WO1999026606A2 - SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS - Google Patents
SUSTAINED RELEASE FORMULATIONS COMPRISING α-GLUCOSIDASE-INHIBITORS Download PDFInfo
- 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
Links
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 title claims abstract description 14
- 239000003888 alpha glucosidase inhibitor Substances 0.000 title claims abstract description 14
- 238000013268 sustained release Methods 0.000 title claims abstract description 10
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 title abstract description 14
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims abstract description 11
- 229960002632 acarbose Drugs 0.000 claims abstract description 11
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims abstract description 11
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims abstract description 3
- 229950000269 emiglitate Drugs 0.000 claims abstract description 3
- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 claims abstract description 3
- 229960001110 miglitol Drugs 0.000 claims abstract description 3
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims abstract 2
- 229960001729 voglibose Drugs 0.000 claims abstract 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 239000011159 matrix material Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 230000002902 bimodal effect Effects 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000009472 formulation Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 12
- 229940057948 magnesium stearate Drugs 0.000 description 7
- 229940086293 acarbose 100 mg Drugs 0.000 description 5
- 206010016766 flatulence Diseases 0.000 description 5
- 206010012735 Diarrhoea Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- -1 Noglibose Chemical compound 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000000291 postprandial effect Effects 0.000 description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 102000016679 alpha-Glucosidases Human genes 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940078495 calcium phosphate dibasic Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
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.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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
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.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000521808A JP2001523704A (en) | 1997-11-25 | 1998-11-11 | Sustained release formulation comprising an α-glucosidase inhibitor |
| AU12343/99A AU1234399A (en) | 1997-11-25 | 1998-11-11 | Sustained release formulations comprising alpha-glucosidase-i nhibitors |
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
ID=22071124
Family Applications (1)
| 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)
| Country | Link |
|---|---|
| JP (1) | JP2001523704A (en) |
| AR (1) | AR017664A1 (en) |
| AU (1) | AU1234399A (en) |
| WO (1) | WO1999026606A2 (en) |
| ZA (1) | ZA9810710B (en) |
Cited By (11)
| 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 |
| EP4364743A3 (en) * | 2014-12-17 | 2024-08-28 | Empros Pharma AB | A modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3134591A1 (en) * | 1981-09-01 | 1983-03-10 | Bayer Ag, 5090 Leverkusen | NEW MEDICINE PREPARATIONS FOR GLYCOSIDE HYDROLASE INHIBITORS |
| EP0194794A3 (en) * | 1985-03-08 | 1986-12-17 | Takeda Chemical Industries, Ltd. | Saccharide digestion inhibiting composition |
| DE68905424T2 (en) * | 1988-08-22 | 1993-06-24 | Takeda Chemical Industries Ltd | ALPHA GLUCOSIDASE INHIBITOR FOR PROMOTING CALCIUM ABSORPTION. |
| TW272942B (en) * | 1993-02-10 | 1996-03-21 | Takeda Pharm Industry Co Ltd |
-
1998
- 1998-11-11 JP JP2000521808A patent/JP2001523704A/en active Pending
- 1998-11-11 WO PCT/EP1998/007198 patent/WO1999026606A2/en not_active Application Discontinuation
- 1998-11-11 AU AU12343/99A patent/AU1234399A/en not_active Abandoned
- 1998-11-24 AR ARP980105946A patent/AR017664A1/en unknown
- 1998-11-24 ZA ZA9810710A patent/ZA9810710B/en unknown
Cited By (11)
| 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 |
| EP4364743A3 (en) * | 2014-12-17 | 2024-08-28 | Empros Pharma AB | A modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders |
| 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 |
|---|---|
| WO1999026606A3 (en) | 1999-08-12 |
| JP2001523704A (en) | 2001-11-27 |
| AU1234399A (en) | 1999-06-15 |
| ZA9810710B (en) | 1999-06-14 |
| AR017664A1 (en) | 2001-09-12 |
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