[go: up one dir, main page]

WO2008060567A1 - Formulations de glycosaminoglycanes dans le traitement d'une maladie vasculaire - Google Patents

Formulations de glycosaminoglycanes dans le traitement d'une maladie vasculaire Download PDF

Info

Publication number
WO2008060567A1
WO2008060567A1 PCT/US2007/023935 US2007023935W WO2008060567A1 WO 2008060567 A1 WO2008060567 A1 WO 2008060567A1 US 2007023935 W US2007023935 W US 2007023935W WO 2008060567 A1 WO2008060567 A1 WO 2008060567A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
pharmaceutical composition
patient
treatment
therapeutically effective
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/023935
Other languages
English (en)
Inventor
Michael S. Weiss
Robert M. Niecestro
William Bennett
Henry Le
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Keryx Biopharmaceuticals Inc
Original Assignee
Keryx Biopharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Keryx Biopharmaceuticals Inc filed Critical Keryx Biopharmaceuticals Inc
Publication of WO2008060567A1 publication Critical patent/WO2008060567A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 such as ACE inhibitors and ARBs
  • 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,
  • 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
  • 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
  • lipid-lowering agents can be used as a single agent or in combination with a second lipid-lowering agent.
  • glycosaminoglycan to reduce the symptoms of vascular disease and to reduce the side effects associated with vascular disease.
  • sulodexide to reduce the symptoms of diabetic renal disease and to reduce the side effects associated with diabetic renal disease.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 (AR)
  • alpha. -methyl-dopa alpha-blockers such as prasozine, urapidil, doxazosine and terazosine; vasodilators such as hydralazine, dihydralazine and minoxidil.
  • alpha-blockers such as prasozine, urapidil, doxazosine and terazosine
  • vasodilators such as hydralazine, dihydralazine and minoxidil.
  • Exemplary oral hypoglycemic agents 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 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
  • a glycosaminoglycan such as sulodexide and one or more agent such a hypertensive agent, an oral hypoglycemic agent and a lipid- lowering agent
  • 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.
  • 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.
  • 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.
  • 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.
  • surfactants such as anionic phosphate ester or lauryl sulfates
  • 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)).
  • 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.
  • 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.
  • 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.
  • excipients suitable for use in solid oral dosage forms 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • compositions of the invention 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.
  • calcium stearate e.g., 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,
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • controlled-release pharmaceutical compositions have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • 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 decom
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour le traitement d'une maladie vasculaire chez un patient, la composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un glycosaminoglycane et un ou plus d'agents tels qu'un agent hypertensif, un agent hypoglycémiant oral ou un agent hypolipidémiant.
PCT/US2007/023935 2006-11-14 2007-11-14 Formulations de glycosaminoglycanes dans le traitement d'une maladie vasculaire Ceased WO2008060567A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85926006P 2006-11-14 2006-11-14
US60/859,260 2006-11-14

Publications (1)

Publication Number Publication Date
WO2008060567A1 true WO2008060567A1 (fr) 2008-05-22

Family

ID=39401984

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/023935 Ceased WO2008060567A1 (fr) 2006-11-14 2007-11-14 Formulations de glycosaminoglycanes dans le traitement d'une maladie vasculaire

Country Status (1)

Country Link
WO (1) WO2008060567A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050014732A1 (en) * 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20060067927A1 (en) * 2004-06-29 2006-03-30 Massachusetts Institute Of Technology Methods and compositions related to the modulation of intercellular junctions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050014732A1 (en) * 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20060067927A1 (en) * 2004-06-29 2006-03-30 Massachusetts Institute Of Technology Methods and compositions related to the modulation of intercellular junctions

Similar Documents

Publication Publication Date Title
AU2018341479B2 (en) Niraparib formulations
EP1392329B1 (fr) Utilisation de sulodexide pour le traitement d'une maladie enterique inflammatoire
EP1441713B1 (fr) Comprimes de tamsulosine a liberation modifiee
KR101012533B1 (ko) 프리가발린, 매트릭스 형성제 및 팽윤제를 함유하는 1일1회 투여를 위한 경구용 고체 제약 조성물
US20050209188A1 (en) Methods using glycosaminoglycans for the treatment of nephropathy
RU2570752C2 (ru) Способы лечения сердечно-сосудистых нарушений
JP2017122115A (ja) ネコの全身性疾患の予防又は治療の為のアンジオテンシンｉｉ受容体アンタゴニスト
WO2014027334A2 (fr) Composition pharmaceutique orale sous forme de microsphères et procédé de préparation
EP3013327B1 (fr) Préparation composite pour gélule pharmaceutique comprenant du tadalafil et de la tamsulosine
ES2374399T3 (es) Piridoxamina para uso en el tratamiento de nefropatía diabética en diabetes tipo ii.
US20250144134A1 (en) Therapeutic Composition and Methods
HUE025705T2 (en) Treatment of thromboembolic disorders with rivaroxaban
EP2804600A2 (fr) Procédés et formulations permettant de traiter les déficiences en acide sialique
CN101416966B (zh) 一种治疗高血压的药物组合物
WO2019130277A1 (fr) Formulations pharmaceutiques d'azilsartan médoxomil
MX2011000909A (es) Composiciones de ramipril de liberacion modificada y usos de las mismas.
WO2008060567A1 (fr) Formulations de glycosaminoglycanes dans le traitement d'une maladie vasculaire
KR100815287B1 (ko) 당뇨성 신장병의 치료에 슐로덱사이드를 사용하는 방법 및조성물
CN1212869A (zh) 血管紧张肽转化酶抑制剂和钙通道拮抗剂的定量结合物及其制备方法和在心血管疾病的治疗中的用途
WO2007056442A1 (fr) Compositions de ramipril stabilise en combinaison avec un autre agent actif
EP4082549A1 (fr) Médicament de prévention du décès par séance de dialyse ou par maladie rénale
KR20090024248A (ko) Ｃｘｃｒ2의 선택적 길항제 또는 ｃｘｃｒ1과 ｃｘｃｒ2 둘다의 선택적 길항제의 약제학적 제형 및 조성물, 및 염증성 질환을 치료하기 위한 이의 사용방법
KR20200110396A (ko) 갑상샘 호르몬 또는 이의 유사체를 제공하는 조성물 및 방법
KR101441355B1 (ko) 레파글리니드 및 메트포르민을 함유하는 이층정 및 그의 제조방법
AU2005292202A1 (en) Methods using glycosaminoglycans for the treatment of kidney disease

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07840049

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07840049

Country of ref document: EP

Kind code of ref document: A1