WO2013095316A1 - Synergic combination comprising anti-diabetic agent - Google Patents
Synergic combination comprising anti-diabetic agent Download PDFInfo
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- WO2013095316A1 WO2013095316A1 PCT/TR2012/000220 TR2012000220W WO2013095316A1 WO 2013095316 A1 WO2013095316 A1 WO 2013095316A1 TR 2012000220 W TR2012000220 W TR 2012000220W WO 2013095316 A1 WO2013095316 A1 WO 2013095316A1
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- alpha
- biguanide
- glucosidase inhibitor
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- 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
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- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- 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
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to alpha-glucosidase inhibitor and biguanide combinations, use of said combinations in the treatment of type-2 diabetes and pharmaceutical compositions comprising them.
- alpha-glucosidase inhibitors are not directly effective on insulin secretion, they cause starch derived glucose to enter the circulation more slowly by slowing down the digestion of starchy food.
- Some examples of the agents in this group are miglitol, acarbose and voglibose.
- agents that act in digestive system, said agents can cause patients to experience side effects such as diarrhoea and bloating.
- biguanides provides to lower the amount of glucose in blood circulation by enabling the cells in body to receive more glucose.
- Agents such as metformin, phenformin, buformin can be given as examples to some of the agents in this group. Lactic acidosis, dyspepsia and diarrhoea are among the side effects frequently encountered in the patients using said drug.
- an unexpected therapeutic benefit and especially a synergistic therapeutic benefit can be obtained in the treatment of type-2 diabetes when a combination therapy comprising alpha-glucosidase inhibitor and biguanide derivative agents are used together.
- Said therapeutic benefit can be in form of;
- the pharmaceutical composition in which alpha-glucosidase inhibitor and biguanide are used together or simultaneously induces a better therapeutic benefit than compositions in which said two agents are used separately.
- using alpha-glucosidase inhibitor and biguanide combination provides the therapeutic effect to be seen in a short time and to be stronger than the effect seen when said two active agents are used separately. In this way, it is possible to provide a more effective treatment for patients.
- the present invention relates to pharmaceutical compositions comprising an alpha-glucosidase inhibitor and a biguanide together in different dosage forms for sequential use, in different dosage forms for simultaneous use or in the same dosage form for concurrent administration.
- the present invention provides a method that treats type-2 diabetes diseases by administrating an alpha-glucosidase inhibitor and a biguanide in effective amounts.
- the alpha-glucosidase inhibitor that shall be used in combinations of the present invention can be selected from a group comprising miglitol, acarbose, voglibose.
- the biguanide that shall be used in the combinations of the present invention can be selected from a group comprising metformin, phenformin, buformin.
- the preferred combinations that can be prepared according to the invention comprise a combination of miglitol and metformin or a combination of acarbose and metformin or a combination of voglibose and metformin.
- the present invention relates to pharmaceutical compositions comprising pharmaceutically effective amounts of an alpha-glucosidase inhibitor and a biguanide and at least one pharmaceutically acceptable excipient.
- the alpha-glucosidase inhibitor and biguanide can be formulated with at least one pharmaceutically acceptable excipient in different formulations as well as formulated together in a single formulation.
- the different formulations obtained can be combined in a single dosage form or can be prepared in different dosage forms. In the case that formulations are in different dosage forms, said dosage forms can be the same or different from each other.
- the present invention relates to use of an alpha-glucosidase inhibitor and a biguanide according to the invention for preparation of a drug that shall be used in combination therapy by simultaneous, sequential or separate administration in the treatment of type-2 diabetes.
- the alpha-glucosidase inhibitor comprised in the pharmaceutical compositions of the present invention can be in its pharmaceutically acceptable salt, hydrate, solvate, ester, enantiomer, diastereomer forms structurally and/or in amorphous, crystalline forms or a combination thereof in terms of polymorphic structure or in form of combinations thereof.
- the biguanide comprised in the pharmaceutical compositions of the present invention can be in its pharmaceutically acceptable salt, hydrate, solvate, ester, enantiomer, diastereomer forms and/or in form of its any polymorphic form such as amorphous, crystalline form or a combination thereof.
- metformin is used as a biguanide agent, it is preferably in salt form, more preferably in hydrochloride salt form.
- compositions of the invention comprising an alpha-glucosidase inhibitor and a biguanide can be prepared in any one of the dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewable tablet. While pharmaceutical compositions comprising an alpha-glucosidase inhibitor and a biguanide in any of these dosage forms together, they can also be in any of these dosage forms in the case that the alpha-glucosidase inhibitor and the biguanide are stored in separate dosage forms.
- compositions comprising the combination of the invention can be in any of abovementioned dosage forms or in form of a combination of these dosage forms or in a treatment package form comprising said combination.
- pharmaceutical formulations of the invention comprising the alpha-glucosidase inhibitor and the biguanide are preferably in form of tablet or effervescent tablet or prolonged release tablet.
- compositions of the present invention comprising an alpha-glucosidase inhibitor and a biguanide can comprise various excipients in addition to the alpha-glucosidase inhibitor and the biguanide as active agents.
- the pharmaceutical compositions of the present invention comprising an alpha-glucosidase inhibitor and a biguanide comprises at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, effervescent couple comprising at least one acidic and one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to the active agents.
- the disintegrant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
- the diluent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
- the lubricant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
- the glidant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
- the binder that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
- the acidic agent used in the effervescent couple comprising at least one acidic and one basic agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
- the pH regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
- the surfactant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising agents such as sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and the like.
- the stabilizing agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
- the sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
- flavouring agent that can be used in the pharmaceutical compositions of the invention can be selected from flavours comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.
- compositions of the invention can comprise an alpha-glucosidase inhibitor in the range of 0.1 to 99%, preferably in the range of 1 to 98%, more preferably in the range of 5 to 95 % by weight, for example, in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90%.
- the pharmaceutical compositions of the invention can comprise a biguanide in the range of 0.1 to 99%, preferably in the range of 1 to 98%, more preferably in the range of 5 to 95 % by weight, for example, in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90%.
- the pharmaceutical compositions of the invention can comprise an alpha-glucosidase inhibitor in the range of 0.01 mg to 500 mg, preferably in the range of 0.1 mg to 300 mg, more preferably in the range of 0.5 mg to 250 mg.
- the pharmaceutical compositions of the invention can comprise a biguanide in the range of 100 mg to 1500 mg, preferably in the range of 300 mg to 1200 mg, more preferably in the range of 500 mg to 1000 mg.
- the pharmaceutical compositions of the invention comprising an alpha-glucosidase inhibitor and a biguanide can optionally comprise a third active agent in addition to the alpha- glucosidase inhibitor and the biguanide.
- the third active agent can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, anti-diabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta block
- a third active agent in addition to said two agents which is preferably selected form a group comprising an anti-diabetic agent meglitinide,
- composition of the invention can be obtained by a method comprising the steps of;
- obtained tablets can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or a coating compositions comprising any combination thereof.
- film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or a coating compositions comprising any combination thereof.
- Saccharose can be used alone as sugar-based coating agent or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
- Water-soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymer and polyvinylpyrrolidone; and polysaccharides such as pullulan or combinations thereof.
- cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
- synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymer and polyvinylpyrrolidone
- polysaccharides such as pullulan or combinations thereof.
- Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose ftalat, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate ftalat; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac or combinations thereof.
- cellulose derivatives such as hydroxypropyl methyl cellulose ftalat, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate ftalat
- acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S
- natural substances such as shellac or combinations thereof.
- Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.
- the pharmaceutical composition according to the invention can be used in the prophylaxis and treatment of type-2 diabetes.
- d 10 value of the alpha-glucosidase inhibitor of the pharmaceutical compositions of the invention is in the range of 0.1 to 50 ⁇ , preferably in the range of 1 to 30 ⁇ while dio value of the biguanide (such as metformin hydrochloride) is in the range of 0.1 to 80 ⁇ , preferably in the range of 1 to 50 ⁇ .
- Metformin and miglitol are granulated. Obtained granules are dried and then mixed with the other excipients. Lubricant is added to the obtained mixture and the final mixture is compressed in tablet compression machine. Tablets are coated with release regulating agent and dried.
- EXAMPLE 2 Pharmaceutical compositions comprising acarbose and metformin combination
- Voglibose and other excipients are mixed and granulated.
- Metformin hydrochloride and lubricant are added to the obtained granules.
- Final composition is compressed in form of tablet and dried after coated with the coating agent.
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Abstract
The present invention relates to pharmaceutical combinations comprising an alpha glucosidase inhibitor and a biguanide that shall be used in the treatment of type-2 diabetes.
Description
SYNERGIC COMBINATION COMPRISING ANTI-DIABETIC AGENT
The present invention relates to alpha-glucosidase inhibitor and biguanide combinations, use of said combinations in the treatment of type-2 diabetes and pharmaceutical compositions comprising them. Although alpha-glucosidase inhibitors are not directly effective on insulin secretion, they cause starch derived glucose to enter the circulation more slowly by slowing down the digestion of starchy food. Some examples of the agents in this group are miglitol, acarbose and voglibose.
Since they are the kind of agents that act in digestive system, said agents can cause patients to experience side effects such as diarrhoea and bloating.
Basically, biguanides provides to lower the amount of glucose in blood circulation by enabling the cells in body to receive more glucose. Agents such as metformin, phenformin, buformin can be given as examples to some of the agents in this group. Lactic acidosis, dyspepsia and diarrhoea are among the side effects frequently encountered in the patients using said drug.
It has been surprisingly observed that an unexpected therapeutic benefit and especially a synergistic therapeutic benefit can be obtained in the treatment of type-2 diabetes when a combination therapy comprising alpha-glucosidase inhibitor and biguanide derivative agents are used together. Said therapeutic benefit can be in form of;
• reducing the dose amount necessary for obtaining the required therapeutic effect in the case that said combination is used in comparison to the dose amounts when only alpha-glucosidase inhibitors or biguanide is used and/or
• reducing undesired side effects and/or
• observing the therapeutic effect in a shorter time and/or
• observing the therapeutic effect for a longer time and/or
• providing a more effective treatment.
Inventors have observed that the most important improvement is that the side effects patients suffer when said agents are taken separately are not experienced in the combined therapy. From another aspect, the pharmaceutical composition in which alpha-glucosidase inhibitor and biguanide are used together or simultaneously induces a better therapeutic benefit than compositions in which said two agents are used separately.
From another aspect, using alpha-glucosidase inhibitor and biguanide combination provides the therapeutic effect to be seen in a short time and to be stronger than the effect seen when said two active agents are used separately. In this way, it is possible to provide a more effective treatment for patients. Surprisingly, all these positive effects observed in combinations in which both active agents are given in a sequential manner are also observed when both active agents are given in the same dosage form at the same time or simultaneously in independent dosage forms. High therapeutic benefit can also be observed as a longer-term therapeutic effect.
According to this, the present invention relates to pharmaceutical compositions comprising an alpha-glucosidase inhibitor and a biguanide together in different dosage forms for sequential use, in different dosage forms for simultaneous use or in the same dosage form for concurrent administration.
In another aspect, the present invention provides a method that treats type-2 diabetes diseases by administrating an alpha-glucosidase inhibitor and a biguanide in effective amounts. The alpha-glucosidase inhibitor that shall be used in combinations of the present invention can be selected from a group comprising miglitol, acarbose, voglibose.
The biguanide that shall be used in the combinations of the present invention can be selected from a group comprising metformin, phenformin, buformin.
The preferred combinations that can be prepared according to the invention comprise a combination of miglitol and metformin or a combination of acarbose and metformin or a combination of voglibose and metformin.
In another aspect, the present invention relates to pharmaceutical compositions comprising pharmaceutically effective amounts of an alpha-glucosidase inhibitor and a biguanide and at least one pharmaceutically acceptable excipient. In said pharmaceutical formulations, the alpha-glucosidase inhibitor and biguanide can be formulated with at least one pharmaceutically acceptable excipient in different formulations as well as formulated together in a single formulation. The different formulations obtained can be combined in a single dosage form or can be prepared in different dosage forms. In the case that formulations are in different dosage forms, said dosage forms can be the same or different from each other.
At the same time, the present invention relates to use of an alpha-glucosidase inhibitor and a biguanide according to the invention for preparation of a drug that shall be used in combination therapy by simultaneous, sequential or separate administration in the treatment of type-2 diabetes. The alpha-glucosidase inhibitor comprised in the pharmaceutical compositions of the present invention can be in its pharmaceutically acceptable salt, hydrate, solvate, ester, enantiomer, diastereomer forms structurally and/or in amorphous, crystalline forms or a combination thereof in terms of polymorphic structure or in form of combinations thereof.
The biguanide comprised in the pharmaceutical compositions of the present invention can be in its pharmaceutically acceptable salt, hydrate, solvate, ester, enantiomer, diastereomer forms and/or in form of its any polymorphic form such as amorphous, crystalline form or a combination thereof. For example, in the case that metformin is used as a biguanide agent, it is preferably in salt form, more preferably in hydrochloride salt form.
Pharmaceutical compositions of the invention comprising an alpha-glucosidase inhibitor and a biguanide can be prepared in any one of the dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewable tablet. While pharmaceutical compositions comprising an alpha-glucosidase inhibitor and a biguanide in any of these dosage forms together, they can also be in any of these dosage forms in the case that the alpha-glucosidase inhibitor and the biguanide are stored in separate dosage forms. In other words, compositions comprising the combination of the invention can be in any of abovementioned dosage forms or in form of a combination of these dosage forms or in a treatment package form comprising said combination. In the case that the alpha-glucosidase inhibitor and the biguanide are in the same dosage form, pharmaceutical formulations of the invention comprising the alpha-glucosidase inhibitor and the biguanide are preferably in form of tablet or effervescent tablet or prolonged release tablet.
The pharmaceutical compositions of the present invention comprising an alpha-glucosidase inhibitor and a biguanide can comprise various excipients in addition to the alpha-glucosidase inhibitor and the biguanide as active agents.
The pharmaceutical compositions of the present invention comprising an alpha-glucosidase inhibitor and a biguanide comprises at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, effervescent couple comprising at least one acidic and one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to the active agents.
The disintegrant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
The diluent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
The lubricant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
The glidant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
The binder that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
The acidic agent used in the effervescent couple comprising at least one acidic and one basic agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
The pH regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
The surfactant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising agents such as sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and the like.
The stabilizing agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin. The sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
The flavouring agent that can be used in the pharmaceutical compositions of the invention can be selected from flavours comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.
The pharmaceutical compositions of the invention can comprise an alpha-glucosidase inhibitor in the range of 0.1 to 99%, preferably in the range of 1 to 98%, more preferably in the range of 5 to 95 % by weight, for example, in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90%.
The pharmaceutical compositions of the invention can comprise a biguanide in the range of 0.1 to 99%, preferably in the range of 1 to 98%, more preferably in the range of 5 to 95 % by weight, for example, in the range of 5, 10, 15, 20, 25, 30% to 35, 40, 45, 50, 55, 60, 65, 70, 80, 90%. The pharmaceutical compositions of the invention can comprise an alpha-glucosidase inhibitor in the range of 0.01 mg to 500 mg, preferably in the range of 0.1 mg to 300 mg, more preferably in the range of 0.5 mg to 250 mg.
The pharmaceutical compositions of the invention can comprise a biguanide in the range of 100 mg to 1500 mg, preferably in the range of 300 mg to 1200 mg, more preferably in the range of 500 mg to 1000 mg.
The pharmaceutical compositions of the invention comprising an alpha-glucosidase inhibitor and a biguanide can optionally comprise a third active agent in addition to the alpha- glucosidase inhibitor and the biguanide. The third active agent can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, anti-diabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha- glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin Bj, vitamin C, vitamin E, vitamin B , vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. The pharmaceutical compositions of the invention comprising an alpha-glucosidase inhibitor and a biguanide comprise a third active agent in addition to said two agents which is preferably selected form a group comprising an anti-diabetic agent meglitinide, tiazolidinedion, sulphonylurea, peptide analogue, organosulfur compound; more preferably an agent selected from a group comprising nateglinide, repaglinide, rosiglitazone, pioglitazone, troglitazone, tolbutamide, acetohexamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, vildagliptin, sitagliptin, saxagliptin, linagliptin.
The pharmaceutical composition of the invention can be obtained by a method comprising the steps of;
• Mixing the active agents alpha-glucosidase inhibitor and biguanide homogeneously and adding at least one of the abovementioned excipients if necessary or
• Granulating a mixture comprising the active agents alpha-glucosidase inhibitor, biguanide and at least one of the abovementioned excipients with a granulation solution, then mixing them homogeneously with the other excipients or
• Mixing the active agents alpha-glucosidase inhibitor and biguanide with at least one of the abovementioned excipients, then granulating them with a granulation solution comprising at least one excipient or
• Using any of the abovementioned methods separately for each active agent composition and combining said formulations together or storing them in different dosage forms in the case that the alpha-glucosidase inhibitor and the biguanide are prepared in two separate formulations. The obtained pharmaceutical composition or compositions can be prepared in any of the abovementioned dosage forms. In the case that it is in tablet form, obtained tablets can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed release coating agents or a coating compositions comprising any combination thereof. Saccharose can be used alone as sugar-based coating agent or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof.
Water-soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymer and polyvinylpyrrolidone; and polysaccharides such as pullulan or combinations thereof.
Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose ftalat, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate ftalat; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac or combinations thereof.
Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.
The pharmaceutical composition according to the invention can be used in the prophylaxis and treatment of type-2 diabetes. d10 value of the alpha-glucosidase inhibitor of the pharmaceutical compositions of the invention (such as voglibose, miglitol, acarbose, etc.) is in the range of 0.1 to 50 μπι,
preferably in the range of 1 to 30 μπι while dio value of the biguanide (such as metformin hydrochloride) is in the range of 0.1 to 80 μηι, preferably in the range of 1 to 50 μηι.
The examples below are given to elucidate the combinations of the invention. Yet the invention cannot be limited to these examples.
EXAMPLE 1 : Pharmaceutical compositions comprising miglitol and metformin combination
Metformin and miglitol are granulated. Obtained granules are dried and then mixed with the other excipients. Lubricant is added to the obtained mixture and the final mixture is compressed in tablet compression machine. Tablets are coated with release regulating agent and dried.
EXAMPLE 2: Pharmaceutical compositions comprising acarbose and metformin combination
Acarbose and some of the other excipients are mixed and wet-granulated with the granulation solution. Granules are dried and mixed with the rest of the excipients and metformin. The homogeneous composition obtained is mixed with the lubricant and compressed in tablet compression machine in tablet form.
EXAMPLE 3: Film tablet formulation comprising voglibose and metformin combination
Voglibose and other excipients are mixed and granulated. Metformin hydrochloride and lubricant are added to the obtained granules. Final composition is compressed in form of tablet and dried after coated with the coating agent.
Claims
A pharmaceutical composition comprising an alpha-glucosidase inhibitor and biguanide combination as active agent.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claim 1, characterized in that said composition comprises an alpha-glucosidase inhibitor in the range of 0.01 mg to 500 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-2, characterized in that said composition comprises an alpha-glucosidase inhibitor in the range of 0.1 mg to 300 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-3, characterized in that said composition comprises an alpha-glucosidase inhibitor in the range of 0.5 mg to 250 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-4, characterized in that said composition comprises a biguanide in the range of 100 mg to 1500 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-5, characterized in that said composition comprises a biguanide in the range of 300 mg to 1200 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-6, characterized in that said composition comprises a biguanide in the range of 500 mg to 1000 mg.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-7, characterized in that the alpha-glucosidase inhibitor is in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers structurally and/or in any of its amorphous, crystalline forms or a combination thereof in terms of polymorphic structure or combinations thereof.
The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-8, characterized in that biguanide is in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers structurally and/or in any of amorphous, crystalline forms or a combination thereof in terms of polymorphic structure or combinations thereof.
10. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-9, characterized in that the alpha-glucosidase inhibitor and biguanide are in the same pharmaceutical formulation.
11. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-9, characterized in that the alpha-glucosidase inhibitor and biguanide are in different pharmaceutical formulations.
12. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-9 and 11, characterized in that different formulations comprising the alpha-glucosidase inhibitor and biguanide are combined in the same dosage form.
13. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-9 and 11, characterized in that different formulations comprising the alpha-glucosidase inhibitor and biguanide are in different dosage forms.
14. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-13, characterized in that said composition is in form of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewable tablet or a combination thereof.
15. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 10-14, characterized in that said composition is in form of film tablet, effervescent tablet or prolonged release tablet.
16. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that said composition comprises at least one pharmaceutically acceptable excipient in addition to the alpha- glucosidase inhibitor and biguanide.
17. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claim 17, characterized in that said composition comprises at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to the alpha-glucosidase inhibitor and biguanide.
18. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that said composition comprises an alpha-glucosidase inhibitor in the range of 0.1 to 99% by weight.
19. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that said composition comprises a biguanide in the range of 0.1 to 99% by weight.
20. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that said composition comprises a third active agent in addition to the alpha-glucosidase inhibitor and biguanide selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, anti-diabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B1? vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
21. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that the third active agent comprised in said composition in addition to the alpha-glucosidase inhibitor and biguanide is an anti-diabetic agent.
22. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 20 and 21, characterized in that the third active agent that shall be used in said composition in addition to the alpha-glucosidase inhibitor and biguanide is selected from the compounds meglitinide, tiazolidinedion, sulfonylurea, peptide analogue, organosulfur.
23. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 20-22, characterized in that the third active agent that shall be used in said composition in addition to the alpha-glucosidase inhibitor and biguanide is selected from a group comprising nateglinide, repaglinide, rosiglitazone, pioglitazone,
troglitazone, tolbutamide, acetohexamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide, vildagliptin, sitagliptin, saxagliptin, linagliptin.
24. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that the alpha-glucosidase inhibitor is selected from a group comprising miglitol, acarbose, voglibose.
25. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that the biguanide is selected from a group comprising metformin, phenformin, buformin.
26. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claim 25, characterized in that biguanide is in metformin hydrochloride salt form in the case that metformin is used as the biguanide.
27. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that the alpha-glucosidase inhibitor is miglitol and the biguanide is metformin.
28. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-26, characterized in that the alpha-glucosidase inhibitor is acarbose and the biguanide is metformin.
29. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to claims 1-26, characterized in that the alpha-glucosidase inhibitor is voglibose and the biguanide is metformin.
30. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and a biguanide according to any preceding claims, characterized in that said composition is used for production of a drug that shall be used in the treatment of type-2 diabetes.
31. A pharmaceutical composition comprising an alpha-glucosidase inhibitor and biguanide combination as active agent, wherein said composition is used sequentially, at the same time or simultaneously.
32. A pharmaceutical composition comprising an a combination of an alpha-glucosidase inhibitor in the range of 0.1 mg to 300 mg and a biguanide in the range of 500 mg to 1000 mg as active agent.
33. A pharmaceutical composition comprising miglitol and metformin hydrochloride combination as active agent, wherein said composition is used sequentially, at the same time or simultaneously.
34. A pharmaceutical composition comprising acarbose and metformin hydrochloride combination as active agent, wherein said composition is used sequentially, at the same time or simultaneously.
35. A pharmaceutical composition comprising voglibose and metformin hydrochloride combination as active agent, wherein said composition is used sequentially, at the same time or simultaneously.
36. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and biguanide combination according to any preceding claims, characterized in that dio value of the alpha-glucosidase inhibitor is in the range of 0.1 to 50 μιη and dio value of the biguanide is in the range of 0.1 to 80 μηι.
37. The pharmaceutical composition comprising an alpha-glucosidase inhibitor and biguanide combination according to any preceding claims, characterized in that di0 value of the alpha-glucosidase inhibitor is in the range of 1 to 30 μη and dio value of the biguanide is in the range of 1 to 50 μπι.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2011/12588 | 2011-12-19 | ||
| TR201112588 | 2011-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013095316A1 true WO2013095316A1 (en) | 2013-06-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000220 WO2013095316A1 (en) | 2011-12-19 | 2012-12-19 | Synergic combination comprising anti-diabetic agent |
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| Country | Link |
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| WO (1) | WO2013095316A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2018528254A (en) * | 2015-09-22 | 2018-09-27 | バイキング セラピューティクス，インコーポレーテッド | Combination therapy with glucose production inhibitors |
| WO2018185669A1 (en) * | 2017-04-07 | 2018-10-11 | Zenvision Pharma Llp | Effervescent compositions comprising saxagliptin or salt thereof |
| WO2019078663A3 (en) * | 2017-10-20 | 2019-06-06 | 주식회사 노브메타파마 | Pharmaceutical composition for preventing or treating diabetes, containing zinc salt, cyclo-hispro and antidiabetic drug as active ingredients |
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| WO2010138535A1 (en) * | 2009-05-27 | 2010-12-02 | Bristol-Myers Squibb Company | Methods for treating type 2 diabetes in patients resistant to previous treatment with other anti-diabetic drugs employing an sglt2 inhibitor and compositions thereof |
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| EP1964562A1 (en) * | 2005-12-20 | 2008-09-03 | Espinosa Abdala, Leopoldo de Jesús | Pharmaceutical compositions containing derivative substances of thiazolidinediones combined with a biguanide for use in type 2 diabetes mellitus |
| WO2010138535A1 (en) * | 2009-05-27 | 2010-12-02 | Bristol-Myers Squibb Company | Methods for treating type 2 diabetes in patients resistant to previous treatment with other anti-diabetic drugs employing an sglt2 inhibitor and compositions thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018528254A (en) * | 2015-09-22 | 2018-09-27 | バイキング セラピューティクス，インコーポレーテッド | Combination therapy with glucose production inhibitors |
| EP3352762A4 (en) * | 2015-09-22 | 2019-06-05 | Viking Therapeutics, Inc. | Conjoint therapies with inhibitors of glucose production |
| WO2018185669A1 (en) * | 2017-04-07 | 2018-10-11 | Zenvision Pharma Llp | Effervescent compositions comprising saxagliptin or salt thereof |
| WO2019078663A3 (en) * | 2017-10-20 | 2019-06-06 | 주식회사 노브메타파마 | Pharmaceutical composition for preventing or treating diabetes, containing zinc salt, cyclo-hispro and antidiabetic drug as active ingredients |
| US11607441B2 (en) | 2017-10-20 | 2023-03-21 | Novmetapharma Co., Ltd. | Pharmaceutical composition for preventing or treating diabetes, containing zinc salt, cyclo-hispro and antidiabetic drug as active ingredients |
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