WO2013077821A1 - Homogeneous biguanide composition - Google Patents

Homogeneous biguanide composition Download PDF

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Publication number
WO2013077821A1
WO2013077821A1 PCT/TR2012/000155 TR2012000155W WO2013077821A1 WO 2013077821 A1 WO2013077821 A1 WO 2013077821A1 TR 2012000155 W TR2012000155 W TR 2012000155W WO 2013077821 A1 WO2013077821 A1 WO 2013077821A1
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Prior art keywords
metformin
pharmaceutical composition
range
composition
vitamin
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Application number
PCT/TR2012/000155
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French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Publication of WO2013077821A1 publication Critical patent/WO2013077821A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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 pharmaceutical compositions comprising metformin that shall be used in the treatment of type 2 diabetes.
  • Metformin (Formula 1) having the chemical name of N,N- dimethylimidodicarbonimidic diamide is a molecule belonging to the class of biguanides. Metformin was first disclosed in the application numbered US3174901. It is known that metformin is effective particularly in the treatment of type 2 diabetes of overweight and obese patients who have healthy kidney functions. In different resources, it has been disclosed that said active agent can also be used in treatment of polycystic ovary syndrome or different diseases caused by insulin resistance.
  • Metformin is available in metformin hydrochloride salt form in 500 mg, 750 mg and 1000 mg film coated tablet and prolonged release tablet forms on the market.
  • the physical characteristics of the formulation comprising said active agent such as flow rate, homogenization, dissolution etc. are quite important as well as the active agent itself.
  • the formulation comprising the active agent has required flow rate in terms of providing content uniformity. Furthermore, in the case that a formulation having good flow characteristics is formed into tablets, the tablets can be prepared by direct compression method. In this way, a possible granulation step is prevented and production costs are reduced.
  • the formulation comprising the active agent is homogeneous and remains homogeneous throughout the process are important for the quality of the end product and providing equal amount of the active agent in each dose.
  • the active agent mixed with the excipients used in the process can separate from the mixture and cause an inhomogeneous composition in progressive phases of the process.
  • Wet granulation and melt granulation methods can be used in order to solve this problem in production method. However, these methods require particular and expensive equipments and increase production costs significantly.
  • the present invention relates to pharmaceutical compositions comprising metformin having an average particle size (d 50 ) in the range of 20 ⁇ to 250 ⁇ .
  • metformin having an average particle size (dso) preferably in the range of 30 ⁇ to 200 ⁇ , more preferably in the range of 50 ⁇ to 150 ⁇ is used in the formulations of the present invention.
  • average particle size refers to average particle size by volume and it is also shown with dso in short. In this sense, the term dso signifies that half of the said substance by volume has a particle size over the value stated with dso and the other half of the substance by volume has a particle size below the value stated with d 5 o.
  • Metformin comprised in the pharmaceutical compositions of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. Metformin is preferably in form of its salts, more preferably in form of its hydrochloride salt.
  • D 50 value 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.).
  • a device which measures particle distribution by laser diffraction for instance, Malvern Mastersizer etc.
  • Metformin of the present invention having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be bought and used as a product which is commercially provided in this form.
  • metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ can also be obtained by pulverizing a product having 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 metformin 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.
  • pulverization is performed by the impact of the rotating hammers in the device.
  • pulverization is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream.
  • compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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.
  • compositions of the present invention comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ are preferably in the form of tablet, prolonged release tablet, film coated tablet or effervescent tablet, more preferably in effervescent tablet form.
  • the present invention relates to pharmaceutical compositions in effervescent tablet form comprising metformin having an average particle size (d 5 o) in the range of 20 ⁇ to 250 ⁇ .
  • the pharmaceutical composition obtained can be formed into any dosage form mentioned above.
  • 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.
  • 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 metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ can comprise various excipients in addition to the active agent metformin.
  • the disintegrant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
  • the lubricant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a dso value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 5 o value in the range of 20 ⁇ to 250 ⁇ 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 metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can comprise metformin in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, preferably in the range of 5 to 95% by weight and more preferably in the range of 10 to 50% by weight.
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 90 value in the range of 70 ⁇ to 400 ⁇ .
  • the inventors have seen that the formulations have proper flow rate, the active agent and the excipients are mixed homogeneously during preparation of the pharmaceutical compositions comprising metformin having a d 90 value in the range of 70 ⁇ to 400 ⁇ and consequently, each unit dosage form prepared with said formulation comprises equal amount of the active agent.
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 9 o value in the range of 70 ⁇ to 400 ⁇ .
  • D 90 value of metformin comprised in the pharmaceutical compositions of the present invention is in the range of 70 ⁇ to 400 ⁇ , preferably in the range of 100 ⁇ to 350 ⁇ , more preferably in the range of 150 ⁇ to 300 ⁇ .
  • the present invention relates to pharmaceutical compositions comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ and a d 90 value in the range of 70 ⁇ to 400 ⁇ .
  • the term 090 signifies that 90% of the said substance by volume has a particle size below the stated value and 10% of the said substance by volume has a particle size over the stated value.
  • compositions of the present invention comprising metformin having a d 50 value in the range of 20 ⁇ to 250 ⁇ can optionally comprise a second active agent in addition to metformin.
  • the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, 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
  • compositions of the present invention comprising metformin having a dso value in the range of 20 ⁇ to 250 ⁇ can optionally comprise a second active agent in addition to metformin.
  • the second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
  • said second active agent can be selected from a group comprising the agents such as repaglinide, nateglinide belonging to the groups of meglitinides; alpha- glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, glibenclamide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin belonging to the group of biguanides or a pharmaceutically acceptable salt thereof; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxa
  • the pharmaceutical composition of the present invention can be obtained by:
  • the pharmaceutical composition of the present invention can be used in prevention and treatment of type 2 diabetes.
  • EXAMPLE 1 Tablet formulation comprising metformin
  • Metformin hydrochloride, organic base, organic acid are mixed and they are subjected to precompression and they are sieved; the granules obtained are mixed with the excipients.
  • Glidant is added into the mixture obtained and mixed.
  • the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
  • Metformin hydrochloride, organic base, organic acids are mixed, the excipients and glidant are added into the mixture obtained.
  • the lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.

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Abstract

The present invention relates to pharmaceutical formulations comprising metformin that shall be used in treatment of type 2 diabetes.

Description

HOMOGENEOUS BIGUANIDE COMPOSITION
The present invention relates to pharmaceutical compositions comprising metformin that shall be used in the treatment of type 2 diabetes.
Metformin (Formula 1) having the chemical name of N,N- dimethylimidodicarbonimidic diamide is a molecule belonging to the class of biguanides. Metformin was first disclosed in the application numbered US3174901. It is known that metformin is effective particularly in the treatment of type 2 diabetes of overweight and obese patients who have healthy kidney functions. In different resources, it has been disclosed that said active agent can also be used in treatment of polycystic ovary syndrome or different diseases caused by insulin resistance.
Figure imgf000002_0001
Formula 1
Metformin is available in metformin hydrochloride salt form in 500 mg, 750 mg and 1000 mg film coated tablet and prolonged release tablet forms on the market.
For efficiency of an active agent, the physical characteristics of the formulation comprising said active agent such as flow rate, homogenization, dissolution etc. are quite important as well as the active agent itself.
When said formulations are formed into a specific dosage form, it is advantageous that the formulation comprising the active agent has required flow rate in terms of providing content uniformity. Furthermore, in the case that a formulation having good flow characteristics is formed into tablets, the tablets can be prepared by direct compression method. In this way, a possible granulation step is prevented and production costs are reduced.
In addition to these, the facts that the formulation comprising the active agent is homogeneous and remains homogeneous throughout the process are important for the quality of the end product and providing equal amount of the active agent in each dose. In some cases, the active agent mixed with the excipients used in the process can separate from the mixture and cause an inhomogeneous composition in progressive phases of the process. Wet granulation and melt granulation methods can be used in order to solve this problem in production method. However, these methods require particular and expensive equipments and increase production costs significantly.
As a result of the studies they conducted so as to improve flow rate and homogenization characteristics of the formulations comprising metformin, the inventors have found that the pharmaceutical compositions comprising metformin having an average particle size (d5o) in the range of 20 μιτι to 250 μηι have the required flow rate and the pharmaceutical compositions comprising metformin having an average particle size (dso) in the range of 20 μηι to 250 μπι have a homogeneous mixture throughout the process. In this respect, the present invention relates to pharmaceutical compositions comprising metformin having an average particle size (d50) in the range of 20 μιη to 250 μηι.
In another aspect, metformin having an average particle size (dso) preferably in the range of 30 μηι to 200 μιη, more preferably in the range of 50 μιη to 150 μηι is used in the formulations of the present invention. The term "average particle size" refers to average particle size by volume and it is also shown with dso in short. In this sense, the term dso signifies that half of the said substance by volume has a particle size over the value stated with dso and the other half of the substance by volume has a particle size below the value stated with d5o.
Metformin comprised in the pharmaceutical compositions of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. Metformin is preferably in form of its salts, more preferably in form of its hydrochloride salt.
D50 value 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.).
Metformin of the present invention having a d50 value in the range of 20 μιη to 250 μηι can be bought and used as a product which is commercially provided in this form. In addition, metformin having a d5o value in the range of 20 μηι to 250 μπι can also be obtained by pulverizing a product having 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 metformin 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 metformin having a d50 value in the range of 20 μπ to 250 μιη 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 metformin having a d5o value in the range of 20 μιτι to 250 μπι are preferably in the form of tablet, prolonged release tablet, film coated tablet or effervescent tablet, more preferably in effervescent tablet form.
In another aspect, the present invention relates to pharmaceutical compositions in effervescent tablet form comprising metformin having an average particle size (d5o) in the range of 20 μηι to 250 μπι.
The pharmaceutical composition obtained can be formed into any dosage form mentioned above. 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 metformin having a d5o value in the range of 20 μιη to 250 μηι can comprise various excipients in addition to the active agent metformin.
The pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μηι to 250 μιη 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 metformin.
The disintegrant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μιη to 250 μηι 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 metformin having a d50 value in the range of 20 μηι to 250 μιη can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
The lubricant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μιη to 250 μιη 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 metformin having a d5o value in the range of 20 μπι to 250 μηι 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 metformin having a dso value in the range of 20 μιη to 250 μπι 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 metformin having a d50 value in the range of 20 μιη to 250 μπι 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 metformin having a d50 value in the range of 20 μηι to 250 μιη can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
The surfactant that can be used in the pharmaceutical compositions of the present invention comprising metformin having a d5o value in the range of 20 μηι to 250 μιη 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 metformin having a d50 value in the range of 20 μηι to 250 μπι 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 metformin having a d5o value in the range of 20 μηι to 250 μπι 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 metformin having a d50 value in the range of 20 μηι to 250 μηι can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μπι to 250 μπι can comprise metformin in the range of 0.1 to 100% by weight, preferably in the range of 1 to 99% by weight, preferably in the range of 5 to 95% by weight and more preferably in the range of 10 to 50% by weight.
In another aspect, the present invention relates to pharmaceutical compositions comprising metformin having a d90 value in the range of 70 μιη to 400 μιη. The inventors have seen that the formulations have proper flow rate, the active agent and the excipients are mixed homogeneously during preparation of the pharmaceutical compositions comprising metformin having a d90 value in the range of 70 μηι to 400 μηι and consequently, each unit dosage form prepared with said formulation comprises equal amount of the active agent.
According to this, the present invention relates to pharmaceutical compositions comprising metformin having a d9o value in the range of 70 μπι to 400 μιη. D90 value of metformin comprised in the pharmaceutical compositions of the present invention is in the range of 70 μηι to 400 μπι, preferably in the range of 100 μιη to 350 μιτι, more preferably in the range of 150 μιη to 300 μιη.
In another aspect, the present invention relates to pharmaceutical compositions comprising metformin having a d50 value in the range of 20 μηι to 250 μηι and a d90 value in the range of 70 μπι to 400 μιη. The term 090 signifies that 90% of the said substance by volume has a particle size below the stated value and 10% of the said substance by volume has a particle size over the stated value.
The pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μηι to 250 μπι can optionally comprise a second active agent in addition to metformin. The second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, 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 Blt vitamin C, vitamin E, vitamin B6> vitamin B2j vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
The pharmaceutical compositions of the present invention comprising metformin having a dso value in the range of 20 μιη to 250 μηι can optionally comprise a second active agent in addition to metformin. The second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
In another aspect, said second active agent can be selected from a group comprising the agents such as repaglinide, nateglinide belonging to the groups of meglitinides; alpha- glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, glibenclamide, chlorpropamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin belonging to the group of biguanides or a pharmaceutically acceptable salt thereof; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate.
Optionally, the pharmaceutical compositions of the present invention comprising metformin having a d50 value in the range of 20 μηι to 250 μπι comprise a second active agent preferably belonging to the group of meglitinides, more preferably nateglinide or repaglinide as a second active agent in addition to metformin.
The pharmaceutical composition of the present invention can be obtained by
• mixing the active agent metformin and, if available, the second active agent homogeneously and adding at least one of the excipients listed above if required or
• after granulating the active agent metformin and, if available, the second active agent with at least one of the excipients, mixing them homogeneously or
• mixing the active agent metformin and, if available, the second active agent with at least one of the excipients and at least one of the excipients listed above and optionally granulating them with the granulation solution comprising excipient or
• a method which is composed of using any abovementioned methods separately for the active agent compositions and combining the formulations obtained in the case that two active agents are used.
The pharmaceutical composition of the present invention can be used in prevention and treatment of type 2 diabetes.
EXAMPLE 1 : Tablet formulation comprising metformin
Figure imgf000009_0001
Metformin hydrochloride, organic base, organic acid are mixed and they are subjected to precompression and they are sieved; the granules obtained are mixed with the excipients. Glidant is added into the mixture obtained and mixed. The lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.
EXAMPLE 2: Tablet formulation comprising metformin
Figure imgf000010_0001
Metformin hydrochloride, organic base, organic acids are mixed, the excipients and glidant are added into the mixture obtained. The lubricant is added into the final mixture and the pharmaceutical composition obtained is compressed in tablet compression machine.

Claims

1. A pharmaceutical composition comprising metformin, characterized in that average particle size (dso) of metformin is in the range of 20 μπι to 250 μπι.
2. The pharmaceutical composition comprising metformin according to claim 1, characterized in that average particle size (d5o) of metformin is in the range of 30 μιη to 200 μιη.
3. The pharmaceutical composition comprising metformin according to claims 1 and 2, characterized in that average particle size (dso) of metformin is in the range of 50 μπι
4. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition can be prepared in any 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.
5. The pharmaceutical composition comprising metformin according to claim 4, wherein said formulation is in the form of effervescent tablet, prolonged release tablet, film coated tablet.
6. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.
7. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin is in its pharmaceutically acceptable salt form.
8. The pharmaceutical composition comprising metformin according to any preceding claims, wherein metformin is in metformin hydrochloride form.
9. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition can comprise pharmaceutically acceptable excipients along with metformin.
10. The pharmaceutical composition comprising metformin according to claim 9, 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 along with the active agent metformin.
11. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 0.1 to 100 % by weight.
12. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 1 to 99% by weight.
13. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 5 to 95% by weight.
14. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises metformin in the range of 10 to 50% by weight.
15. The pharmaceutical composition comprising metformin according to any preceding claims, wherein said composition comprises at least a second active agent selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, 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 analogs, vitamin Bi; vitamin C, vitamin E, vitamin B6; vitamin B2j vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium in addition to metformin.
16. The pharmaceutical composition comprising metformin according to claim 15, wherein said composition comprises at least a second active agent selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors in addition to metformin.
17. The pharmaceutical composition comprising metformin according to claim 16, wherein said composition comprises at least a second active agent selected from a group comprising the agents repaglinide, nateglinide belonging to the group of meglitinides; alpha-glucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, glibenclamide, tolbutamide belonging to the group of sulfonylureas; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to the group of thiazolidinediones; phenformin, belonging to the group of biguanides; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin phosphate monohydrate in addition to metformin.
18. The pharmaceutical composition comprising metformin, characterized in that dgo value of metformin comprised in said composition is in the range of 70 μιη to 400 μιη.
19. The pharmaceutical composition comprising metformin according to claim 16, characterized in that d o value of metformin comprised in said composition is in the range of 100 μπι to 350 μιη.
20. The pharmaceutical composition comprising metformin according to claim 17, characterized in that dgo value of metformin comprised in said composition is in the range of 150 μπι to 300 μηι.
PCT/TR2012/000155 2011-11-23 2012-09-28 Homogeneous biguanide composition WO2013077821A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US20040175424A1 (en) * 2000-11-17 2004-09-09 Catherine Castan Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same
US20050163842A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Rosiglitazone and metformin formulations
EP1559419A1 (en) * 2004-01-23 2005-08-03 Fournier Laboratories Ireland Limited Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention
EP1738754A1 (en) * 2004-04-14 2007-01-03 Takeda Pharmaceutical Company Limited Solid pharmaceutical preparation
US20070020335A1 (en) * 2005-07-07 2007-01-25 Farnam Companies, Inc. Sustained release pharmaceutical compositions for highly water soluble drugs
WO2008101943A1 (en) * 2007-02-21 2008-08-28 Laboratori Guidotti S.P.A. Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
US20040175424A1 (en) * 2000-11-17 2004-09-09 Catherine Castan Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same
US20050163842A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Rosiglitazone and metformin formulations
EP1559419A1 (en) * 2004-01-23 2005-08-03 Fournier Laboratories Ireland Limited Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention
EP1738754A1 (en) * 2004-04-14 2007-01-03 Takeda Pharmaceutical Company Limited Solid pharmaceutical preparation
US20070020335A1 (en) * 2005-07-07 2007-01-25 Farnam Companies, Inc. Sustained release pharmaceutical compositions for highly water soluble drugs
WO2008101943A1 (en) * 2007-02-21 2008-08-28 Laboratori Guidotti S.P.A. Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation

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