WO2013115745A1 - A process for production of pharmaceutical (effervescent) composition comprising alpha - glucosidase inhibitor (e.g. vogliobose and metformin) - Google Patents

A process for production of pharmaceutical (effervescent) composition comprising alpha - glucosidase inhibitor (e.g. vogliobose and metformin) Download PDF

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Publication number
WO2013115745A1
WO2013115745A1 PCT/TR2013/000054 TR2013000054W WO2013115745A1 WO 2013115745 A1 WO2013115745 A1 WO 2013115745A1 TR 2013000054 W TR2013000054 W TR 2013000054W WO 2013115745 A1 WO2013115745 A1 WO 2013115745A1
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Prior art keywords
effervescent
voglibose
acarbose
miglitol
active agent
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PCT/TR2013/000054
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2013115745A1 publication Critical patent/WO2013115745A1/en

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    • 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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other 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

Definitions

  • the present invention relates to a process used for production of effervescent formulations comprising an alpha-glucosidase inhibitor derivative active agent so as to be used in the prophylaxis and treatment of type 2 diabetes (non-insulin dependent) mellitus cases wherein hyperglycemia cannot be controlled by diet and exercise.
  • alpha-glucosidase inhibitors Primary active agents known as alpha-glucosidase inhibitors are voglibose, acarbose and miglitol.
  • Effervescent formulations comprise high amounts of effervescent acid and base in order to enable sufficient dispersion in water. This results in pretty high unit dosage weight. There appear problems in the case that formulations having such high unit dosage weights are compressed in tablet form. These formulations obtained by dry blending and dry granulation methods cannot be formed into dosage forms possessing desired tablet hardness values after tablet compression and this causes problems for producers during packing and carrying phases. Furthermore, compressibility of these formulations comprising an alpha-glucosidase inhibitor such as voglibose, acarbose or miglitol is low too and problems are experienced during tableting.
  • an alpha-glucosidase inhibitor such as voglibose, acarbose or miglitol is low too and problems are experienced during tableting.
  • wet granulation method that can be used as an alternative may lead to negative results since it causes the effervescent acid and base to react during production. This results in production of rather large granules, failure to dry the granules effectively and observation of problems of stability of the obtained product.
  • the present invention relates to use of a granulation solution at 2.5% maximum in proportion to total weight of effervescent acid and effervescent base in a method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent.
  • the production method of the present invention comprises the steps of;
  • step III Granulating the mixture obtained in step II with the granulation solution obtained in step I, rV. Drying the granules,
  • step VI Compressing the obtained mixture in tablet form.
  • water, ethanol, methanol, acetone, ethyl acetate, hexane, heptane, n-octane, n-butyl acetate, propanol, t-butyl alcohol, dicloromethane or aqueous NaOH solution or a mixture thereof can be used as granulation solvent.
  • Water is preferably used as the granulation solvent.
  • At least one pharmaceutically acceptable excipient that can be used in steps I, II and V can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, effervescent base, glidant.
  • the pharmaceutical formulations 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 acid, effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent.
  • the disintegrant that can be used in the pharmaceutical formulations 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 lubricant that can be used in the pharmaceutical formulations 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 diluent that can be used in the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol 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 glidant that can be used in the pharmaceutical formulations 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 formulations 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 effervescent acid that can be used in the pharmaceutical formulations 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.
  • the effervescent base can be selected from a group comprising sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the pH regulating agent that can be used in the pharmaceutical formulations 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 formulations of the present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
  • the stabilizing agent that can be used in the pharmaceutical formulations 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 formulations 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 flavoring agent that can be used in the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavors.
  • At least one pharmaceutically acceptable excipient to be used in steps I and II is a binder.
  • the binders to be used can be the same as well as different.
  • Moisture content of the granules obtained in step IV is in the range of 0.1% to 0.9%, more preferably in the range of 0.2% to 0.7%. It is seen that formulations obtained using the granules having the specified moisture content rates are stabile. Furthermore, it is one of the advantages of the invention that the granules produced can be dried in a way that they have the moisture content rates specified above.
  • the present invention relates to use of a granulation solution in the range of 0.5% to 2.4% in proportion to total weight of effervescent acid and effervescent base in a method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent.
  • a second active agent can optionally be used in addition to voglibose, acarbose or miglitol.
  • the second active agent can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, 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
  • the second active agent can be selected from a group comprising repaglinide belonging to the group 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
  • the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol and lubricant optionally comprise active agents preferably from biguanide group, more preferably metformin or a pharmaceutically acceptable salt thereof, for example metformin hydrochloride.
  • the present invention is for use of said pharmaceutical formulation in combination of voglibose, acarbose or miglitol with metformin or a pharmaceutically acceptable salt thereof.
  • Said formulations are preferably in effervescent tablet, effervescent powder, effervescent pellet and granule form.
  • the production method of the present invention comprises the steps of;
  • step III Granulating the mixture obtained in step II with the granulation solution obtained in step I, r . Drying the granules,
  • the present invention relates to having a tablet hardness value in the range of 2 to 15 kPa in the case that the pharmaceutical formulation comprising voglibose, acarbose or miglitol and optionally metformin hydrochloride is formed into tablets.
  • Effervescent formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that moisture ratio of the formulation is in the range of 0.1% to 0.9% .
  • Effervescent tablet formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that tablet hardness is in the range of 1 to 15 kPa, preferably in the range of 2 to 13 kPa, more preferably in the range of 3 to 10 kPa.
  • EXAMPLE 1 Formulation and process for preparation of tablets comprising voglibose and metformin combination
  • the mixture comprising the binder, effervescent acid and effervescent base is mixed with the granulation solution and granulated.
  • the obtained granules are dried.
  • the dried granules are mixed with voglibose, metformin and at least one excipient.
  • the formulation obtained is compressed in tablet compression machine.
  • EXAMPLE 2 Formulation and process for preparation of formulation comprising acarbose .
  • a granulation solution is prepared with at least one excipient.
  • Acarbose is granulated with this granulation solution.
  • the obtained granules are mixed with the lubricant and the other excipients.
  • the formulation prepared can be packed as powder or granule as well as compressed in tablet form.

Abstract

The present invention relates to a process used for production of effervescent formulations comprising alpha-glucosidase inhibitor derivative active agent (e.g. voglibose, acarbose, miglitol possibly in combination with metformin), whereby the amount of the granulation solvent should be no more than 2.5% in proportion to the effervescent acid and effervescent base).

Description

A PROCESS FOR PRODUCTION OF PHARMACEUTICAL (EFFERVESCENT) COMPOSITION COMPRISING ALPHA - GLUCOSIDASE INHIBITOR (E.G. VOGLIOBOSE AND METFORMIN)
The present invention relates to a process used for production of effervescent formulations comprising an alpha-glucosidase inhibitor derivative active agent so as to be used in the prophylaxis and treatment of type 2 diabetes (non-insulin dependent) mellitus cases wherein hyperglycemia cannot be controlled by diet and exercise.
Primary active agents known as alpha-glucosidase inhibitors are voglibose, acarbose and miglitol.
Effervescent formulations comprise high amounts of effervescent acid and base in order to enable sufficient dispersion in water. This results in pretty high unit dosage weight. There appear problems in the case that formulations having such high unit dosage weights are compressed in tablet form. These formulations obtained by dry blending and dry granulation methods cannot be formed into dosage forms possessing desired tablet hardness values after tablet compression and this causes problems for producers during packing and carrying phases. Furthermore, compressibility of these formulations comprising an alpha-glucosidase inhibitor such as voglibose, acarbose or miglitol is low too and problems are experienced during tableting.
On the other hand, wet granulation method that can be used as an alternative may lead to negative results since it causes the effervescent acid and base to react during production. This results in production of rather large granules, failure to dry the granules effectively and observation of problems of stability of the obtained product.
Considering the prior art, there is need for new processes which can be used for production of effervescent formulations comprising an alpha-glucosidase inhibitor such as voglibose, acarbose or miglitol and enable obtainment of stabile products having desired hardness value.
The present invention relates to use of a granulation solution at 2.5% maximum in proportion to total weight of effervescent acid and effervescent base in a method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent.
The production method of the present invention comprises the steps of;
I. Preparing a granulation solution comprising a granulation solvent and at least one excipient
II. Mixing effervescent acid, effervescent base and at least one excipient,
III. Granulating the mixture obtained in step II with the granulation solution obtained in step I, rV. Drying the granules,
V. Adding voglibose, acarbose or miglitol and at least one excipient into the obtained granules and mixing them together,
VI. Compressing the obtained mixture in tablet form. In the granulation solution prepared in step I; water, ethanol, methanol, acetone, ethyl acetate, hexane, heptane, n-octane, n-butyl acetate, propanol, t-butyl alcohol, dicloromethane or aqueous NaOH solution or a mixture thereof can be used as granulation solvent. Water is preferably used as the granulation solvent.
At least one pharmaceutically acceptable excipient that can be used in steps I, II and V can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, effervescent base, glidant.
In addition, the pharmaceutical formulations 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 acid, effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent.
The disintegrant that can be used in the pharmaceutical formulations 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 lubricant that can be used in the pharmaceutical formulations 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 diluent that can be used in the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol 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 glidant that can be used in the pharmaceutical formulations 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 formulations 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 effervescent acid that can be used in the pharmaceutical formulations 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.
The effervescent base, on the other hand, can be selected from a group comprising sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
The pH regulating agent that can be used in the pharmaceutical formulations 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 formulations of the present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
The stabilizing agent that can be used in the pharmaceutical formulations 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 formulations 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 flavoring agent that can be used in the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol can be selected from a group comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavors.
It has been observed in the studies conducted according to the present invention that the technical problems mentioned above are solved in the case that at least one pharmaceutically acceptable excipient to be used in steps I and II is a binder. The binders to be used can be the same as well as different.
Moisture content of the granules obtained in step IV is in the range of 0.1% to 0.9%, more preferably in the range of 0.2% to 0.7%. It is seen that formulations obtained using the granules having the specified moisture content rates are stabile. Furthermore, it is one of the advantages of the invention that the granules produced can be dried in a way that they have the moisture content rates specified above.
In another aspect, the present invention relates to use of a granulation solution in the range of 0.5% to 2.4% in proportion to total weight of effervescent acid and effervescent base in a method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent.
In the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol and lubricant, a second active agent can optionally be used in addition to voglibose, acarbose or miglitol. The second active agent can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, 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 e, vitamin B2i vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
In another aspect, the second active agent can be selected from a group comprising repaglinide belonging to the group 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.
As the second active agent in addition to voglibose, acarbose or miglitol, the pharmaceutical formulations of the present invention comprising voglibose, acarbose or miglitol and lubricant optionally comprise active agents preferably from biguanide group, more preferably metformin or a pharmaceutically acceptable salt thereof, for example metformin hydrochloride.
In another aspect, the present invention is for use of said pharmaceutical formulation in combination of voglibose, acarbose or miglitol with metformin or a pharmaceutically acceptable salt thereof. Said formulations are preferably in effervescent tablet, effervescent powder, effervescent pellet and granule form.
In another aspect, the production method of the present invention comprises the steps of;
I. Preparing a granulation solution comprising water as granulation solvent and binder as at least one excipient II. Mixing effervescent acid, effervescent base and binder as at least one excipient,
III. Granulating the mixture obtained in step II with the granulation solution obtained in step I, r . Drying the granules,
V. Adding voglibose, acarbose or miglitol and metformin as the second active agent and at least one excipient into the granules obtained, then mixing them together,
VI. Compressing the obtained formulation in tablet form.
In another aspect, the present invention relates to having a tablet hardness value in the range of 2 to 15 kPa in the case that the pharmaceutical formulation comprising voglibose, acarbose or miglitol and optionally metformin hydrochloride is formed into tablets.
Effervescent formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that moisture ratio of the formulation is in the range of 0.1% to 0.9% .
Effervescent tablet formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that tablet hardness is in the range of 1 to 15 kPa, preferably in the range of 2 to 13 kPa, more preferably in the range of 3 to 10 kPa.
There are examples relating to the formulations of the invention given below. Said examples are given in order to explain the invention, yet the present invention should not be limited to these.
EXAMPLE 1: Formulation and process for preparation of tablets comprising voglibose and metformin combination
Figure imgf000007_0001
The mixture comprising the binder, effervescent acid and effervescent base is mixed with the granulation solution and granulated. The obtained granules are dried. The dried granules are mixed with voglibose, metformin and at least one excipient. The formulation obtained is compressed in tablet compression machine.
EXAMPLE 2: Formulation and process for preparation of formulation comprising acarbose .
Figure imgf000007_0002
A granulation solution is prepared with at least one excipient. Acarbose is granulated with this granulation solution. The obtained granules are mixed with the lubricant and the other excipients. The formulation prepared can be packed as powder or granule as well as compressed in tablet form.

Claims

1. A method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent, characterized in that;
said formulation comprises a granulation solvent at 2.5% maximum in proportion to total weight of effervescent acid and effervescent base.
2. The method so as to be used for production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent according to claim 1, characterized in that said method comprises the steps of;
I. Preparing a granulation solution comprising a granulation solvent and at least one excipient
II. Mixing at least one effervescent acid, at least one effervescent base and at least one excipient
III. Granulating the mixture obtained in step II with the granulation solution obtained in step I
IV. Drying the granules
V. Adding voglibose, acarbose or miglitol and at least one excipient into the obtained granules and mixing them together
VI. Compressing the obtained formulation in tablet form.
3. The production method according to claim 2, characterized in that the granulation solvent is selected from a group comprising water, ethanol, methanol, acetone, ethyl acetate, hexane, heptane, n-octane, n-butyl acetate, propanol, t-butyl alcohol, dicloromethane or aqueous NaOH solution.
4. The production method according to claims 2 and 3, characterized in that the granulation solvent is water.
5. The production method according to claims 2-4, characterized in that at least one excipient used in step I is binder.
6. The production method according to claims 2-5, characterized in that at least one excipient comprised in the mixture granulated along with the effervescent acid and effervescent base in step II is binder.
7. The production method according to claims 2-6, characterized in that the binders used in step I and step II are the same.
8. The production method according to claims 2-7, characterized in that the binders used in step I and step II are different.
9. The production method according to claims 2-8, characterized in that the moisture content of the granules obtained in step IV is in the range of 0.1% to 0.9%.
10. The production method according to claims 2-9, characterized in that the moisture content of the granules obtained in step IV is in the range of 0.2% to 0.7%.
1 1. The production method according to any preceding claims, characterized in that said formulation comprises a granulation solvent in the range of 0.5% to 2.4% in proportion to total weight of the effervescent acid and effervescent base.
12. The production method according to claims 2-1 1, characterized in that the second active agent is added in step V in the case that a second active agent is comprised in addition to voglibose, acarbose or miglitol.
13. The production method according to claims 2-11, characterized in that the second active agent is added in step II in the case that a second active agent is comprised in addition to voglibose, acarbose or miglitol.
14. Effervescent pharmaceutical composition prepared by a production method according to claims 2-13, characterized in that said effervescent pharmaceutical composition comprises at least one excipient in addition to voglibose, acarbose or miglitol as active agent and at least one effervescent acid and at least one effervescent base.
15. The pharmaceutical composition according to claims 2-14, characterized in that the excipient is selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, effervescent acid, effervescent base, glidant.
16. The pharmaceutical composition according to claims 14-15, characterized in that said composition comprises a second active agent in addition to voglibose, acarbose or miglitol.
17. The pharmaceutical composition according to claims 14-16, characterized in that the second active agent used in addition to voglibose, acarbose or miglitol is selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, 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 B] vitamin C, vitamin E, vitamin B6> vitamin B2i vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
18. The pharmaceutical composition according to claims 14-16, characterized in that the second active agent used in addition to voglibose, acarbose or miglitol is selected from a group comprising repaglinide belonging to the group 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.
19. The pharmaceutical composition according to claims 14-18, characterized in that the second active agent to be used in addition to voglibose, acarbose or miglitol is metformin hydrochloride.
20. The pharmaceutical composition according to claims 14-19, characterized in that tablet hardness is in the range of 2 to 5 kPa in the case that said formulation is formed into tablets.
21. An effervescent formulation comprising the combination of voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that moisture content of said formulation is in the range of 0.1% to 0.9%.
22. An effervescent tablet formulation comprising the combination of voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that tablet hardness is in the range of 1 to 15 kPa.
23. The effervescent tablet formulation according to claim 22, characterized in that hardness value of the tablet obtained with this formulation is in the range of 2 to 13 kPa.
24. The effervescent tablet formulation according to claim 23, characterized in that the hardness value of the tablet obtained with this formulation is in the range of 3 to 10 kPa.
PCT/TR2013/000054 2012-01-31 2013-01-31 A process for production of pharmaceutical (effervescent) composition comprising alpha - glucosidase inhibitor (e.g. vogliobose and metformin) WO2013115745A1 (en)

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* Cited by examiner, † Cited by third party
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US3773922A (en) * 1971-04-06 1973-11-20 Fr Dev Rech Sofrader Method for the manufacture of effervescent tablets
EP0203768A2 (en) * 1985-05-31 1986-12-03 Warner-Lambert Company A therapeutic effervescent composition and a method of preparing the same
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