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WO2013115741A1 - Pharmaceutical compositions comprising alpha-glucosidase inhibitor - Google Patents

Pharmaceutical compositions comprising alpha-glucosidase inhibitor Download PDF

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Publication number
WO2013115741A1
WO2013115741A1 PCT/TR2013/000050 TR2013000050W WO2013115741A1 WO 2013115741 A1 WO2013115741 A1 WO 2013115741A1 TR 2013000050 W TR2013000050 W TR 2013000050W WO 2013115741 A1 WO2013115741 A1 WO 2013115741A1
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WO
WIPO (PCT)
Prior art keywords
voglibose
acarbose
miglitol
pharmaceutical composition
range
Prior art date
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Ceased
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PCT/TR2013/000050
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French (fr)
Inventor
Mahmut Bilgic
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Individual
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Individual
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Publication of WO2013115741A1 publication Critical patent/WO2013115741A1/en
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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)
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to pharmaceutical compositions comprising alpha-glucosidase derivative active agents or pharmaceutically acceptable derivatives thereof or combinations of these active agents with different substances that shall be used in the treatment of non-insulin dependent type II diabetes.
  • Alpha-glucosidase inhibitors prevent the digestion of carbohydrates and therefore production of monosachharides that are absorbed through the intestine. By this way, they affect blood sugar level positively.
  • the active agents known as alpha-glucosidase inhibitors are principally voglibose, acarbose and miglitol. Bioavailability characteristics of the products taken by the oral route are closely related to their dissolutions. When the compositions having low dissolution are taken by the patients, the active agent cannot reach sufficient therapeutic amounts in body as a result of insufficient dissolution of the active agent taken in the body and this affects the treatment negatively.
  • compositions when the pharmaceutical compositions are formed into various dosage forms they should have content uniformity therefore comprise equal amounts of active agent in unit dosage form. This depends on flow characteristics of the formulations prepared. Each unit dose of the formulations having free flow property comprises equal amount of active agent. By this respect, content uniformity is provided and patients can take equal and precise amount of the drug per drug intake.
  • the inventors have surprisingly achieved to develop formulations comprising voglibose, acarbose or miglitol having both free flow and good dissolution properties.
  • the formulations comprising voglibose, acarbose or miglitol as the active agent wherein - the ratio of bulk density to compressed density is minimum 0.75, preferably in the range of 0.8 to 0.99 and more preferably in the range of 0.82 to 0.95 and
  • voglibose, acarbose or miglitol is in the range of 10 to 600 ⁇ have both free flow and good dissolution properties.
  • dgs signifies that 95% of the said substance by volume has a particle size below the value stated with and 5% of the said substance by volume has a particle size over the value stated with d95.
  • d 95 value of voglibose, acarbose or miglitol is preferably in the range of 15 to 550 ⁇ , more preferably in the range of 20 to 500 ⁇ , for instance in the range of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105 to 120, 130, 140, 150, 160, 200, 250, 300, 350, 400, 450 ⁇ .
  • the present invention relates to formulations comprising voglibose, acarbose or miglitol as the active agent wherein the bulk density is in the range of 0.10 g/ml to 10 g/ml, preferably in the range of 0.15g/ml to 9 g/ml, more preferably in the range of 0.2 g/ml to 8.5 g/ml and the compressed density is in the range of 0.12 g/ml to 14 g/ml, preferably in the range of 0.15 g/ml to 13.5 g/ml, more preferably in the range of 0.2 g/ml to 13.0 g/ml.
  • Voglibose, acarbose or miglitol comprised in the pharmaceutical compositions of the present invention is in the form its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure.
  • Voglibose, acarbose or miglitol comprised in the pharmaceutical compositions of the present invention is in amorphous or crystalline form or a combination thereof in terms of polymorphic structure.
  • the term d 95 can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
  • Voglibose, acarbose or miglitol of the present invention having a d 50 value in the range of 10 ⁇ to 600 ⁇ can be bought and used as a product which is commercially provided in this form.
  • voglibose, acarbose or miglitol having a d 50 value in the range of 10 ⁇ to 600 ⁇ can also be obtained by pulverizing a product having a coarser particle size singly or with an excipient (for instance microcrystalline cellulose etc.).
  • pulverization can be performed by using the methods of impact mill, jet mill, blade mill etc. Pulverization can be performed before preparation of the pharmaceutical composition comprising voglibose, acarbose or miglitol as the active agent as well as during preparation of the pharmaceutical composition of the present invention or before post- production storage of the pharmaceutical composition prepared.
  • pulverization is performed by the impact of the rotating blades in the device.
  • compositions of the present invention comprising voglibose, acarbose or miglitol can be prepared in 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.
  • the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol are preferably in the form of effervescent tablet, tablet, film coated tablet modified release tablet or sachet.
  • the pharmaceutical composition obtained can be formed into any abovementioned dosage form.
  • the composition is in tablet form
  • the tablets obtained can be treated with film coating agents for instance sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising a combination thereof.
  • Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
  • the 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 aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
  • the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; 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.
  • the 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.
  • compositions of the present invention comprising voglibose, acarbose or miglitol can comprise various excipients in addition to the active agent voglibose, acarbose or migltiol.
  • excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent voglibose, acarbose or
  • the disintegrant that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising calcium carbonate, 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
  • the stabilizing agent that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • compositions of the present invention comprising voglibose, acarbose or miglitol can optionally comprise a second active agent in addition to voglibose, acarbose or miglitol.
  • the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacneantibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid
  • the second active agent that can optionally be used in the pharmaceutical compositions comprising voglibose, acarbose or miglitol can be selected from a group comprising repaglinide belonging to the groups of meglitinides; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin, metformin, metformin hydrochloride belonging to the group of biguanides; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxa
  • the pharmaceutical compositions comprising voglibose, acarbose or miglitol comprise metformin hydrochloride as the second active agent.
  • the present invention relates to pharmaceutical compositions
  • dg 5 value of voglibose, acarbose or miglitol and metformin hydrochloride is in the range of 10 to 600 ⁇ .
  • the pharmaceutical composition of the present invention can be obtained by ⁇ mixing the active agent voglibose, acarbose or miglitol and the second active agent if available homogeneously and adding at least one of the abovementioned excipients if required or
  • the formulations of the present invention are preferably produced by production methods comprising granulation process.
  • the inventors have seen that the formulations comprising the granules produced by granulation process and having d 5 o value less than 800 ⁇ , preferably in the range of 10 ⁇ to 800 ⁇ , more preferably in the range of 50 ⁇ to 750 ⁇ , for instance in the range of 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 to 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 450, 500, 530, 550, 600 have free flow, dose uniformity and required dissolution properties.
  • the present invention relates to pharmaceutical compositions comprising voglibose, acarbose or miglitol and optionally a second active agent, for instance metformin hydrochloride wherein d 50 value of the granules are less than 800 ⁇ , preferably in the range of 10 ⁇ to 800 ⁇ , more preferably in the range of 50 ⁇ to 750 ⁇ .
  • Said granules comprise at least one active agent and/or at least one excipient.
  • said granules may comprise only one or more active agents or only one or more excipients or a combination of one or more active agents and one or more excipients.
  • Said active agent and excipients can be comprised in the mixture granulated as well as in the granulation solution.
  • the pharmaceutical composition of the present invention can be used in prevention and treatment of non-insulin dependent type II diabetes.
  • Example 1 Effervescent tablet formulation comprising Voglibose and Metformin HCI
  • Voglibose, effervescent acid and effervescent base are granulated.
  • the granules obtained are dried and mixed with metformin HCI and other excipients.
  • the final mixture is compressed in tablet compression machine.
  • Example 2 Effervescent tablet formulation comprising acarbose
  • Acarbose, effervescent acid and effervescent base are granulated.
  • the granules obtained are dried and mixed with other excipients.
  • the final mixture is compressed in tablet compression machine.
  • Example 3 Modified release tablet formulation comprising voglibose
  • Voglibose and other excipients are mixed.
  • the final mixture obtained is compressed in tablet compression machine.
  • the tablets obtained are coated with the coating agent and dried.
  • Example 4 Film tablet formulation comprising miglitol
  • Voglibose and other excipients are mixed.
  • the final mixture obtained is compressed in tablet compression machine.
  • the tablets obtained are coated with the coating agent and dried.

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Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ALPHA-GLUCOSIDASE INHIBITOR
The present invention relates to pharmaceutical compositions comprising alpha-glucosidase derivative active agents or pharmaceutically acceptable derivatives thereof or combinations of these active agents with different substances that shall be used in the treatment of non-insulin dependent type II diabetes. Alpha-glucosidase inhibitors prevent the digestion of carbohydrates and therefore production of monosachharides that are absorbed through the intestine. By this way, they affect blood sugar level positively.
The active agents known as alpha-glucosidase inhibitors are principally voglibose, acarbose and miglitol. Bioavailability characteristics of the products taken by the oral route are closely related to their dissolutions. When the compositions having low dissolution are taken by the patients, the active agent cannot reach sufficient therapeutic amounts in body as a result of insufficient dissolution of the active agent taken in the body and this affects the treatment negatively.
Furthermore, when the pharmaceutical compositions are formed into various dosage forms they should have content uniformity therefore comprise equal amounts of active agent in unit dosage form. This depends on flow characteristics of the formulations prepared. Each unit dose of the formulations having free flow property comprises equal amount of active agent. By this respect, content uniformity is provided and patients can take equal and precise amount of the drug per drug intake.
The processes implemented in order to improve dissolution usually pose problems in flow of the formulation and they damage free flow property of the formulation obtained.
The inventors have surprisingly achieved to develop formulations comprising voglibose, acarbose or miglitol having both free flow and good dissolution properties. As a result of the studies they conducted, the inventors have found that the formulations comprising voglibose, acarbose or miglitol as the active agent wherein - the ratio of bulk density to compressed density is minimum 0.75, preferably in the range of 0.8 to 0.99 and more preferably in the range of 0.82 to 0.95 and
- d95 value of voglibose, acarbose or miglitol is in the range of 10 to 600 μπι have both free flow and good dissolution properties.
The term dgs signifies that 95% of the said substance by volume has a particle size below the value stated with and 5% of the said substance by volume has a particle size over the value stated with d95. In a preferred embodiment of the present invention, d95 value of voglibose, acarbose or miglitol is preferably in the range of 15 to 550 μπι, more preferably in the range of 20 to 500 μπι, for instance in the range of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105 to 120, 130, 140, 150, 160, 200, 250, 300, 350, 400, 450 μιη. In another aspect, the present invention relates to formulations comprising voglibose, acarbose or miglitol as the active agent wherein the bulk density is in the range of 0.10 g/ml to 10 g/ml, preferably in the range of 0.15g/ml to 9 g/ml, more preferably in the range of 0.2 g/ml to 8.5 g/ml and the compressed density is in the range of 0.12 g/ml to 14 g/ml, preferably in the range of 0.15 g/ml to 13.5 g/ml, more preferably in the range of 0.2 g/ml to 13.0 g/ml. Voglibose, acarbose or miglitol comprised in the pharmaceutical compositions of the present invention is in the form its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure.
Voglibose, acarbose or miglitol comprised in the pharmaceutical compositions of the present invention is in amorphous or crystalline form or a combination thereof in terms of polymorphic structure. The term d95 can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
Voglibose, acarbose or miglitol of the present invention having a d50 value in the range of 10 μπι to 600 μπι can be bought and used as a product which is commercially provided in this form. In addition, voglibose, acarbose or miglitol having a d50 value in the range of 10 μπι to 600 μιη can also be obtained by pulverizing a product having a coarser particle size singly or with an excipient (for instance microcrystalline cellulose etc.). At this point, pulverization can be performed by using the methods of impact mill, jet mill, blade mill etc. Pulverization can be performed before preparation of the pharmaceutical composition comprising voglibose, acarbose or miglitol as the active agent as well as during preparation of the pharmaceutical composition of the present invention or before post- production storage of the pharmaceutical composition prepared.
In the case that blade mill is used, pulverization is performed by the impact of the rotating blades in the device.
In the case that impact mill is used, pulverization is performed by the impact of the rotating hammers in the device. In the case that jet mill is used, pulverization is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream. The pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol can be prepared in 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. The pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol are preferably in the form of effervescent tablet, tablet, film coated tablet modified release tablet or sachet.
The pharmaceutical composition obtained can be formed into any abovementioned dosage form. In the case that the composition is in tablet form, the tablets obtained can be treated with film coating agents for instance sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising a combination thereof.
Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent. The 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 aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof. The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; 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. The 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 compositions of the present invention comprising voglibose, acarbose or miglitol can comprise various excipients in addition to the active agent voglibose, acarbose or migltiol. The pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent voglibose, acarbose or miglitol.
The disintegrant that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising calcium carbonate, 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts. The surfactant that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
The stabilizing agent that can be used in the pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol 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 present invention comprising voglibose, acarbose or miglitol can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol can comprise voglibose, acarbose or miglitol in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, more preferably in the range of 5 to 95% by weight.
The pharmaceutical compositions of the present invention comprising voglibose, acarbose or miglitol can optionally comprise a second active agent in addition to voglibose, acarbose or miglitol. The second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacneantibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic 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 Bi_ vitamin C, vitamin E, vitamin Be, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. In another aspect, the second active agent that can optionally be used in the pharmaceutical compositions comprising voglibose, acarbose or miglitol can be selected from a group comprising repaglinide belonging to the groups of meglitinides; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin, metformin, metformin hydrochloride belonging to the group of biguanides; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate.
In a preferred embodiment of the present invention, the pharmaceutical compositions comprising voglibose, acarbose or miglitol comprise metformin hydrochloride as the second active agent.
According to this, in one aspect the present invention relates to pharmaceutical compositions
• comprising the combination of voglibose, acarbose or miglitol and metformin hydrochloride, · wherein the ratio of bulk density to compressed density is minimum 0.75, preferably in the range of 0.8 to 0.99 and more preferably in the range of 0.82 to 0.95 and
• wherein dg5 value of voglibose, acarbose or miglitol and metformin hydrochloride is in the range of 10 to 600 μηι.
The pharmaceutical composition of the present invention can be obtained by · mixing the active agent voglibose, acarbose or miglitol and the second active agent if available homogeneously and adding at least one of the abovementioned excipients if required or
• granulating the active agent voglibose, acarbose or miglitol and the second active agent if available with at least one of the abovementioned excipients and then mixing them homogeneously or
• mixing the active agent voglibose, acarbose or miglitol and the second active agent if available with at least one of the excipients and optionally granulating the mixture with the granulation solution comprising excipient or
• using any of the abovementioned methods separately for active agent compositions and combining the formulations obtained in the case that two active agents are used.
The formulations of the present invention are preferably produced by production methods comprising granulation process. The inventors have seen that the formulations comprising the granules produced by granulation process and having d5o value less than 800 μπι, preferably in the range of 10 μηι to 800 μπι, more preferably in the range of 50 μιη to 750 μηι, for instance in the range of 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 to 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 450, 500, 530, 550, 600 have free flow, dose uniformity and required dissolution properties. In one aspect, the present invention relates to pharmaceutical compositions comprising voglibose, acarbose or miglitol and optionally a second active agent, for instance metformin hydrochloride wherein d50 value of the granules are less than 800 μπι, preferably in the range of 10 μπι to 800 μηι, more preferably in the range of 50 μπι to 750 μιη. Said granules comprise at least one active agent and/or at least one excipient. According to this, said granules may comprise only one or more active agents or only one or more excipients or a combination of one or more active agents and one or more excipients. Said active agent and excipients can be comprised in the mixture granulated as well as in the granulation solution.
The pharmaceutical composition of the present invention can be used in prevention and treatment of non-insulin dependent type II diabetes.
The examples given below are given in order to explain the present invention. Yet, the present invention should not be limited to these examples.
Example 1 : Effervescent tablet formulation comprising Voglibose and Metformin HCI
Figure imgf000008_0001
Voglibose, effervescent acid and effervescent base are granulated. The granules obtained are dried and mixed with metformin HCI and other excipients. The final mixture is compressed in tablet compression machine.
* the ratio of bulk density: compressed density of the formulation: 0.76
** d95 value of voglibose: 50 μιη
*** d95 value of metformin HCI: 75 μπι Example 2: Effervescent tablet formulation comprising acarbose
Figure imgf000009_0001
Acarbose, effervescent acid and effervescent base are granulated. The granules obtained are dried and mixed with other excipients. The final mixture is compressed in tablet compression machine.
* the ratio of bulk density: compressed density of the formulation: 0.78
** dg5 value of acarbose: 320μιη
Example 3 : Modified release tablet formulation comprising voglibose
Figure imgf000009_0002
Voglibose and other excipients are mixed. The final mixture obtained is compressed in tablet compression machine. The tablets obtained are coated with the coating agent and dried.
* the ratio of bulk density: compressed density of the formulation: 0.91
**dg value of voglibose: 300 μηι Example 4: Film tablet formulation comprising miglitol
Figure imgf000010_0001
Voglibose and other excipients are mixed. The final mixture obtained is compressed in tablet compression machine. The tablets obtained are coated with the coating agent and dried.
* the ratio of bulk density: compressed density of the formulation: 0.82 value of miglitol: 425 μπι

Claims

1. The pharmaceutical composition comprising voglibose, acarbose or miglitol, characterized in that
- the ratio of bulk density to compressed density of the formulation is minimum 0.75,
- d95 value of voglibose, acarbose or miglitol is in the range of 10 to 600 μιη.
2. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to claim 1, characterized in that d95 value of voglibose, acarbose or miglitol is in the range of 15 to 550 μηι.
3. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to claims 1 and 2, characterized in that d9s value of voglibose, acarbose or miglitol is in the range of 20 to 500 μηι.
4. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the ratio of bulk density to compressed density is in the range of 0.80 to 0.99.
5. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the ratio of bulk density to compressed density is in the range of 0.82 to 0.95.
6. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the bulk density of the formulation is in the range of 0.1 g/ml to 10 g/ml.
7. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the bulk density of the formulation is in the range of 0.15 g/ml to 9 g/ml.
8. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the bulk density of the formulation is in the range of 0.20 g/ml to 8.5 g/ml.
9. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the compressed density of the formulation is in the range of 0.12 g/ml to 14 g/ml.
10. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the compressed density of the formulation is in the range of 0.15 g/ml to 13.5 g/ml.
1 1. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, characterized in that the compressed density of the formulation is in the range of 0.2 g/ml to 13.0 g/ml.
12. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition can be prepared in any tablet dosage forms 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.
13. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to claim 12, wherein said formulation is in the form of tablet, film tablet, modified release tablet, effervescent tablet, effervescent powder or effervescent granule.
14. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein voglibose, acarbose or miglitol can be in the form of its pharmaceutically acceptable salts, hydrate, solvates, esters, enantiomers, diastereomers or combinations thereof.
15. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition comprises pharmaceutically acceptable excipients in addition to voglibose, acarbose or miglitol used as the active agent.
16. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to claim 16, wherein said composition comprises at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to voglibose, acarbose or miglitol used as the active agent.
17. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition comprises voglibose, acarbose or miglitol in the range of 0.1 to 100% by weight.
18. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition comprises voglibose, acarbose or miglitol in the range of I to 99% by weight.
19. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition comprise voglibose, acarbose or miglitol in the range of 5 to 95% by weight.
20. The pharmaceutical composition comprising voglibose, acarbose or miglitol according to any preceding claims, wherein said composition comprises at least a second active agent selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacneantibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic 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 Btj vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium in addition to voglibose, acarbose or miglitol.
21. The pharmaceutical formulation comprising voglibose, acarbose or miglitol according to any preceding claims, wherein the second active agent that can be comprised in the formulation in addition to voglibose, acarbose or miglitol is selected from biguanides.
22. The pharmaceutical formulation comprising voglibose, acarbose or miglitol according to any preceding claims, wherein the second active agent that can be comprised in the formulation in addition to voglibose, acarbose or miglitol is metformin hydrochloride.
23. The pharmaceutical formulation comprising the combination of voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that
• the ratio of bulk density to compressed density is minimum 0.75 and
• d95 value of voglibose, acarbose or miglitol and metformin hydrochloride is in the range of 10 to 600 μηι.
24. The pharmaceutical formulation comprising voglibose, acarbose or miglitol and optionally metformin hydrochloride, characterized in that
• said pharmaceutical composition comprises granules composed of at least one active agent and/or at least one excipient and
• d5o value of the granules is maximum 800 μπι.
25. The pharmaceutical formulation comprising voglibose, acarbose or miglitol and optionally metformin hydrochloride according to claim 24, characterized in that
• said pharmaceutical composition comprises granules which are composed of at least one active agent and/or at least one excipient and
• d50 value of the granules is in the range of 10 to 800 μπι.
6. The pharmaceutical formulation comprising voglibose, acarbose or miglitol and optionally metformin hydrochloride according to 25, characterized in that
• said pharmaceutical composition comprises granules which are composed of at least one active agent and/or at least one excipient and
• d5o value of the granules is in the range of 50 to 750 μπι.
PCT/TR2013/000050 2012-01-31 2013-01-31 Pharmaceutical compositions comprising alpha-glucosidase inhibitor Ceased WO2013115741A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015124195A (en) * 2013-12-27 2015-07-06 株式会社三和化学研究所 Coating preparation containing miglitol

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Publication number Priority date Publication date Assignee Title
JP2001002567A (en) * 1999-04-20 2001-01-09 Takeda Chem Ind Ltd Sustained release preparation containing water-soluble medicine
WO2009071219A2 (en) * 2007-12-08 2009-06-11 Bayer Schering Pharma Aktiengesellschaft Oral dispersable tablet
WO2009135951A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a tablet comprising metformin
WO2011134962A2 (en) * 2010-04-27 2011-11-03 Bayer Pharma Aktiengesellschaft Orally disintegrating tablet containing acarbose
WO2012093972A1 (en) * 2011-01-06 2012-07-12 Mahmut Bilgic Water soluble dosage forms

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001002567A (en) * 1999-04-20 2001-01-09 Takeda Chem Ind Ltd Sustained release preparation containing water-soluble medicine
WO2009071219A2 (en) * 2007-12-08 2009-06-11 Bayer Schering Pharma Aktiengesellschaft Oral dispersable tablet
WO2009135951A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a tablet comprising metformin
WO2011134962A2 (en) * 2010-04-27 2011-11-03 Bayer Pharma Aktiengesellschaft Orally disintegrating tablet containing acarbose
WO2012093972A1 (en) * 2011-01-06 2012-07-12 Mahmut Bilgic Water soluble dosage forms

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015124195A (en) * 2013-12-27 2015-07-06 株式会社三和化学研究所 Coating preparation containing miglitol

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