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WO2013066278A1 - Procédé de fabrication de formulations pharmaceutiques comprenant du natéglinide - Google Patents

Procédé de fabrication de formulations pharmaceutiques comprenant du natéglinide Download PDF

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Publication number
WO2013066278A1
WO2013066278A1 PCT/TR2012/000154 TR2012000154W WO2013066278A1 WO 2013066278 A1 WO2013066278 A1 WO 2013066278A1 TR 2012000154 W TR2012000154 W TR 2012000154W WO 2013066278 A1 WO2013066278 A1 WO 2013066278A1
Authority
WO
WIPO (PCT)
Prior art keywords
nateglinide
group
binder
formulation
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/TR2012/000154
Other languages
English (en)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2013066278A1 publication Critical patent/WO2013066278A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to granulation of a mixture comprising nateglinide and at least one excipient with a granulation solution comprising binder in the range of 1-5% in a method used for production of pharmaceutical formulations comprising nateglinide.
  • Nateglinide is a low water-soluble active agent. Therefore the dispersion of the formulations comprising this active agent in the body takes a long time.
  • nateglinide should act within a short time after intake in order to quickly decrease blood sugar level which particularly increases after meals. Thus the formulations comprising nateglinide should disperse within a short time.
  • nateglinide is structurally an amino acid derivative. This kind of molecules may cause various degradation products by reacting with some excipients or solvents used basically in pharmaceutical technology. As a result, the amount of active agent in the formulation decreases and thus the efficiency of treatment is affected negatively.
  • the inventors have observed that the process used in preparation of the formulations comprising nateglinide considerably affects the quality of final product. Surprisingly, the inventors have observed that when the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient is granulated with a granulation solution comprising a binder agent in the range of 1-5% by weight, the nateglinide formulations obtained disperse within a short time, for example in less than 10 minutes, and no degradation product occurs.
  • the inventors confirmed that the phase of the process in which the substance used as binder is added plays a deterministic role in dissolution profile and stability of the final product.
  • the inventors have ascertained that the formulations obtained through the method of granulating the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient with a granulation solution comprising binder in the range of 1-5% by weight have the desired dissolution and stability properties.
  • the present invention relates to granulating the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient with a granulation solution comprising binder in the range of 1-5% by weight.
  • binder is preferably used in the range of 2-4%.
  • Binders that can be used in the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch.
  • the inventors have tried various binders in the preparation of nateglinide formulations. As a result of the studies conducted, it has been observed that polymeric binders produce more successful results. Especially synthetic polymer binders have had much more successful results.
  • the process is one in which the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient is granulated with a granulation solution comprising a water-soluble synthetic polymer binder in the range of 1-5%, preferably in the range of 2-4% by weight.
  • the process is one in which the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient is granulated with a granulation solution comprising polyvinylpyrrolidone in the range of 1-5%, preferably in the range of 2-4% by weight.
  • the production method of the invention comprises these steps: I. Granulating the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient with a granulation solution comprising binder in the range of 1-5% by weight II. Drying the obtained granules
  • the pharmaceutically acceptable excipient to be used in steps I and IV can be selected from a group comprising diluent, disintegrant, binder, lubricant, flavoring agent, effervescent acid, effervescent base, glidant.
  • step II the obtained granules are dried such that their moisture content is preferably in the range of 1-3%. It was observed that more stable formulations are obtained this way.
  • step III the obtained granules are sieved through sieves mesh sizes of which are between 15-35 ⁇ , preferably between 20-30 ⁇ . This was observed to have a positive effect on improving the dissolution profile.
  • the production method of the present invention comprises the steps: I. Granulating the mixture comprising nateglinide and at least one pharmaceutically acceptable excipient with an aqueous granulation solution comprising polyvinylpyrrolidone in the range of 1-5%
  • the formulations prepared according to the invention are in various forms appropriate for oral intake, for example in any of tablet, film tablet, extended-release tablet, modified-release tablet, capsule, dry powder to be prepared as suspension, effervescent tablet, orodispersible tablet, chewable tablet, sachet forms.
  • the formulations of the invention are preferably in the form of tablet, more preferably film- coated tablet.
  • the formulation obtained is compressed in the form of tablet, it can be optionally coated with film-coating agents such as sugar-based coating agents, water-soluble film-coating agents, enteric coating or modified-release coating agents.
  • film-coating agents such as sugar-based coating agents, water-soluble film-coating agents, enteric coating or modified-release coating agents.
  • saccharose can be used on its own or optionally with any of the agents such as talc, calcium, carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof.
  • agents such as talc, calcium, carbonate, calcium phosphate, calcium sulphate, gelatin, 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.
  • 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
  • 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 phtalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances like shellac or combinations thereof.
  • cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phtalate
  • acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S
  • natural substances like shellac or combinations thereof.
  • 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 present invention relates to formulations comprising nateglinide which are prepared through the production method of the present invention.
  • Said nateglinide formulations comprise at least one pharmaceutically acceptable excipient in addition to nateglinide.
  • the pharmaceutically acceptable excipient (at least one) that can be used in said nateglinide formulations can be selected from a group comprising disintegrant, binder, lubricant, flavoring agent, diluent, effervescent acid, effervescent base, glidant.
  • the binder can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyvinylpyrrolidone, starch.
  • the lubricant can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talc, stearic acid, zinc stearate.
  • the diluent 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 flavoring agent can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel etc.
  • the glidant can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the effervescent acid can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid.
  • the effervescent base can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
  • the disintegrant can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • the formulations of the invention comprise nateglinide in the range of 5-35%, preferably in the range of 10-30%, more preferably in the range of 15-30% by weight in proportion to the total weight of unit dosage amount.
  • Nateglinide in the formulations of the invention can be in crystalline or amorphous form and/or in the form of its hydrates, solvates or combinations thereof.
  • compositions comprising nateglinide according to the present invention can comprise a second active agent.
  • Said second active agent can be selected from a group comprising meglitinides, alpha-glucosidase inhibitors, sulphonylurea, tiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
  • said second active agent can be selected from a group comprising repaglinide from the group meglitinide; alphaglucosidase inhibitor acarbose; acetohexamide, glindeclamide, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide from the group sulfonylurea; pioglitazone, rosiglitazone, rivoglitazone maleate, pioglitazone hydrochloride, troglitazone from the group tiazolidinedione; phenformin, metformin, metformin hydrochloride from the group biguanide; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagliptin hydrochloride, sitagliptin phosphate, sitagliptin
  • the second active agent can optionally be used in the same formulation as nateglinide formulations, it can also be used in a different formulation and then combined with the nateglinide formulation according to the invention.
  • Said formulations can be in one dosage form or in the form of treatment packages in different dosage forms.
  • the mixture comprising nateglinide and at least one excipient is granulated with an aqueous granulation solution comprising polyvinylpyrrolidone and the obtained granules are dried.
  • the dried granules are sieved and the sieved granules are mixed with at least one pharmaceutically acceptable excipient.
  • the formulations prepared according to the invention can be in various dosage forms appropriate for oral intake.
  • EXAMPLE 2 The Formulation and Process for Preparation of the Treatment Package Comprising Nateglinide and Metformin
  • the mixture comprising nateglinide and diluent is granulated with the granulation solution comprising polyvinylpyrrolidone.
  • the obtained granules are mixed with the other excipients after being dried and they are compressed into tablet form and coated with a coating agent.
  • Metformin and the excipients are mixed and after adding flavoring agent and sweetener into the final mixture, the mixture is brought into its final form.
  • the mixture obtained is filled into sachets.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne la granulation d'un mélange comprenant du natéglinide et au moins un excipient avec une solution de granulation comprenant un liant dans la plage de 1-5 % dans un procédé utilisé pour la fabrication de formulations pharmaceutiques comprenant du natéglinide.
PCT/TR2012/000154 2011-11-03 2012-09-28 Procédé de fabrication de formulations pharmaceutiques comprenant du natéglinide Ceased WO2013066278A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR201110979 2011-11-03
TR2011/10979 2011-11-03
TR201111959 2011-12-02
TR2011/11959 2011-12-02

Publications (1)

Publication Number Publication Date
WO2013066278A1 true WO2013066278A1 (fr) 2013-05-10

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ID=47297384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2012/000154 Ceased WO2013066278A1 (fr) 2011-11-03 2012-09-28 Procédé de fabrication de formulations pharmaceutiques comprenant du natéglinide

Country Status (1)

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WO (1) WO2013066278A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334721A1 (fr) * 2000-10-24 2003-08-13 Ajinomoto Co., Inc. Preparations de medicament contenant du nateglinide
WO2005020979A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Procede de preparation de compositions pharmaceutiques a base de nateglinide
US20060127475A1 (en) * 2003-08-08 2006-06-15 Ajinomoto Co., Inc. Nateglinide-containing preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334721A1 (fr) * 2000-10-24 2003-08-13 Ajinomoto Co., Inc. Preparations de medicament contenant du nateglinide
US20060127475A1 (en) * 2003-08-08 2006-06-15 Ajinomoto Co., Inc. Nateglinide-containing preparation
WO2005020979A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Procede de preparation de compositions pharmaceutiques a base de nateglinide

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