilat, Zofenopril, ceronapril, enalapril, Microcrystalline cellulose 2O 60 indolapril, lisinopril, alacepril and cilaZapril, or a pharma Magnesium stearate 2.O ceutically acceptable Salt thereof. 4. The pharmaceutical composition as claimed in claim 1, wherein the aldose reductase inhibitor is ZD5522, or a EXAMPLE 4 pharmaceutically acceptable Salt thereof. A patient requiring treatment for diabetic neuropathy is 65 5. The pharmaceutical composition as claimed in claim 1, treated with ZD5522 (70 mg) and lisinopril (10 mg). Each wherein the angiotensin converting enzyme inhibitor is compound is administered twice daily. lisinopril, or a pharmaceutically acceptable Salt thereof. US 6,337,327 B1 7 8 6. The pharmaceutical composition as claimed in claim 2 9. The pharmaceutical composition as claimed in claim 4 wherein the angiotenisin converting enzyme inhibitor is wherein the angiotensin converting enzyme inhibitor is Selected from benazepril, benazeprilat, captopril, delapril, lisinopril, or a pharmaceutically acceptable Salt thereof. fentiapril, foSinopril, libenzapril, moexipril, pentopril, perindopril, pivopril, quinapril, quinaprilat, ramipril, 10. A method of treating diabetic complications in a warm Spirapril, Spiraprilat, Zofenopril, ceronapril, enalapril, blooded animal in need thereof comprising administering a indolapril, lisinopril, alacepril and cilaZapril, or a pharma treatment-Sufficient amount of the pharmaceutical composi ceutically acceptable Salt thereof. tion as claimed in any one of claims 1, 7 or 9. 7. The pharmaceutical composition as claimed in claim 3 11. A method of treating diabetic neuropathy in a warm wherein the aldose reductase inhibitor is ZD5522, or a blooded animal in need thereof comprising administering a pharmaceutically acceptable Salt thereof. treatment-Sufficient amount of the pharmaceutical composi 8. The pharmaceutical composition as claimed in claim 2 tion as claimed in any one of claims 1, 7 or 9. wherein the angiotensin converting enzyme inhibitor is lisinopril, or a pharmaceutically acceptable Salt thereof.