WO2013115744A1 - 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
WO2013115744A1
WO2013115744A1 PCT/TR2013/000053 TR2013000053W WO2013115744A1 WO 2013115744 A1 WO2013115744 A1 WO 2013115744A1 TR 2013000053 W TR2013000053 W TR 2013000053W WO 2013115744 A1 WO2013115744 A1 WO 2013115744A1
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Prior art keywords
formulation
effervescent
production method
voglibose
acarbose
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PCT/TR2013/000053
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2013115744A1 publication Critical patent/WO2013115744A1/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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • 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

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 or 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 effervescent base.
  • Alpha-glucosidase inhibitor agents such as voglibose, acarbose or miglitol are not durable against acidic agents. This problem could be solved by using the acidic agents in small amounts.
  • use of small amounts of acidic agents causes the obtained dosage forms to have longer dispersion times than expected and this poses problems for users and producers who have to attain quality standards.
  • Adding an effervescent acid into the formulation in the required amount to enable dispersion in sufficient time leads to decrease in stability of the formulation during storing. This stability decrease is observed as impurity increase in the unit dosage form.
  • the present invention relates to a method for use in production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent, characterized in that said method comprises the steps of;
  • the production method of the present invention comprises the steps of;
  • step III Granulating the mixture obtained in step II with the granulation solution prepared in step I IV. - Drying the granules
  • step VI Filling the formulation obtained into sachets or compressing it in tablet form.
  • water, ethanol, methanol, acetone, ethyl acetate, hexane, heptane, n-octane, n-butyl acetate, propanol, t-butyl alcohol, dicloromethane or aqueous HCL solution, aqueous NaOH solution or any mixture thereof can be used as the granulation solvent.
  • Water is preferably used as the granulation solvent.
  • At least one pharmaceutically acceptable excipient that shall be used in steps I, II and V can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, glidant.
  • At least one pharmaceutically acceptable excipient that shall be used in steps I and II is preferably binder.
  • the binders to be used in these two steps can be the same as well as different.
  • Impurity amount of the pharmaceutical compositions obtained by mixing the granules obtained in step IV with the active agent voglibose, acarbose or miglitol and the other excipients is in the range of 0.00% to 0.1 %, preferably in the range of 0.01% to 0.08%, more preferably in the range of 0.01% to 0.05%.
  • a characteristic feature of the present invention is formulations comprising voglibose, acarbose, miglitol with an impurity amount in the range of 0.00% to 0.1%.
  • 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 gtidant 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 inventors preferably use citric acid as effervescent acid. It has been seen that it depends on the effervescent acid used and the characteristics of said effervescent acid that the obtained formulation has the desired stability and dissolution time in water. According to this, the inventors use citric acid having a moisture rate in the range of 0.01% to 0.3%, preferably in the range of 0.05% to 0.1% in a preferred embodiment of the invention.
  • the production method of the present invention comprises the steps of;
  • step III Granulating the mixture obtained in step II with the granulation solution prepared in step I IV. Drying the granules
  • 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, tartrate, 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.
  • 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
  • said 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 prepared in step I, rV. Drying the granules
  • Effervescent formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that impurity rate of said formulation and the dosage form obtained with this formulation is maximum 0.1%, preferably in the range of 0.00% to 0.10%, preferably in the range of 0.00% to 0.08%, more preferably in the range of 0.01% to 0.05%.
  • the formulations of the present invention comprise voglibose, acarbose or miglitol in the range of 1% to 80% in proportion to unit dosage weight.
  • said formulations comprise the second active agent, for instance metformin hydrochloride, in the range of 1% to 80% in proportion to unit dosage weight.
  • the present invention relates to effervescent pharmaceutical formulations which dissolve or disperse in water or in a similar solvent in less than 10 minutes, preferably in 1-8 minutes, more preferably in 1-5 minutes, for instance in a short period of time in the range of 1.5, 2, 2.5, 3 to 3.5, 4, 4.5 minutes and comprise an alpha-glucosidase inhibitor as active agent, for instance voglibose, acarbose or miglitol and optionally a second active agent 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, pioglita
  • EXAMPLE 1 Formulation and process for preparation of tablets comprising voglibose and metformin combination
  • the mixture comprising the binder 1, effervescent acid and effervescent base is granulated with the granulation solution comprising the binder (binder 2).
  • the granules obtained are dried.
  • the dried granules are mixed with voglibose, metformin hydrochloride and at least one excipient.
  • the obtained formulation is compressed in tablet compression machine.
  • EXAMPLE 2 Formulation and process for preparation of formulation comprising acarbose
  • Effervescent acid, effervescent base are granulated and dried. Acarbose and other excipients are added into the mixture obtained. Lubricant is added into the final mixture and the formulation prepared is filled into sachets.

Abstract

The present invention relates to a process used form production of effervescent formulations comprising an alpha.glucosidase inhibitor derivative active agent (voglibose, acarbose, miglitol, possibly combined with metformin) whereby the effervescent couple is granulated and the active agent is added to the dried granules.

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 or exercise.
Primary active agents known as alpha-glucosidase inhibitors are voglibose, acarbose and miglitol.
In order to enable sufficient dispersion in water, effervescent formulations comprise high amounts of effervescent acid and effervescent base. Alpha-glucosidase inhibitor agents such as voglibose, acarbose or miglitol are not durable against acidic agents. This problem could be solved by using the acidic agents in small amounts. However, use of small amounts of acidic agents causes the obtained dosage forms to have longer dispersion times than expected and this poses problems for users and producers who have to attain quality standards.
Adding an effervescent acid into the formulation in the required amount to enable dispersion in sufficient time, on the other hand, leads to decrease in stability of the formulation during storing. This stability decrease is observed as impurity increase in the unit dosage form.
When the prior art is taken into consideration, there is need for new processes that can be used for production of effervescent formulations comprising one of the alpha-glucosidase inhibitors such as voglibose, acarbose or miglitol so as to be used for obtainment of stabile products having the required dispersion times. The present invention relates to a method for use in production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent, characterized in that said method comprises the steps of;
• Granulating the mixture comprising at least one effervescent acid, at least one effervescent base and at least one pharmaceutically acceptable excipient and granulation solvent with a granulation solution comprising optionally one or more excipients, and then drying it
• Dry-mixing the alpha-glucosidase inhibitor (voglibose, acarbose or miglitol) and at least one excipient with the obtained granules.
The production method of the present invention comprises the steps of;
I. Preparing a granulation solution comprising a granulation solvent and optionally one or more excipients
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 prepared 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. Filling the formulation obtained into sachets or compressing it 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 HCL solution, aqueous NaOH solution or any mixture thereof can be used as the granulation solvent. Water is preferably used as the granulation solvent.
At least one pharmaceutically acceptable excipient that shall be used in steps I, II and V can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, glidant.
At least one pharmaceutically acceptable excipient that shall be used in steps I and II is preferably binder. The binders to be used in these two steps can be the same as well as different.
Impurity amount of the pharmaceutical compositions obtained by mixing the granules obtained in step IV with the active agent voglibose, acarbose or miglitol and the other excipients is in the range of 0.00% to 0.1 %, preferably in the range of 0.01% to 0.08%, more preferably in the range of 0.01% to 0.05%. According to this, a characteristic feature of the present invention is formulations comprising voglibose, acarbose, miglitol with an impurity amount in the range of 0.00% to 0.1%.
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 gtidant 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 inventors preferably use citric acid as effervescent acid. It has been seen that it depends on the effervescent acid used and the characteristics of said effervescent acid that the obtained formulation has the desired stability and dissolution time in water. According to this, the inventors use citric acid having a moisture rate in the range of 0.01% to 0.3%, preferably in the range of 0.05% to 0.1% in a preferred embodiment of the invention.
According to this, in a preferred embodiment of the invention, the production method of the present invention comprises the steps of;
I. Preparing a granulation solution comprising a granulation solvent and optionally one or more excipients
II. Mixing citric acid, at least one effervescent base and at least one excipient
III. Granulating the mixture obtained in step II with the granulation solution prepared 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. Filling the formulation obtained into sachets or compressing it in tablet form.
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, tartrate, 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.
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 B6> vitamin B2j vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
In another aspect, said 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 the granulation solution comprising water as the granulation solvent and the binder as at least one excipient,
II. Mixing the effervescent acid, effervescent base and the binder,
III. Granulating the mixture obtained in step II with the granulation solution prepared in step I, rV. Drying the granules
V. Adding voglibose, acarbose or miglitol and metformin or one of its pharmaceutically acceptable salts as the second active agent and at least one excipients into the obtained granules and mixing them together,
VI. Compressing the formulation obtained in tablet form or filling it into sachets.
Effervescent formulation comprising voglibose, acarbose or miglitol and metformin hydrochloride, characterized in that impurity rate of said formulation and the dosage form obtained with this formulation is maximum 0.1%, preferably in the range of 0.00% to 0.10%, preferably in the range of 0.00% to 0.08%, more preferably in the range of 0.01% to 0.05%.
The formulations of the present invention comprise voglibose, acarbose or miglitol in the range of 1% to 80% in proportion to unit dosage weight. In the case that there is a second active agent, said formulations comprise the second active agent, for instance metformin hydrochloride, in the range of 1% to 80% in proportion to unit dosage weight.
In another aspect, the present invention relates to effervescent pharmaceutical formulations which dissolve or disperse in water or in a similar solvent in less than 10 minutes, preferably in 1-8 minutes, more preferably in 1-5 minutes, for instance in a short period of time in the range of 1.5, 2, 2.5, 3 to 3.5, 4, 4.5 minutes and comprise an alpha-glucosidase inhibitor as active agent, for instance voglibose, acarbose or miglitol and optionally a second active agent 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, preferably metformin hydrochloride. 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 1, effervescent acid and effervescent base is granulated with the granulation solution comprising the binder (binder 2). The granules obtained are dried. The dried granules are mixed with voglibose, metformin hydrochloride and at least one excipient. The obtained formulation is compressed in tablet compression machine. EXAMPLE 2: Formulation and process for preparation of formulation comprising acarbose
Figure imgf000008_0001
Effervescent acid, effervescent base are granulated and dried. Acarbose and other excipients are added into the mixture obtained. Lubricant is added into the final mixture and the formulation prepared is filled into sachets.

Claims

LAIMS
1. A method for use in production of effervescent formulations comprising voglibose, acarbose or miglitol as active agent, characterized in that said method comprises the steps of;
I. granulating the mixture comprising at least an effervescent acid, at least one effervescent base and at least one pharmaceutically acceptable excipient with a granulation solution comprising optionally one or more excipients and granulation solvent, then drying it and
II. dry-mixing the alpha-glucosidase inhibitor (voglibose, acarbose or miglitol) and at least one excipient with the obtained granules.
2. The production method according to claim 1, characterized in that said method comprises the steps of;
I. Preparing a granulation solution comprising granulation solvent and optionally one or more excipients
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 prepared 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. Filling the obtained formulation into sachets or compressing it in tablet form.
3. The production method according to claims 1 and 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 HC1 solution, aqueous NaOH solution or a combination thereof.
4. The production method according to claims 1-3, characterized in that the granulation solvent is water.
5. The production method according to claims 1-4, characterized in that at least one pharmaceutically acceptable excipient is selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, glidant.
6. The production method according to any preceding claims, characterized in that at least one excipient granulated with at least one effervescent acid and at least one effervescent base and at least one excipient added to the granulation solution are binders.
7. The production method according to claim 6, characterized in that the binder granulated with at least one effervescent acid and at least one effervescent base and the binder added to the granulation solution are the same.
8. The production method according to claim 6, characterized in that the binder granulated with at least one effervescent acid and at least one effervescent base and the binder added to the granulation solution are different.
9. The production method according to claims 6-8, characterized in that the binder is 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.
10. The production method according to any preceding claims, characterized in that the effervescent acid is selected from a group comprising malic acid, citric acid, tartaric acid, fumaric acid.
11. The production method according to any preceding claims, characterized in that the effervescent acid is citric acid.
12. The production method according to claim 11, characterized in that moisture rate of citric acid is in the range of 0.01% to 0.3%.
13. The production method according to claims 11-12, characterized in that moisture rate of citric acid is in the range of 0.05% to 0.1%.
14. The production method according to claims 1 1-13, wherein said method comprises a second active agent in addition to voglibose, acarbose or miglitol.
15. The production method according to claims 1-14, wherein said method comprises a second active agent in addition to voglibose, acarbose or miglitol selected from a group comprising repaglinide, acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide, pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone, phenformin, metformin, metformin hydrochloride, sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate.
16. The production method according to claims 1-15, wherein said method comprises metformin or metformin hydrochloride in addition to voglibose, acarbose or miglitol.
17. The production method according to claims 1-16, wherein metformin hydrochloride is added in step V of said method.
18. A pharmaceutical composition comprising voglibose, acarbose or miglitol and optionally a second active agent, characterized in that said composition is produced by a production method claimed in claims 1-17.
19. The pharmaceutical composition according to claim 18, characterized in that the second active agent is metformin or a pharmaceutically acceptable salt thereof.
20. An effervescent formulation comprising voglibose, acarbose or miglitol and optionally a second active agent, characterized in that impurity rate of said formulation and the dosage form obtained with said formulation is maximum 0.1%.
21. The effervescent formulation according to claim 20, characterized in that impurity rate of said formulation and the dosage form obtained with said formulation is in the range of 0.0% to 0.1%.
22. The effervescent formulation according to claims 20-21, characterized in that impurity rate of said formulation and the dosage form obtained with said formulation is in the range of 0.00% to 0.08%.
23. The effervescent formulation according to claims 20-22, characterized in that impurity rate of said formulation and the dosage form obtained with said formulation is in the range of 0.01% to 0.05%.
24. An effervescent formulation comprising voglibose, acarbose or miglitol and optionally a second active agent, characterized in that said formulation and the dosage form obtained with said formulation dissolve/disperse in water in less than 10 minutes.
25. The formulation according to claim 24, characterized in that said formulation and the dosage form obtained with said formulation dissolve/disperse in water in 1-8 minutes.
26. The formulation according to claims 24-25, characterized in that said formulation and the dosage form obtained with said formulation dissolve/disperse in water in 1-5 minutes.
PCT/TR2013/000053 2012-01-31 2013-01-31 A process for production of pharmaceutical (effervescent) composition comprising alpha - glucosidase inhibitor (e.g. vogliobose and metformin) WO2013115744A1 (en)

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