WO2013077820A1 - Treatment package composed of dosage forms comprising nateglinide -metformin hydrochloride - Google Patents

Treatment package composed of dosage forms comprising nateglinide -metformin hydrochloride Download PDF

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Publication number
WO2013077820A1
WO2013077820A1 PCT/TR2012/000151 TR2012000151W WO2013077820A1 WO 2013077820 A1 WO2013077820 A1 WO 2013077820A1 TR 2012000151 W TR2012000151 W TR 2012000151W WO 2013077820 A1 WO2013077820 A1 WO 2013077820A1
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range
metformin
tablet
nateglinide
combination
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PCT/TR2012/000151
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2013077820A1 publication Critical patent/WO2013077820A1/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
    • A61K31/155—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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • the present invention relates to a treatment package which is composed of dosage forms comprising Nateglinide-Metformin Hydrochloride.
  • Nateglinide is a low water-soluble active agent. Therefore, dispersion of the formulations comprising said active agent in body takes long periods of time.
  • nateglinide should be effective shortly after taken in order to reduce blood sugar level quickly which increases especially after meal. In this respect, the formulations comprising nateglinide should dissolve in a short time.
  • nateglinide is structurally an amino acid derivative. Reacting with some excipients and solvents which are used basically in pharmaceutical technology, such molecules lead to formation of various degradation products. As a result, active agent amount in the formulation decreases due to degradation and this negatively affects efficiency of the treatment.
  • the excipients used in preparation of the formulations comprising metformin react with nateglinid having amino acid structure, for instance, maillard reaction etc., and they cause degradation of nateglinide.
  • undesired by-products are formed in unit formulation and active agent amount in the formulation is decreased. This causes negative results such as decrease in quality of the end product and increase in amount of the impurities. Furthermore, this is an undesired situation since efficiency of the treatment performed with the obtained product decreases.
  • One of the alternatives that can be used in order to solve the said problems can be to produce nateglinide and metformin formulations in bilayer tablet form.
  • this requires extra equipment and material, increases production cost and lengthens the production period.
  • a separation layer is placed between the layers in order to separate the layers and this increases complexity of the production process and therefore increases cost of the process.
  • the present invention relates to pharmaceutical combinations obtained by formulating metformin and nateglinide separately and storing them in different dosage forms.
  • the formulation comprising nateglinide can be in various dosage forms suitable for oral use, for instance, in any of the forms of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, pellet, dry powder for suspension preparation, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet.
  • the formulation comprising nateglinide is preferably in the form of tablet or film coated tablet, more preferably in film coated tablet form.
  • the formulation can optionally be coated with film coating agents for instance, sugar based coating agents, water soluble film coating agents, enteric coating agents or modified release coating agents.
  • film coating agents for instance, sugar based coating agents, water soluble film coating agents, enteric coating agents or modified release coating agents.
  • saccharose can be used singly or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum Arabic, polyvinylpyrrolidone and pullulan or any combination thereof.
  • 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 copolimer L, methacrylic acid copolimer LD and methacrylic acid copolimer 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, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
  • the formulation comprising nateglinide comprises at least one excipient along with the active agent.
  • the excipient can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
  • the binder that can be used in nateglinide combination of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch.
  • the lubricant that can be used in nateglinid combination of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
  • the diluent that can be used in nateglinid combination of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
  • the flavouring agent that can be used in nateglinide combination of the present invention can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • the glidant that can be used in nateglinide combination of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the effervescent acid that can be used in nateglinide combination of the present invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid.
  • the effervescent base that can be used in nateglinide combination of the present invention can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the disintegrant that can be used in nateglinid combination of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • Nateglinide formulations of the present invention comprises nateglinide in the range of 5-35%, preferably in the range of 10-30%, more preferably in the range of 15-30% in proportion to total weight of unit dose amount.
  • Nateglinide comprised in the formulation of the present invention can be in form of salt, ester, hydrates, solvates or free form structurally; in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure.
  • the formulation comprising nateglinide can comprise diluent in the range of 35-70%, disintegrant in the range of 10-20%, binder in the range of 1-5%, lubricant in the range of 0.1-5%, effervescent acid in the range of 0-60%, effervescent base in the range of 0-60%, glidant in the range of 0-20%, flavour in the range of 0-10% in proportion to total weight of the unit dose.
  • the formulations comprising nateglinid can be prepared by any methods of dry granulation, wet granulation, drying, sieving, blending or by using at least two of them consecutively, in any sequence.
  • the formulation comprising metformin can be in any of orally applicable dosage forms, for instance in the form of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, pellet, dry powder to form suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet.
  • the formulation comprising metformin is preferably in the form of tablet or effervescent tablet, more preferably in the form of effervescent tablet.
  • the formulation comprising metformin comprises at least one excipient along with the active agent.
  • the excipient can be selected from a group comprising diluent, disintegrant, binder, sweetener, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
  • the disintegrant that can be used in metformin combination of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • the diluent that can be used in metformin combination of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
  • the binder that can be used in metformin combination of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch.
  • the effervescent acid that can be used in metformin combination of the present invention can be selected from a group which is composed of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid.
  • the effervescent base that can be used in metformin combination of the present invention can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the flavouring agent that can be used in metformin combination of the present invention can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • the giidant that can be used in metformin combination of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the lubricant that can be used in metformin combination of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
  • the sweetener that can be used in metformin combination of the present invention can be selected from a group comprising acesulfame, alitame, aspartame, glucose, lactitol, maltitol, saccharin sodium, sucrose, xylitol, cyclamate, dextrose, fructose, maltose, mannitol, sorbitol, saccharin, sucralose.
  • Metformin formulations of the present invention comprise metformin in the range of 10-50%, preferably in the range of 20-40%, more preferably in the range of 25-35% in proportion to total weight of unit dosage amount.
  • Metformin can be in form of salt, ester, hydrate, solvate of free base form structurally; it can be in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure.
  • metformin is in metformin hydrochloride salt form.
  • the formulation comprising metformin can comprise effervescent acid in the range of 30-50%, effervescent base in the range of 10-40%, binder in the range of 1-5%, lubricant in the range of 0.1- 5%, sweetener in the range of 0.1-2%, flavour in the range of 0.1-3%, giidant in the range of 0-20%, diluent in the range of 0-50%, disintegrant in the range of 0-20% in proportion to total weight of unit dosage amount.
  • the formulation comprising metformin comprises metformin in the range of 100 mg to 2000 mg, preferably in the range of 500 mg to 1000 mg or its salt, for instance, metformin hydrochloride in an equivalent amount.
  • the formulations comprising metformin can be produced by any of dry granulation, wet granulation, drying, sieving, blending, tablet compression methods or by using at least two of these methods consecutively, in any sequence.
  • formulations comprising metformin and nateglinide prepared according to the present invention can be administered to patients as two different dosage forms in a single dosage form, for instance as combined in a capsule or in a similar dosage form though they can also be administered in treatment package form after packed separately.
  • the inventors have observed that the most appropriate dosage form for nateglinide formulation is film coated tablet considering that film coated tablet presents more ideal dissolution profile and the active agent shows efficiency in a shorter time.
  • the present invention relates to combinations comprising nateglinide formulation in film coated tablet dosage form and metformin formulation in effervescent tablet dosage form.
  • the mixture which is composed of nateglinide and the diluent is granulated. After the obtained granules are dried, they are mixed with the other excipients and compressed in tablet form and coated with the coating agent. Metformin and the excipients are mixed; the mixture takes its final shape after the flavouring agent and the sweetener are added into the final mixture. The mixture obtained is compressed in effervescent tablet form.
  • the combination of the present invention is indicated for treatment of type 2 (non insulin dependent) diabetes mellitus cases wherein hyperglycaemia cannot be controlled with diet and exercise.

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Abstract

The present invention relates to a treatment package which is composed of dosage forms comprising Nateglinide-Metformin Hydrochloride.

Description

TREATMENT PACKAGE COMPOSED OF DOSAGE FORMS
COMPRISING NATEGLINIDE -METFORMIN HYDROCHLORIDE
The present invention relates to a treatment package which is composed of dosage forms comprising Nateglinide-Metformin Hydrochloride. Nateglinide is a low water-soluble active agent. Therefore, dispersion of the formulations comprising said active agent in body takes long periods of time. However, nateglinide should be effective shortly after taken in order to reduce blood sugar level quickly which increases especially after meal. In this respect, the formulations comprising nateglinide should dissolve in a short time.
In other aspect, nateglinide is structurally an amino acid derivative. Reacting with some excipients and solvents which are used basically in pharmaceutical technology, such molecules lead to formation of various degradation products. As a result, active agent amount in the formulation decreases due to degradation and this negatively affects efficiency of the treatment.
Furthermore, the excipients used in preparation of the formulations comprising metformin react with nateglinid having amino acid structure, for instance, maillard reaction etc., and they cause degradation of nateglinide. In this case, undesired by-products are formed in unit formulation and active agent amount in the formulation is decreased. This causes negative results such as decrease in quality of the end product and increase in amount of the impurities. Furthermore, this is an undesired situation since efficiency of the treatment performed with the obtained product decreases.
One of the alternatives that can be used in order to solve the said problems can be to produce nateglinide and metformin formulations in bilayer tablet form. However, this requires extra equipment and material, increases production cost and lengthens the production period. Most of the time, a separation layer is placed between the layers in order to separate the layers and this increases complexity of the production process and therefore increases cost of the process.
In the studies they conducted in order to solve the said problem, the inventors have seen that the best successful result in regard to production cost and solving the technical problem required to be solved is to formulate the two active agents separately and storing them in different dosage forms.
According to this, the present invention relates to pharmaceutical combinations obtained by formulating metformin and nateglinide separately and storing them in different dosage forms.
The formulation comprising nateglinide can be in various dosage forms suitable for oral use, for instance, in any of the forms of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, pellet, dry powder for suspension preparation, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet. The formulation comprising nateglinide is preferably in the form of tablet or film coated tablet, more preferably in film coated tablet form.
In the case that the obtained formulation is compressed in tablet form, the formulation can optionally be coated with film coating agents for instance, sugar based coating agents, water soluble film coating agents, enteric coating agents or modified release coating agents.
As the sugar based coating agent, saccharose can be used singly or optionally together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum Arabic, polyvinylpyrrolidone and pullulan or any combination thereof. 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 copolimer L, methacrylic acid copolimer LD and methacrylic acid copolimer 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, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
The formulation comprising nateglinide comprises at least one excipient along with the active agent. The excipient can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
The binder that can be used in nateglinide combination of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch. The lubricant that can be used in nateglinid combination of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
The diluent that can be used in nateglinid combination of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
The flavouring agent that can be used in nateglinide combination of the present invention can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The glidant that can be used in nateglinide combination of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
The effervescent acid that can be used in nateglinide combination of the present invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid.
The effervescent base that can be used in nateglinide combination of the present invention can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. The disintegrant that can be used in nateglinid combination of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
Nateglinide formulations of the present invention comprises nateglinide in the range of 5-35%, preferably in the range of 10-30%, more preferably in the range of 15-30% in proportion to total weight of unit dose amount.
Nateglinide comprised in the formulation of the present invention can be in form of salt, ester, hydrates, solvates or free form structurally; in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure. The formulation comprising nateglinide can comprise diluent in the range of 35-70%, disintegrant in the range of 10-20%, binder in the range of 1-5%, lubricant in the range of 0.1-5%, effervescent acid in the range of 0-60%, effervescent base in the range of 0-60%, glidant in the range of 0-20%, flavour in the range of 0-10% in proportion to total weight of the unit dose. The formulations comprising nateglinid can be prepared by any methods of dry granulation, wet granulation, drying, sieving, blending or by using at least two of them consecutively, in any sequence.
The formulation comprising metformin can be in any of orally applicable dosage forms, for instance in the form of tablet, film tablet, prolonged release tablet, modified release tablet, capsule, pellet, dry powder to form suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet.
The formulation comprising metformin is preferably in the form of tablet or effervescent tablet, more preferably in the form of effervescent tablet.
The formulation comprising metformin comprises at least one excipient along with the active agent. The excipient can be selected from a group comprising diluent, disintegrant, binder, sweetener, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
The disintegrant that can be used in metformin combination of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate. The diluent that can be used in metformin combination of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol. The binder that can be used in metformin combination of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch.
The effervescent acid that can be used in metformin combination of the present invention can be selected from a group which is composed of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid. The effervescent base that can be used in metformin combination of the present invention can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
The flavouring agent that can be used in metformin combination of the present invention can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The giidant that can be used in metformin combination of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
The lubricant that can be used in metformin combination of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
The sweetener that can be used in metformin combination of the present invention can be selected from a group comprising acesulfame, alitame, aspartame, glucose, lactitol, maltitol, saccharin sodium, sucrose, xylitol, cyclamate, dextrose, fructose, maltose, mannitol, sorbitol, saccharin, sucralose. Metformin formulations of the present invention comprise metformin in the range of 10-50%, preferably in the range of 20-40%, more preferably in the range of 25-35% in proportion to total weight of unit dosage amount.
Metformin can be in form of salt, ester, hydrate, solvate of free base form structurally; it can be in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure. Preferably, metformin is in metformin hydrochloride salt form.
The formulation comprising metformin can comprise effervescent acid in the range of 30-50%, effervescent base in the range of 10-40%, binder in the range of 1-5%, lubricant in the range of 0.1- 5%, sweetener in the range of 0.1-2%, flavour in the range of 0.1-3%, giidant in the range of 0-20%, diluent in the range of 0-50%, disintegrant in the range of 0-20% in proportion to total weight of unit dosage amount.
The formulation comprising metformin comprises metformin in the range of 100 mg to 2000 mg, preferably in the range of 500 mg to 1000 mg or its salt, for instance, metformin hydrochloride in an equivalent amount. The formulations comprising metformin can be produced by any of dry granulation, wet granulation, drying, sieving, blending, tablet compression methods or by using at least two of these methods consecutively, in any sequence.
The formulations comprising metformin and nateglinide prepared according to the present invention can be administered to patients as two different dosage forms in a single dosage form, for instance as combined in a capsule or in a similar dosage form though they can also be administered in treatment package form after packed separately.
In the studies they conducted, the inventors have observed that the most appropriate dosage form for nateglinide formulation is film coated tablet considering that film coated tablet presents more ideal dissolution profile and the active agent shows efficiency in a shorter time. In another study conducted, on the other hand, it has been observed that swallowing difficulties encountered related to use of too much active agent are removed by administering metformin formulations in effervescent tablet dosage form.
In another aspect, the present invention relates to combinations comprising nateglinide formulation in film coated tablet dosage form and metformin formulation in effervescent tablet dosage form.
EXAMPLE: Formulation and Process for Preparation of Treatment Package Comprising Nateglinide and Metformin
Figure imgf000007_0001
The mixture which is composed of nateglinide and the diluent is granulated. After the obtained granules are dried, they are mixed with the other excipients and compressed in tablet form and coated with the coating agent. Metformin and the excipients are mixed; the mixture takes its final shape after the flavouring agent and the sweetener are added into the final mixture. The mixture obtained is compressed in effervescent tablet form.
The combination of the present invention is indicated for treatment of type 2 (non insulin dependent) diabetes mellitus cases wherein hyperglycaemia cannot be controlled with diet and exercise.

Claims

1. A combination comprising metformin and nateglinide, characterized in that said combination is obtained by formulating metformin and nateglinide separately and storing them in different dosage forms.
2. The combination according to claim 1 , characterized in that the formulation comprising nateglinide is in any of orally applicable dosage forms, for instance in the form of tablet, film coated tablet, pellet, prolonged release tablet, modified release tablet, capsule, dry powder to form suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet.
3. The combination according to claims 1 and 2, characterized in that the formulation comprising nateglinide is in film coated tablet form.
4. The combination according to claims 1-3, characterized in that nateglinide is in the form of salt, ester, hydrates, solvates or free form structurally; in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure.
5. The combination according to claims 1-4, characterized in that the formulation comprising metformin is in any of orally applicable dosage forms, for instance in the form of tablet, film coated tablet, prolonged release tablet, modified release tablet, capsule, pellet, dry powder to form suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet, microcapsule, micropellet, microtablet.
6. The combination according to claims 1-5, characterized in that the formulation comprising metformin is in effervescent tablet form.
7. The combination according to claims 1-6, characterized in that metformin is in form of salt, ester, hydrates, solvates or free form structurally; in crystalline or amorphous form and/or a combination thereof in terms of polymorphic structure.
8. The combination according to claims 1-7, characterized in that metformin is in hydrochloride salt form.
9. The combination according to claims 1-8, characterized in that said combination comprises nateglinide in the range of 15-30% in proportion to total weight of unit dosage amount.
10. The combination according to claims 1-9, characterized in that said combination comprises metformin in the range of 25-35% in proportion to total weight of unit dosage amount.
1 1. The combination according to claims 1-10, characterized in that said combination comprises at least one pharmaceutically acceptable excipient in addition to the active agents during formulation of metformin and nateglinide separately.
12. The combination according to claims 1-11, characterized in that the pharmaceutically acceptable excipients that shall be used in the formulations in addition to the active agents during formulating metformin and nateglinide separately are selected from a group comprising diluent, disintegrant, binder, sweetener, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
13. The combination according to claims 1-12, characterized in that the formulation comprising nateglinide comprises diluent in the range of 35 -70%, disintegrant in the range of 10-20%, binder in the range of 1-5%, lubricant in the range of 0.1-5%, effervescent acid in the range of 0-60%, effervescent base in the range of 0-60%, glidant in the range of 0-20%, flavour in the range of 0- 10% in proportion to total weight of unit dosage amount.
14. The combination according to claims I and 13, characterized in that the formulation comprising metformin comprises effervescent acid in the range of 30-50%, effervescent base in the range of 10-40%), binder in the range of 1-5%, lubricant in the range of 0.1-5%, sweetener in the range of 0.1-2%, flavour in the range of 0.1-3%, glidant in the range of 0-20%, diluent in the range of 0- 50%, disintegrant in the range of 0-20% in proportion to total weight of unit dosage amount.
15. The combination according to claims 1-14, characterized in that metformin and nateglinidine are formulated separately and said combination comprises nateglinide formulation in film coated tablet dosage form and metformin formulation in effervescent tablet dosage form.
16. The combination comprising nateglinide and metformin according to any preceding claims, characterized in that said combination is used in production of a drug that shall be used in treatment of type 2 (non insulin dependent) diabetes mellitus cases wherein hyperglycaemia cannot be controlled with diet and exercise.
PCT/TR2012/000151 2011-11-23 2012-09-24 Treatment package composed of dosage forms comprising nateglinide -metformin hydrochloride WO2013077820A1 (en)

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TR2011/11590 2011-11-23

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021159A2 (en) * 1999-09-17 2001-03-29 Novartis Ag Pharmaceutical composition of nateglinide and another antidiabetcagent
US20030224046A1 (en) * 2002-06-03 2003-12-04 Vinay Rao Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent
WO2007038979A1 (en) * 2005-09-22 2007-04-12 Swissco Development Ag Effervescent metformin composition and tablets and granules made therefrom
WO2007056387A2 (en) * 2005-11-07 2007-05-18 Elixir Pharmaceuticals, Inc. Combinations of metformin and meglitinide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021159A2 (en) * 1999-09-17 2001-03-29 Novartis Ag Pharmaceutical composition of nateglinide and another antidiabetcagent
US20030224046A1 (en) * 2002-06-03 2003-12-04 Vinay Rao Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent
WO2007038979A1 (en) * 2005-09-22 2007-04-12 Swissco Development Ag Effervescent metformin composition and tablets and granules made therefrom
WO2007056387A2 (en) * 2005-11-07 2007-05-18 Elixir Pharmaceuticals, Inc. Combinations of metformin and meglitinide

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