WO2008060567A1

WO2008060567A1 - Glycosaminoglycan formulations in the treatment of vascular disease

Info

Publication number: WO2008060567A1
Application number: PCT/US2007/023935
Authority: WO
Inventors: Michael S. Weiss; Robert M. Niecestro; William Bennett; Henry Le
Original assignee: Keryx Biopharmaceuticals, Inc.
Priority date: 2006-11-14
Filing date: 2007-11-14
Publication date: 2008-05-22

Abstract

The present invention is directed to a pharmaceutical composition for the treatment of vascular disease in a patient, the pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and one or more agents such as a hypertensive agent, an oral hypoglycemic agent or a lipid- lowering agent.

Description

GLYCOSAMINOGLYCAN FORMULATIONS IN THE TREATMENT OF VASCULAR DISEASE

1. FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a glycosaminoglycan and one or more additional agents such as a hypertensive agent, a lipid-lowering agent or an oral hypoglycemic agent each at its effective therapeutic dose. The formulations of the invention are effective in the treatment of the symptoms and the side effects of vascular disease. The pharmaceutical compositions of the invention improve patient compliance and ease the burden of multiple pill taking.

2. BACKGROUND OF THE INVENTION

The glycosaminoglycans are products of natural origin, obtained from animal tissues, composed of heterogeneous mixtures of chains of polysaccharides sulfated in different ways, having a very wide range of molecular weights, comprised from few thousands and some tens of thousands of Daltons. Heparin is the most known among them, mainly made by units containing D-glucosamine and L-iduronic or D- glucuronic acid sulfated in different ways, having a range of molecular weights comprised between about 6,000 and 30,000 Daltons, and is generally used as an anticoagulant and antithrombotic drug in the form of sodium, potassium, calcium or magnesium salts. Low molecular weight heparins, derivatives having a lesser degree of polymerization, with molecular weights comprised between about 1,500 and about 8,000 Daltons, having therapeutic characteristics like those of heparin, are obtained by means of enzymatic or chemical treatment. Chondroitins are other kinds of glycosaminoglycans extracted from tissues of animal origin, and one of them, previously known as chondroitin sulfate B, is dermatan sulfate having antithrombotic and antihyperlipoproteinemic activity. Low molecular weight fractions, between about 2,000 and about 8,000 Daltons, can also be obtained from dermatan sulfate. Glycosaminoglycans have been widely studied in the prevention and treatment of many pathologies of thrombotic and atherosclerotic origin. Glucoronylglycosaminoglycan sulfate also known as sulodexide has been approved for "vascular indications" and has been marketed in multiple countries for such indications. Suodexide has also been evaluated for diabetic renal disease. U.S. Patent No. 5,496,807 reports on the evaluation of sulodexide in the treatment of diabetic nephropathy, and when administered intramuscularly or orally in doses of approximately 50 to 100 mg/day, produces reductions in albumin excretion rate (AER) of 35 to 62% in macroalbuminuric patients and 20 to 50% in microalbuminuric patients. Sulodexide has also been evaluated at a dose of at least 200 mg/day (U.S. Patent Publication No. 2002/0065233) and normoalbuminuria was achieved in 42% of patients. The precise mechanism by which sulodexide decreases albumin excretion in patients with diabetic nephropathy may include the following: (1) the restoration of the physiologic glomerular membrane anionic charge barrier via enhanced synthesis and sulfation of heparan sulfate in renal vascular membranes, and direct replenishment of renal heparan sulfate, (2) the inhibition of TGF beta-1 mediated mesangial matrix overproduction, (3) the inhibition of endothelin mediated tubulo- interstitial fibrosis, and (4) the inhibition of mesangial cell hyperplasia. See Harenberg J., Med. Res. Rev. vol. 18, 1-20 (1998), Gambaro G. and Van Der Woude, J. Am. Soc. Nephrol. 11 :359-368 (2000). Kanwar Y. S. et al., Sem. Nephrol., 5, 307, (1985) and Groggel G. C. et al., Kidney Int., 33, 517, (1988), have produced evidence of the probable role of glycosaminoglycans in helping the integrity and the functioning of the renal cells. Moreover, Canfield J. P. et al., Lab. Invest., 39, 505, (1978), previously showed a decrease of glycosaminoglycans in the glomerular basement membrane in many conditions of nephropathy, while Baggio B. et al., Nephron., 43, 187, (1986) showed an increased urinary elimination of glycosaminoglycans in diabetic, non-albuminuric, patients. This increased excretion of glycosaminoglycans in diabetic nephropathies was shown also by Partasarathy N. et al., Diabetes, 31 , 738, (1982). In addition, Diamond J. R. et al., Renal Physiol., 9, 366, (1986) and Parkerson M. B. et al., J. Clin. Invest., 81 , 69, (1988), showed in animals the potential protective effect of heparin and its derivatives in models of experimental nephropathy not related to diabetic nephropathy, like chronic nephrosis from aminoglycosides and renal pathologies resulting from the subtotal renal ablation in the rat.

Hypertensive agents include thiazidic and similar diuretics such as hydrochlorothiazide, cicletanine, xipamide, indapamide and clopamide; loop diuretics such as furosemide, piretanide and bumetanide; hyperkalemia causing (potassium-sparing) diuretics such as amiloride, spironolactone and canrenone; beta-blockers such as propranolol, acebutolol, atenolol, nadolol, bisoprolol, metoprolol, pindolol, oxprenolol and betaxolol; angiotensin converting enzyme inhibitor (ACE) such as captopril, enalapril, benazepril, lisinopril, quinapril, ramipril and imidapril; angiotensin Il receptor blockers (ARBs), such as losartan, candesartan, cilexetil, irbesartan, telmisartan, and valsartan; slow calcium channel antagonists, such as nifedipine, amlodipine, felodipine, isradipine, diltiazem, bepridil, lacidipine, nitrendipine, nicardipine and verapamil; central antihypertensive agents such as clonidine, guanfacine, monoxidine, rilmenidine and alpha-methyl-dopa; alpha-blockers such as prasozine, urapidil, doxazosine and terazosine; vasodilators such as hydralazine, dihydralazine and minoxidil. 5 Hypertensive agents such as ACE inhibitors and ARBs exhibit differential clinical effects. The final active messenger of the renin-angiotensin pathway is angiotensin Il which binds to AT1 receptors to cause vasoconstriction and fluid retention, both of which lead to an increase in blood pressure. ARBs reduce blood pressure by blocking the AT1 receptors.

10 Hypertensive agents such as ACE inhibitors and ARBs have been used to treat diabetic renal disease. Therapies involving ACE inhibitors and ARBs have been shown to reduce levels of albuminuria in select patient populations. Patients suffering from vascular disease and more particularly diabetic renal disease have also been shown to suffer from high blood glucose level. Oral hypoglycemic agents

15 are often used in combination with insulin to reduce high blood glucose level. Oral hypoglycemic agents operate by different mechanisms, for example alpha- glucosidase inhibitors slow down the absorption of sugars from the gut, sulfonylurease, meglinides and d-phenylalanine derivatives increase insulin production from the pancreas, biguanides decrease glucose release from the liver,

20. and thiazoldinediones increase glucose uptake by fat and muscle cells.

Patients suffering from vascular disease and more particularly diabetic renal disease have also been shown to suffer from high cholesterol and triglycerides. Lipid-lowering agents can be used for reducing the amounts of cholesterol and triglycerides in the serum and for reducing the amounts of cholesterol and

25 triglycerides in the liver. Such lipid-lowering agents include the statins which reduce LDL levels and block cholesterol synthesis, ezetimibe which blocks cholesterol absorption and is typically administered with a statin, bile acid binding agents (BABRs) which are effective in the treatment of hypercholesterolemias

(Type Na and lib), nicotininc acid which significantly increases HDL while decreasing LDL, and total cholesterol, gemfibrozil which is useful in the treatment of elevated triacyglycerol (TG) levels (i.e., Types II, IV and V). These lipid-lowering agents can be used as a single agent or in combination with a second lipid-lowering agent.

There is a need to optimize the oral administration of glycosaminoglycan to reduce the symptoms of vascular disease and to reduce the side effects associated with vascular disease. There is a further need to optimize the oral administration of sulodexide to reduce the symptoms of diabetic renal disease and to reduce the side effects associated with diabetic renal disease.

Citation or identification of any reference in Section 2 or in any other section of this application shall not be construed as an admission that such reference is available as prior art to the present invention.

3. SUMMARY OF THE INVENTION

The present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a glycosaminoglycan and a hypertensive agent in a therapeutically effective amount sufficient to reduce the symptoms of vascular disease in a patient. The hypertensive agent can be an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin Il (A2) receptor blocker (ARB).

In another embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of a glycosaminoglycan and an oral hypoglycemic agent in therapeutically effective amount to reduce the symptoms of vascular disease in a patient. The oral hypoglycemic agent can be an alpha- glucosidase inhibitor a sulfonyurea, a meglitimide, a d-phenylalanine derivative, a biguanide, or a thjiasolodinedione.

In another embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of a glycosaminoglycan and a lipid- lowering agent in a therapeutically effective amount to reduce the symptoms of vascular disease in a patient. The lipid-lowering agent can be a statin, ezetimibe, a bile acid binding agent (BABRs), nicotininc acid, gemfibrozil.

In another embodiment of the invention, the glycosaminoglycan may be combined with at least two agents such as of a hypertensive agent and an oral hypoglycemic agent, or a hypertensive agent and a lipid-lowering agent, or an oral hypoglycemic agent and a lipid-lowering agent, or a combination of all three agents.

The pharmaceutical compositions of the invention can be administered to patients suffering from vascular disease such that one or more symptoms of such disease is at least reduced or ameliorated. In one embodiment of the invention, the glycosaminoglycan is sulodexide.

The present invention is also directed to pharmaceutical compositions comprising a therapeutically effective amount of sulodexide and a hypertensive agent in a therapeutically effective amount to reduce the symptoms of diabetic renal disease in a patient. The hypertensive agent can be an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin Il (A2) receptor blocker (ARB).

In another embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of sulodexide and an oral hypoglycemic agent in therapeutically effective amount to reduce the symptoms of diabetic renal disease in a patient. The oral hypoglycemic agent can be an alpha- glucosidase inhibitor a sulfonyurea, a meglitimide, a d-phenylalanine derivative, a biguanide, or a thjiasolodinedione.

In another embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of sulodexide and a lipid-lowering agent in a therapeutically effective amount to reduce the symptoms of diabetic renal disease in a patient The lipid-lowering agent can be a statin, ezetimibe, a bile acid binding agent (BABRs), nicotininc acid, gemfibrozil.

In another embodiment of the invention, sulodexide is combined with at least two agents such as of a hypertensive agent and an oral hypoglycemic agent, or a hypertensive agent and a lipid-lowering agent, or an oral hypoglycemic agent and a lipid-lowering agent, or a combination of all three agents.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to pharmaceutical compositions for the treatment of vascular disease in a patient. The pharmaceutical compositions of the invention comprise a glycosaminoglycan in a therapeutically effective amount to reduce the symptoms of vascular disease. In one embodiment, the pharmaceutical compositions also comprise one or more hypertensive agent, an oral hypoglycemic agent or a lipid-lowering agent or any combination of the foregoing. The oral hypoglycemic agent and the lipid-lowering agent are employed at a therapeutically effective dose to reduce the side effects associated with vascular disease.

The present invention is directed to pharmaceutical compositions for the treatment of diabetic renal disease in a patient. The pharmaceutical compositions of the invention comprise a glycosaminoglycan such as sulodexide in a therapeutically effective amount to reduce the symptoms of diabetic renal disease. In one embodiment, the pharmaceutical compositions also comprise one or more hypertensive agent, an oral hypoglycemic agent or a lipid-lowering agent or any combination of the foregoing, The oral hypoglycemic agent and the lipid-lowering agent are employed at a therapeutically effective dose to reduce the side effects associated with diabetic renal disease. Exemplary hypertensive agents according to the invention include thiazidic and similar diuretics such as hydrochlorothiazide, cicletanine, xipamide, indapamide and clopamide; loop diuretics such as furosemide, piretanide and bumetanide; hyperkalemia causing (potassium-sparing) diuretics such as amiloride, spironolactone and canrenone; beta-blockers such as propranolol, acebutolol, atenolol, nadolol, bisoprolol, metoprolol, pindolol, oxprenolol and betaxolol; angiotensin converting enzyme inhibitor (ACE) such as captopril, enalapril, benazepril, lisinopril, quinapril, ramipril and imidapril; Angiotensin Il receptor blockers (ARBs), such as losartan, candesartan, cilexetil, irbesartan, telmisartan, and valsartan; slow calcium channel antagonists, such as nifedipine, amlodipine, felodipine, isradipine, diltiazem, bepridil, lacidipine, nitrendipine, nicardipine and verapamil; central anti-hypertensive agents such as clonidine, guanfacine, monoxidine, rilmenidine and . alpha. -methyl-dopa; alpha-blockers such as prasozine, urapidil, doxazosine and terazosine; vasodilators such as hydralazine, dihydralazine and minoxidil. The quantities in which each of the hypertensive agents will be present in the final therapeutic compositions will vary depending upon the nature of the agents selected and the desired therapeutic effect to be achieved.

Exemplary oral hypoglycemic agents according to the invention include alpha-glucosidase inhibitor (for example, prandase), a sulfonyurea (for example, diabeta Glyburidel), a meglitimide (for example, gluconorm (repaglinidel)), a d- phenylalanine derivative (for example, Starlix (nateglnide), a biguanide (glucophage (metforn), or a thjiasolodinedione ("glitazone") (for example, Actos (pioglitazone) or Avandia (rosiglitazone). The quantities in which each of the oral hypoglycemic agents will be present in the final therapeutic compositions will vary depending upon the nature of the agents selected and the desired therapeutic effect to be achieved.

Exemplary lipid-lowering agents according to the present invention include the statins which are HMG-CoA reductase inhibitors. Ezetimibe which is typically administered with a statin (for example, simvastatin), bile acid binding agents (BABRs), gemfibrozil, dextrothyroxine, the fibrates, (for example, fenofibrate, clofibrate, bezafibrate, ciprofibrate, mevinolin, synvinolin, niacin, hormonal preparations, e.g., T3- and/or T4- containing agents, fish oils and/or extracts of such oils, eptastin, the neomycins, probucol, nicotinic acid, and the like, as well as their pharmaceutically acceptable salts and esters, e.g., dextrothyroxine sodium, gemfibrozil HCI and the like. The quantities in which each of the lipid reducing agents will be present in the final therapeutic compositions will vary depending upon the nature of the agents selected and the desired therapeutic effect to be achieved.

By way of example, a glycosaminoglycan such as sulodexide and one or more agent such a hypertensive agent, an oral hypoglycemic agent and a lipid- lowering agent can be formulated into a capsule. The capsule may include a glycosaminoglycan, from about 5 to about 20%, triacetin USP from about 35 to about 70%, sodium lauroyl sarcosinate form about 1 to about 6%. One or more agent can be incorporated into the capsule in at a therapeutic composition to reduce the symptoms of diabetic renal disease and/or reduce any side effect associated with diabetic renal disease. The capsule may have a total shell (gel mass) of gelatin NF, from about 10 to about 30%, colorant from about 0 to about 3%, water from about 1 to about 8%. An exemplary pharmaceutical composition of the invention comprises sulodexide of from about 25 mg to about 1000 mg and one or more agents such as a hypertensive agent, an oral hypoglycemic agent or a lipid-lowering agent in a therapeutically effective amount sufficient to achieve the desired therapeutic effect.

Other pharmaceutical compositions comprising a glycosaminoglycan and one or more agent such a hypertensive agent, a oral hypoglycemic agent and a lipid-lowering agent can also formulated by methods know in the art. The pharmaceutical compositions of the invention provide for a synergistic effect and the same therapeutic effect of glycosaminoglycan and one or more agents is achieved at lower therapeutic effective amounts.

Pharmaceutical compositions of the present invention are suitable for oral administration and may be presented as discrete pharmaceutical unit dosage form, such as capsules, cachets, soft elastic gelatin capsules, tablets, caplets, or aerosol sprays, each containing a predetermined amount of the active ingredient, such as a powder or granules, or as a solution or a suspension in an aqueous liquid, a nonaqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Dosage forms such as oil-in-water emulsions typically comprise surfactants such as anionic phosphate ester or lauryl sulfates, but other types of surfactants such as cationic or nonionic surfactants may be used in the compositions of the present invention. (See generally, Remington's Pharmaceutical Sciences, 18^th ed., Mack Publishing, Easton PA (1990)).

The pharmaceutical compositions of the present invention are suitable for oral administration and may be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form by using conventional methods well known in the art. See, e.g., Ebert, Pharm. Tech. 1(5):44-50 (1977). Pharmaceutical compositions in the form of capsules or tablets coated by an enterosoluble gastro-resistant film and which contains a lyophilisate consisting of glycosaminoglycan, a thickening agent, and a surfactant have been previously described in U.S. Patent No. 5,252,339, which is incorporated herein by reference in its entirety.

Soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. Varying the type of gelatin used and the amounts of plasticizer and water may change the hardness of the capsule shell. The soft gelatin shells may contain a preservative, such as methyl and propylparabens and sorbic acid, to prevent the growth of fungi. The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols, such as polyethylene glycol and propylene glycol, triglycerides, surfactants, such as polysorbates, or a combination thereof.

Typical oral dosage forms of the pharmaceutical compositions of the invention are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case one or solid excipient are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL® PH-101 , AVICEL® PH-103 AVICEL® RC-581, AVICEL® PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL® RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH-103 and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to talc, calcium carbonate (e.g. granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Pharmaceutical stabilizers may also be used to stabilize the compositions of the invention. Acceptable stabilizers include but are not limited to L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L-cysteine dihydrochloride.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally after the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

In addition to the common dosage forms set out above, the glycosaminoglycans, the hypertensive agents, oral hypoglycemic agents and lipid- lowering agents of the present invention may be administered by controlled release means or delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591 ,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566. These pharmaceutical compositions can be used to provide slow or controlled-release of one or more of the active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, may be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled- release are encompassed by the present invention.

The glycosaminoglycans, the hypertensive agents, oral hypoglycemic agents and lipid-lowering agents of the present invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients, using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical compositions have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled- release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. Controlled-release of an active ingredient can be stimulated by conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. Further, when it is desired to temporally space the release, and hence the effect, of two or more active ingredients used in the method of the invention, it is possible to use: (a) a controlled-release preparation for the release of at least one of the active ingredients; or (b) two or more controlled-release preparations having different release coefficients, for the separate release of each active ingredient.

Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.

The pharmaceutical compositions may be prepared by any methods well known in the art of pharmacy, but all methods include the step of bringing into association one or more active ingredient(s) with the carrier. In general, the compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. Oral solid preparations are preferred over oral liquid preparations. One preferred oral solid preparation is tablets, but the most preferred oral solid preparation is capsules. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and stored , such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. Other factors include the patient's general condition, age, and weight, as well as the severity of the disease. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. Such modifications are intended to fall within the scope of the appended claims. All references, patent and non-patent, cited herein are incorporated herein by reference in their entireties and for all purposes, to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for the treatment of vascular disease in a patient, the pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and a hypertensive agent.

2. The composition of claim 1 , wherein the hypertensive agent is an angiotensin converting enzyme (ACE) inhibitor.

3. The composition of claim 1 , wherein the hypertensive agent is an angiotensin Il receptor blocker.

4. A pharmaceutical composition for the treatment of vascular disease and for reducing any side effect associated with vascular disease, the pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and an oral hypoglycemic agent.

5. A pharmaceutical composition for the treatment of vascular disease and for reducing any side effect associated with vascular disease, the pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and a lipid-lowering agent.

6. A method for the treatment of vascular disease in a patient, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and a hypertensive agent.

7. The method of claim 6, wherein the high hypertensive agent is an angiotensin converting enzyme inhibitor.

8. The method of claim 6, wherein the high blood-pressure reducing agent is an angiotensin Il receptor blocker.

9. A method for the treatment of vascular disease in a patient and reducing any side effect associated with vascular disease, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and an oral hypoglycemic agent.

10. A method for the treatment of vascular disease in a patient and reducing any side effect associated with vascular disease, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and a lipid-lowering agent.

1 1. A method for the treatment of vascular disease in a patient, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a glycosaminoglycan and a lipid-lowering agent.

12. A pharmaceutical composition for the treatment of diabetic renal disease in a patient, the pharmaceutical composition comprising a therapeutically effective amount of sulodexide and a hypertensive agent.

13. The composition of claim 12, wherein the hypertensive agent is an angiotensin converting enzyme inhibitor.

14. The composition of claim 12, wherein the hypertensive agent is an angiotensin Il receptor blocker.

15. A pharmaceutical composition for the treatment of diabetic renal disease and for reducing any side effect associated with diabetic renal disease, the pharmaceutical composition comprising sulodexide and an oral hypoglycemic agent at their effective therapeutic dose.

16. A pharmaceutical composition for the treatment of diabetic renal disease and for reducing any side effect associated with diabetic renal disease, the pharmaceutical composition comprising a therapeutically effective amount of sulodexide and a lipid-lowering agent.

17. A method for the treatment of diabetic renal disease in a patient, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of sulodexide and a hypertensive agent.

18. The method of claim 17, wherein the high hypertensive agent is an angiotensin converting enzyme inhibitor.

19. The method of claim 17, wherein the high blood-pressure reducing agent is an angiotensin Il receptor blocker.

20. A method for the treatment of diabetic renal disease in a patient and reducing any side effect associated with diabetic renal disease, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of sulodexide and an oral hypoglycemic agent.

21. A method for the treatment of diabetic renal disease in a patient and reducing any side effect associated with diabetic renal disease, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of sulodexide and a lipid- lowering agent.

22. A method for the treatment of diabetic renal disease in a patient, the method comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of sulodexide and a lipid- lowering agent.