WO1999026606A2 - SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS - Google Patents

SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS Download PDF

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Publication number
WO1999026606A2
WO1999026606A2 PCT/EP1998/007198 EP9807198W WO9926606A2 WO 1999026606 A2 WO1999026606 A2 WO 1999026606A2 EP 9807198 W EP9807198 W EP 9807198W WO 9926606 A2 WO9926606 A2 WO 9926606A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
acarbose
sustained release
formulation according
inhibitors
Prior art date
Application number
PCT/EP1998/007198
Other languages
French (fr)
Other versions
WO1999026606A3 (en
Inventor
David Goldman
John Amatruda
Carola PÖRTNER
Erich Brendel
Patrick Bosche
Original Assignee
Bayer Aktiengesellschaft
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 Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU12343/99A priority Critical patent/AU1234399A/en
Priority to JP2000521808A priority patent/JP2001523704A/en
Publication of WO1999026606A2 publication Critical patent/WO1999026606A2/en
Publication of WO1999026606A3 publication Critical patent/WO1999026606A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Acarbose is the first compound on the market of a new class of oral antidiabetic drugs, the alpha-glucosidase inhibitors. After oral administration, it competitively inhibits alpha-glucosidases, which are located in the brush-border membrane of the small intestine. As a consequence, the digestion of disaccharides, oligosaccharides and polysaccharides to monosaccharides is retarded, which delays the postprandial absorption of glucose. Thus, excessive postprandial rises of blood glucose as observed in inadequately treated diabetes patients are reduced and 24-hour blood glucose profiles smoothed.
  • oral administration of an alpha-glucosidase inhibitor may result in a greater portion of dietary carbohydrates reaching the colon undigested. These carbohydrates may then be fermented by the intestinal flora resulting in an increased formation of intestinal gas, which may cause gastrointestinal adverse events such as meteorism, flatulence or diarrhoea.
  • acarbose approximately 50% and 15% of the patients report flatulence and diarrhoea, respectively, compared to 18% and 5%, respectively, after treatment with placebo.
  • the present invention relates to a new better tolerable formulation principle for alpha-glucosidase inhibitors based on sustained release characteristics.
  • the invention relates to new pharmaceutical dosage forms of alpha glucosidase inhibitors (formulations and manufacturing processes).
  • the formulations are distinguished by a delayed release of the active drug.
  • Alpha glucosidase inhibitors can be used for example for the treatment of diabetes mellitus prevention of diabetes and treatment of atheriosclerosis or obesity.
  • Examples for this class of drug substances are Acarbose, Noglibose, Miglitol and Emiglitate possibly in combination with other pharmaceuticals as for example sulphonyl urea (glibenelamid, tolbutamid, glimeperide) or with an insulin sensitizer (graglitazone, prioglitazone) or a biguanide (methformin).
  • compositions with a sustained release of alpha glucosidase inhibitors can be formulated based on different galenic principles and therefore comprising different excipients.
  • matrix building agents can be used Hydroxypropyl Methylcellulose, Hydroxy- ethyl Cellulose, Hydroxypropyl Cellulose, Methylcellulose, Xanthan Gum, Chitosan, Alginic Acid Sodium Salt or Carboxymethylcellulose Sodium e.g 2.
  • Lipophilic matrix systems :
  • matrix building agents can be used different kinds of wax, glycerides or polymers (Ethylcellulose, Polyvinyl Chloride, Methacrylic Acid Copolymers and the esters thereof e.g.).
  • Swelling excipients that can be used are Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose or Methylcellulose. CO 2 forming additives like Sodium Carbonate can be used.
  • the drug substance can be released from the dosage form within a time period of 30 minutes up to 4 hours in a linear or non linear manner.
  • sustained release formulations show a dissolution of 80% of the drug substance within a time period longer than 30 minutes (dissolution method: USP basket method, 100 rpm, water).
  • formulations can be manufactured as tablets, capsules, pellets, powders or liquids.
  • Suitable manufacturing methods are direct compression, compression following a granulation step, formation of pellets using extrusion/spheronization or generated by a fluidized bed process (Wurster process e.g.).
  • the tablets can be compressed as monolayer tablets, bilayer tablets or coat core tablets.

Abstract

The present invention relates to pharmaceutical sustained release formulations of α-glucosidase inhibitors as for example acarbose, miglitol, emiglitate or voglibose leading to a reduction of side effects.

Description

Sustained Release Formulations comprising α-Glucosidase-Inhibitors
Acarbose is the first compound on the market of a new class of oral antidiabetic drugs, the alpha-glucosidase inhibitors. After oral administration, it competitively inhibits alpha-glucosidases, which are located in the brush-border membrane of the small intestine. As a consequence, the digestion of disaccharides, oligosaccharides and polysaccharides to monosaccharides is retarded, which delays the postprandial absorption of glucose. Thus, excessive postprandial rises of blood glucose as observed in inadequately treated diabetes patients are reduced and 24-hour blood glucose profiles smoothed.
Owing to its mode of action, oral administration of an alpha-glucosidase inhibitor may result in a greater portion of dietary carbohydrates reaching the colon undigested. These carbohydrates may then be fermented by the intestinal flora resulting in an increased formation of intestinal gas, which may cause gastrointestinal adverse events such as meteorism, flatulence or diarrhoea. During treatment with acarbose, approximately 50% and 15% of the patients report flatulence and diarrhoea, respectively, compared to 18% and 5%, respectively, after treatment with placebo.
The surprising result of a pilot study investigating the pharmacodynamic profile of acarbose after slightly sustained release in comparison to the standard formulation in healthy young volunteers, was a distinct reduction in gastrointestinal adverse events after administration of the new application form. While 33% of the subjects reported flatulence and 5% diarrhoea after treatment with the standard formulation compared to 14% and 5% after placebo, only 5% suffered from flatulence and 0% from diarrhoea after sustained release of acarbose which was surprising.
Thus, the present invention relates to a new better tolerable formulation principle for alpha-glucosidase inhibitors based on sustained release characteristics. In particular, the invention relates to new pharmaceutical dosage forms of alpha glucosidase inhibitors (formulations and manufacturing processes). The formulations are distinguished by a delayed release of the active drug.
Alpha glucosidase inhibitors can be used for example for the treatment of diabetes mellitus prevention of diabetes and treatment of atheriosclerosis or obesity. Examples for this class of drug substances are Acarbose, Noglibose, Miglitol and Emiglitate possibly in combination with other pharmaceuticals as for example sulphonyl urea (glibenelamid, tolbutamid, glimeperide) or with an insulin sensitizer (graglitazone, prioglitazone) or a biguanide (methformin).
Approaches to develop a sustained release formulation are described in „Modern Pharmaceutics, Banker, G.S., Rhodes, Ch.T., 3rd ed., Marcel Dekker, Inc., New York, 1996.
None of the there mentioned opportunities are used for the approved and marketed pharmaceutical formulations of the above mentioned class of drugs. All marketed formulations are immediate release tablets. Formulations exhibiting a delayed release of alpha glucosidase inhibitors are not known
Principle
Pharmaceutical preparations with a sustained release of alpha glucosidase inhibitors can be formulated based on different galenic principles and therefore comprising different excipients.
1 Hydrocolloidmatrix-systems:
As matrix building agents can be used Hydroxypropyl Methylcellulose, Hydroxy- ethyl Cellulose, Hydroxypropyl Cellulose, Methylcellulose, Xanthan Gum, Chitosan, Alginic Acid Sodium Salt or Carboxymethylcellulose Sodium e.g 2. Lipophilic matrix systems:
As matrix building agents can be used different kinds of wax, glycerides or polymers (Ethylcellulose, Polyvinyl Chloride, Methacrylic Acid Copolymers and the esters thereof e.g.).
3. Floating formulations (tablets or capsules):
Swelling excipients that can be used are Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose or Methylcellulose. CO2 forming additives like Sodium Carbonate can be used.
4. Liquid formulations containing dispersed alpha glucosidase inhibitors or pellets containing these drug substances
5. Combinations of alpha glucosidase inhibitors with food
6. Drug dissolution profile:
The drug substance can be released from the dosage form within a time period of 30 minutes up to 4 hours in a linear or non linear manner.
The described sustained release formulations show a dissolution of 80% of the drug substance within a time period longer than 30 minutes (dissolution method: USP basket method, 100 rpm, water).
Manufacturing processes:
The above mentioned formulations can be manufactured as tablets, capsules, pellets, powders or liquids.
Suitable manufacturing methods are direct compression, compression following a granulation step, formation of pellets using extrusion/spheronization or generated by a fluidized bed process (Wurster process e.g.). The tablets can be compressed as monolayer tablets, bilayer tablets or coat core tablets.
Examples
Example for a monolayertablet:
Acarbose 100 mg
Hydroxypropyl Cellulose-L 70 mg Calcium Phosphate dibasic 100 ms: Magnesium Stearate 1.35 mg
Example for a bilayer tablet with bimodal dissolution profile:
Layer 1: Acarbose 55 mg
Microcrystalline Cellulose 90 mg
Hydroxypropyl Methylcellulose 60SH50 30 mg
Magnesium Stearate 0.9 mg
Layer 2: Acarbose 45 mg
Microcrystalline Cellulose 42.5 mg
Croscarmellose Sodium 10 mg
Magnesium Stearate 0.5 mg
Example for a tablet with linear dissolution profile:
Acarbose 100 mg
Microcrystalline Cellulose 135 mg Hydroxypropyl Methylcellulose 60SH50 35 ms
Magnesium Stearate 1.35 mg Example for a tablet with a dissolution time > 120 minutes:
Acarbose 100 mg
Microcrystalline Cellulose 120 mg
Hydroxypropyl Methylcellulose 60SH50 50 mg
Magnesiumstearate 1.35 mg
Example for a tablet with a dissolution time > 60 minutes:
Acarbose 100 mg
Microcrystalline Cellulose 125 mg
Hydroxypropyl Methylcellulose 60SH50 45 mg
Magnesiumstearate 1.3 mg
Example for a small sized tablet with a dissolution time > 60 minutes:
Acarbose 100 mg
Hydroxypropyl Methylcellulose 60SH50 35 mg
Magnesiumstearate 0.7 mg

Claims

Claims
1. A pharmaceutical formulation of alpha glucosidase inhibitor having a sustained release.
2. The pharmaceutical formulation according to claim 1 wherein the alpha glucosidase inhibitor is selected from the group acarbose, miglitol, emiglitate and voglibose.
3. The pharmaceutical formulation according to claim 1 comprising matrix building agents.
4. The pharmaceutical formulation according to claim 3 whrein the matrix building agent is Hydroxypropyl Methylcellulose.
5. The pharmaceutical formulation according to claim 1 having a bimodal dissolution profile.
6. The pharmaceutical formulation according to claim 5 in form of a bilayer tablet comprising in
layer 1 : Acarbose
Microcrystalline Cellulose Hydroxypropyl Methylcellulose Magnesium Stearate
and layer 2: Acarbose
Microcrystalline Cellulose Croscarmellose Sodium
Magnesium Stearate.
7. A method of treatment or prevention of diabetes obesity or atheriosclerosis comprising administering the pharmaceutical formulation of claim 1 to a patient.
PCT/EP1998/007198 1997-11-25 1998-11-11 SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS WO1999026606A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU12343/99A AU1234399A (en) 1997-11-25 1998-11-11 Sustained release formulations comprising alpha-glucosidase-i nhibitors
JP2000521808A JP2001523704A (en) 1997-11-25 1998-11-11 Sustained release formulation comprising an α-glucosidase inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6669897P 1997-11-25 1997-11-25
US60/066,698 1997-11-25

Publications (2)

Publication Number Publication Date
WO1999026606A2 true WO1999026606A2 (en) 1999-06-03
WO1999026606A3 WO1999026606A3 (en) 1999-08-12

Family

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Application Number Title Priority Date Filing Date
PCT/EP1998/007198 WO1999026606A2 (en) 1997-11-25 1998-11-11 SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS

Country Status (5)

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JP (1) JP2001523704A (en)
AR (1) AR017664A1 (en)
AU (1) AU1234399A (en)
WO (1) WO1999026606A2 (en)
ZA (1) ZA9810710B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014932A1 (en) 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof
WO2005085267A1 (en) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Nitrogenous fused-ring derivatives, medicinal compositions containing the derivatives, and use thereof as drugs
AU785303B2 (en) * 2000-05-24 2007-01-04 Pfizer Inc. Treatment of rumen acidosis with a-amylase inhibitors
CN102631332A (en) * 2012-04-28 2012-08-15 邹立兴 Voglibose tablet and preparation method thereof
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
CN104013590A (en) * 2014-05-09 2014-09-03 万特制药(海南)有限公司 Acarbose-containing medicinal composition and preparation method thereof
US9144547B2 (en) 2002-02-12 2015-09-29 Glaxo Group Limited Oral dosage form for controlled drug release
WO2016001843A1 (en) * 2014-06-30 2016-01-07 Sun Pharmaceutical Industries Limited Extended-release gastroretentive tablets of voglibose
CN110898025A (en) * 2019-12-12 2020-03-24 湖北欣泽霏药业有限公司 Acarbose sustained-release preparation and preparation method thereof
CN111265489A (en) * 2020-03-10 2020-06-12 乐普制药科技有限公司 Divisible acarbose pellet sustained-release tablet

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073428A2 (en) * 1981-09-01 1983-03-09 Bayer Ag Medicinal preparations for glycoside-hydrolase inhibitors
EP0194794A2 (en) * 1985-03-08 1986-09-17 Takeda Chemical Industries, Ltd. Saccharide digestion inhibiting composition
EP0364696A2 (en) * 1988-08-22 1990-04-25 Takeda Chemical Industries, Ltd. Alpha-glucosidase inhibitor as a calcium absorption promotor
EP0610854A1 (en) * 1993-02-10 1994-08-17 Takeda Chemical Industries, Ltd. Tablets with improved abrasion resistance and method to produce them

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073428A2 (en) * 1981-09-01 1983-03-09 Bayer Ag Medicinal preparations for glycoside-hydrolase inhibitors
EP0194794A2 (en) * 1985-03-08 1986-09-17 Takeda Chemical Industries, Ltd. Saccharide digestion inhibiting composition
EP0364696A2 (en) * 1988-08-22 1990-04-25 Takeda Chemical Industries, Ltd. Alpha-glucosidase inhibitor as a calcium absorption promotor
EP0610854A1 (en) * 1993-02-10 1994-08-17 Takeda Chemical Industries, Ltd. Tablets with improved abrasion resistance and method to produce them

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU785303B2 (en) * 2000-05-24 2007-01-04 Pfizer Inc. Treatment of rumen acidosis with a-amylase inhibitors
US9144547B2 (en) 2002-02-12 2015-09-29 Glaxo Group Limited Oral dosage form for controlled drug release
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
WO2004014932A1 (en) 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof
WO2005085267A1 (en) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Nitrogenous fused-ring derivatives, medicinal compositions containing the derivatives, and use thereof as drugs
CN102631332A (en) * 2012-04-28 2012-08-15 邹立兴 Voglibose tablet and preparation method thereof
CN104013590A (en) * 2014-05-09 2014-09-03 万特制药(海南)有限公司 Acarbose-containing medicinal composition and preparation method thereof
WO2016001843A1 (en) * 2014-06-30 2016-01-07 Sun Pharmaceutical Industries Limited Extended-release gastroretentive tablets of voglibose
CN110898025A (en) * 2019-12-12 2020-03-24 湖北欣泽霏药业有限公司 Acarbose sustained-release preparation and preparation method thereof
CN111265489A (en) * 2020-03-10 2020-06-12 乐普制药科技有限公司 Divisible acarbose pellet sustained-release tablet

Also Published As

Publication number Publication date
ZA9810710B (en) 1999-06-14
WO1999026606A3 (en) 1999-08-12
AU1234399A (en) 1999-06-15
JP2001523704A (en) 2001-11-27
AR017664A1 (en) 2001-09-12

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