CN1805738A - Extended-release tablets of metformin - Google Patents
Extended-release tablets of metformin Download PDFInfo
- Publication number
- CN1805738A CN1805738A CNA2004800167682A CN200480016768A CN1805738A CN 1805738 A CN1805738 A CN 1805738A CN A2004800167682 A CNA2004800167682 A CN A2004800167682A CN 200480016768 A CN200480016768 A CN 200480016768A CN 1805738 A CN1805738 A CN 1805738A
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- CN
- China
- Prior art keywords
- tablet
- continuous release
- release tablet
- metformin
- cellulose
- 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.)
- Pending
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 229960003105 metformin Drugs 0.000 title claims abstract description 64
- 238000013265 extended release Methods 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
- 238000004220 aggregation Methods 0.000 claims description 25
- 230000002776 aggregation Effects 0.000 claims description 25
- -1 hydrobromate Chemical compound 0.000 claims description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 230000002045 lasting effect Effects 0.000 claims description 17
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 15
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- 239000008187 granular material Substances 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 12
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 9
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- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 229940127021 low-dose drug Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000010363 phase shift Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000004901 spalling Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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
- A61K9/20—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- Health & Medical Sciences (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)
- Epidemiology (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to extended-release unit dosage formulations of metformin or its pharmaceutically acceptable salt thereof and the process for their preparation.
Description
Technical field
The present invention relates to the lasting release of metformin (metformin) or its pharmaceutically acceptable salt unit dose formulations, and preparation method thereof.
Background technology
In recent years, the pharmaceutical dosage form that continues release (extended-release) receives a lot of concerns, wishes very much with its next pharmaceutical preparation that constant basis is provided to patient.The character of delivery system is subjected to the character of medicine and dosage, required release profile and the control of physiologic factor.For example, a kind of very challenging property of lasting delivery systme that is used for heavy dose, has the water soluble drug of narrow absorption distribution window (intestinal that is limited to stomach and/or top) of exploitation.
Because the dosed administration frequency reduces, sustained release forms has not only increased is obedient to, and has reduced the seriousness and the occurrence frequency of side effect, because the blood levels that they remain unchanged substantially and avoid the relevant fluctuation of quick releasing formulation with routine.
Metformin has been widely used in and has reduced (NIDDM) patient's blood glucose of noninsulin dependent diabetes (diabetes mellitus).Yet as a kind of short time drugs with function, metformin needs be administered twice every day or three times.A tangible advantage that continues the metformin dosage form of release is to reduce administration frequency.
Using relevant side effect with metformin often is that intestinal is relevant with stomach, for example anorexia, feel sick, vomit and the diarrhoea of chance etc.Can be by reducing initial and/or keeping (maintenance) dosage or use sustained release forms partly to avoid these side effect.
Metformin causes intestines and stomach top that it is absorbed in the inherent poor permeability in the bottom of intestines and stomach.It has very high dissolubility (under 25 ℃＞300 mg/ml) in water.These parameters cause the difficulty when preparation provides a kind of medicine of lasting release, also have and the relevant adjoint problem of initial spalling of control said preparation.By pharmaceutical pack being embedded in polymeric matrix (matrix) lining or coming coating medicine (medicine must diffuse through this film and be released absorption) to reduce the dissolution rate of this class high solubility agents with the polymer Obstruct membrane.
This method may be favourable to low-dose drugs because need a large amount of polymer, but for every day be disadvantageous with the medicine of the rank administration of hundreds of milligram.
Metformin has commercially available, and at present, the commodity of Bristol Mayers Squibb are called Glucophage (routine) and Glucophage XR (continuous release tablet).The conventional tablet of Glucophage contains the Metformin of 500 milligrams, 800 milligrams and 1000 milligrams.Glucophage XR tablet (500 milligrams Metformin, sustained releasing type) contains two kinds of United States Patent (USP)s 6,457, dual hydrophilic matrix system described in 521, above-mentioned patent relate to the preparation method of the biphase controlled release delivery systme that is used to discharge metformin.This patent has been described the two-phase system that comprises solid particles inside phase and outer solid continuous phase, and described solid particles inside contains medicine and lasting releasable material mutually, and described outer solid continuous phase contains lasting releasable material.When contacting with release medium, the medicine that discharges in the granule of phase shifts by outer solid continuous phase internally, is discharged into the top intestines and stomach then.
Yet the total tablet weight that contains each tablet of 500 milligrams of active component is about 1000 milligrams, because need the polymer of a great deal of to control release rate of drugs.When the method according to this invention prepares, contain heavy at least 2 grams of the preparation that scales up of 1000 milligrams of medicines.This is edible for the mankind, and is unacceptablely big.For the dosage of being grown up every day is the tablet of two 500 milligrams of intensity of administration needs of 1000 milligrams of metformin.
Metformin is mobile and all very poor water-soluble medicine of height of briquettability, therefore, can not suppress with its pure form.In addition, it still is a kind of high dose medicament, and therefore capping (capping) tendency is high especially in the process of producing tablet.Described capping not only causes loss of yield, and damages its quality.High like this medicament contg does not allow the great changes of the amount of excipient.
Attempted much making great efforts to obtain by suppressing the tablet that medicine and appropriate excipients are directly suppressed, described excipient helps to handle and improve the character of product.Yet directly compacting only limits to following situation, medicine be crystal structure and physical property be fit to formation pharmaceutically can tablet.But, under the situation that active component can not directly be suppressed, need to add one or more excipient.Because add the size that excipient in the preparation can increase tablet to, directly drawing method only limits to contain the low dosage formulations of active ingredients in practice.In addition, contain under the situation of high dose active component in direct compacting, the capping tendency is high especially.
United States Patent (USP) 6,117,451 have done such trial, and this patent has been described flowability and the briquettability that the particular excipient of using specific size and density range is improved Metformin.These excipient are mixed with metformin, then the mixture that obtains is directly suppressed.In this patent, use wet granulation (wetgranulation) mixture of powders to be converted into granule with the required adequate liquidity of tablet and viscosity.Described method comprises mixes powder in suitable blender, add granulating liquid then and obtain granule under shearing in mixed-powder.Screen these wet pieces (mass) and dry by suitable screening washer then.Wet granulation has also produced variable releasing properties according to the polymer hydration degree.In addition, the use of organic solvent causes the problem of residual solvent.
United States Patent (USP) 5,955,106 have disclosed a kind of method, and described method comprises that the delayed-action activator (retarding agent) with metformin and formation hydrocolloid forms grain products with the aqueous solvent granulation, and dry described grain products.When the delayed-action activator of hydrocolloid contacted with aqueous medium, swelling also formed gel-type vehicle, and described gel-type vehicle corrosion is to discharge medicine.
Also used other technology to make the metformin compositions that continues release.United States Patent (USP) 6,340,475 have described a kind of peroral dosage form, in described peroral dosage form, medicine is incorporated in the polymeric matrix of being made up of hydrophilic polymer, swollen to enough big size behind the described hydrophilic polymer absorption water and be detained under one's belt to promote dosage form.Described swollen polymeric matrix is kept perfectly in for a long time, and basic all medicines were discharged before stromatolysis.
Yet, still need a kind of metformin dosage form that can introduce high dosage and be easy to make and can provide lasting release.Also need to give the good flowability of mixture and briquettability, solution capping problem and the method for required lasting release is provided.
The inventor has found the pharmaceutical composition of the lasting release of metformin, described compositions keeps the blood content concentration of the medicine of therapeutic dose in patient body in the sufficiently long time, and can be made into monoblock substrate, slow release of active ingredients in the time that prolongs.
Summary of the invention
On the one hand, the lasting dimethyldiguanide tablet that discharges is formulated as the monoblock substrate (monolithic matrix) that contains metformin, control rate aggregation thing and other pharmaceutically acceptable excipient.
On the other hand, provide the dimethyldiguanide tablet that continues release, described tablet comprises the metformin of high dose, and has acceptable size, makes it easy to oral.
On the other hand, the dimethyldiguanide tablet that continues to discharge comprises monoblock system (monolithic system), and with the soluble metformin of constant relatively speed release altitude, described monoblock system is easy to make described monoblock system in the time that prolongs.
Again on the one hand, provide the dimethyldiguanide tablet that continues release, described tablet contains the control rate aggregation thing of 5-25% w/w.Use the control rate aggregation thing of less amount to guarantee that the gross weight of dosage form is lower than previously known preparation, single dosage device enough provides the therapeutic dose of medicine.Therefore, continuous release tablet provides benefit, make patient convenient, be obedient to.
Provide continuous release tablet on the one hand, described tablet especially controllably discharges metformin in 12 hours time in 24 hours time.
On the other hand, provide the dimethyldiguanide tablet of the lasting release of 850 milligrams of intensity, described tablet contains the control rate aggregation thing of 5-25% w/w and other pharmaceutically acceptable excipient.
On the other hand, provide the dimethyldiguanide tablet of the lasting release of 1000 milligrams of intensity, described tablet contains the control rate aggregation thing of 5-25% w/w and other pharmaceutically acceptable excipient.
A total aspect provides the continuous release tablet of monoblock, and described tablet contains 500-1000 milligram metformin, and wherein the gross weight of tablet is no more than 1500 milligrams.
The aspect that another is total provides the method for the tablet of metformin that preparation continue to discharge or its avirulent acid-addition salts, and described method comprises mixes described component, then with roller compacting or compacting.Described compact is suitable size, and is pressed into tablet.
The aspect that another is total provides by prepare the dimethyldiguanide tablet of the lasting release of 850 milligrams of intensity with the roller compacting.
The aspect that another is total provides by prepare the dimethyldiguanide tablet of the lasting release of 1000 milligrams of intensity with the roller compacting.
The roller compacting relates generally to screen step, and described screening causes narrow particle size distribution, and granule is seldom arranged at the two ends of size range.Roller compacting provides several other advantages, for example, obtains having the mixture of single-size magnitude range, improves flowing property, helps dust Control, increases bulk density, the control pellet hardness.
On the other hand, provide the dimethyldiguanide tablet that continues release, described tablet comprises:
The metformin of a. about 500-1000 milligram,
B.5-25% w/w control rate aggregation thing and
C. other pharmaceutically acceptable excipient.
On the other hand, the method for the lasting dimethyldiguanide tablet that discharges of preparation comprises:
E. mix the control rate aggregation thing of metformin, 5-25% w/w and other pharmaceutically acceptable excipient,
F. compacting/compacting,
G. the material of compacting in the step (b)/compacting is ground or pulverize into granule and
H. lubricate and suppress described granule and form tablet.
According to the Indian patent application that we await the reply, 1002/DEL/2001 (by being incorporated herein by reference in full), with control rate aggregation thing and other mixed with excipients before, the humidity that can regulate metformin is with the energy that further improves liquidity.Perhaps, metformin can with control rate aggregation thing and/or other mixed with excipients, regulate humidity then.
Therefore, the method for the lasting dimethyldiguanide tablet that discharges of preparation comprises:
A. regulate the humidity of metformin,
B. with the control rate aggregation thing of 5-25% w/w and other pharmaceutically acceptable mixed with excipients,
C. compacting/compacting,
D. the material of compacting in the step (b)/compacting is ground or pulverize into granule and
E. lubricate and suppress described granule and form tablet.
Therefore, the another kind of method of the lasting dimethyldiguanide tablet that discharges of preparation comprises:
A. mix the control rate aggregation thing of metformin, 5-25% w/w and other pharmaceutically acceptable excipient,
B. regulate the humidity of mixture,
C. compacting/compacting,
D. the material of compacting in the step (b)/compacting is ground or pulverize into granule and
E. lubricate and suppress described granule and form tablet.
According to one embodiment of the invention, provide the method for the continuous release tablet of preparation metformin.Wherein said tablet has better intensity, aesthetic appeal, required profile (profile) and productive rate, and can introduce the very medicine of high dose, and tablet is unacceptably swallowed to being difficult to greatly.
On the other hand, for the patient of needs treatments provides the method for the diabetes of the non--insulin dependency of treatment, described method comprises the dimethyldiguanide tablet that continues release, and described tablet comprises:
The metformin of a. about 500-1000 milligram,
B.5-25% the control rate aggregation thing of w/w and
C. other pharmaceutically acceptable excipient.
Described continuous release tablet also can comprise one or more sulfonylureas, insulin, lattice row ketone (glitazone), Alpha-glucosidase inhibitor, Ge Lienai (meglitinide), Bei Te (fibrate), Si Dating (statin), zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.
The specific embodiment
Convenient, worthwhile by the monoblock system (for example sustained release forms) that hydrophilic polymer and other excipient are formed.
Term as herein described " monoblock substrate " refers to medicine is dispersed or dissolved in the substrate that contains medicine that forms in the suitable polymers equably.Can prepare the monoblock system by direct compacting, wet and dry granulation method.In this dosage form, medicine is the step of limiting speed by the diffusion of substrate.The speed that discharges from this substrate meets the square root of time usually.In the monoblock preparation of being made by hydrophilic polymer, the release of medicine is subjected to the control of polymeric matrix swelling rate.
Metformin can use with the form of inorganic or organic acid acid-addition salts.These acid such as but not limited to, hydrochloric acid, formic acid, acetic acid, malic acid, tartaric acid or fumaric acid.
In every tablet of tablet, metformin can account for 1000 milligrams.
Control rate aggregation thing can be selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic acid and methacrylic acid derivative, poly(ethylene oxide), natural gum (gum), based on the polymer and the materials similar of carbohydrate.
Cellulose derivative can be selected from ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or the materials similar of different replacement degree and molecular weight.These polymer can be used singly or in combination.
Acrylate copolymer can be for example commercially available commodity Carbopol (B.F.Goodrich, CVP Carbopol ETD2050 USA) by name.Polymer based on carbohydrate can be selected from xanthan gum, tragacanth, karaya, guar gum, Radix Acaciae senegalis, gelling carbohydrate gum (gellan gum), locust bean gum etc.Control rate aggregation thing accounts for the 5-25% w/w of preparation.
Pharmaceutically acceptable excipient can be selected from diluent, binding agent, lubricant, fluidizer and flavoring agent, these excipient and metformin physically and chemically can be compatible and help to optimize hardness, fragility, medicine dissolution and the production method of tablet.
Diluent can be selected from the pharmaceutically acceptable excipient of any this class, and it gives the certain volume of compositions and improves its briquettability.These diluent can be selected from starch and starch derivatives, dicalcium phosphate, calcium sulfate, Sorbitol, microcrystalline Cellulose, lactose, glucose, mannitol, alginate, alkali salt, clay, Polyethylene Glycol or materials similar.
Binding agent can be selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol and materials similar or its mixture.
Lubricant can be selected from stearate (for example zinc stearate and calcium stearate etc.), sodium lauryl sulfate, hydrogenant vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, Polyethylene Glycol and the materials similar of Talcum, magnesium stearate, other alkaline-earth metal.
Fluidizer can be selected from colloidal silica, Talcum and materials similar.
Suppress mixture compacted by roller.Perhaps, this mixture can be suppressed and form fragment (slug).A kind of embodiment comprise with the independent compacting of metformin or compacting or its with control rate aggregation thing and/or mixed with excipients after compacting or compacting.
The material of described compacting or compacting pulverizes/grind also with suitable grater (for example oscillating granulator/many grind (Fitzmil) now with mill (multimil)/phenanthrene), and sieving becomes required particle size.
These granules with lubricator are lubricated and are pressed into tablet.
If necessary, before compacting step, metformin can be mixed with one or more antidiabetics.The antidiabetic that is fit to comprises and is selected from the mixture that sulfonylureas (for example glyburide, glipizide, glimepiride and gliclazide), Alpha-glucosidase inhibitor (for example acarbose and miglitol), lattice row ketone (for example rosiglitazone and pioglitazone) also have two or more above-mentioned antidiabetics.
The following examples illustrate various embodiments, but limit claim never in any form.
Embodiment 1
| Composition | Weight (milligram)/tablet |
| Metformin | 1000.00 |
| Sodium carboxymethyl cellulose | 25.00 |
| Microcrystalline Cellulose | 85.00 |
| Hydroxypropyl emthylcellulose | 275.00 |
| Magnesium stearate | 3.75 |
| Colloidal silica | 16.25 |
| Water | 45.00 |
| Altogether | 1450.00 |
Step:
1. the mentioned component of weighing is also by suitable sieve sieve.
2. in blender, Metformin is mixed with microcrystalline Cellulose, and spray the pure water of aequum.
3. the mixture in the step 2 is mixed with sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, magnesium stearate and part colloidal silica.
4. block (mass) in the screening step 3 uses the roller compactor to carry out compacting then.
5. suitably starching of the material of compacting (sized).
6. the granule of starching is lubricated and is pressed into tablet.
Embodiment 2
| Composition | Weight (milligram)/tablet |
| Metformin | 850.00 |
| Sodium carboxymethyl cellulose | 21.25 |
| Microcrystalline Cellulose | 72.25 |
| Hydroxypropyl emthylcellulose | 233.75 |
| Magnesium stearate | 3.1875 |
| Colloidal silica | 13.8175 |
| Water | 38.25 |
| Altogether | 1232.5 |
Step: the step given as embodiment 1.
Table 1 provides the release profile according to the tablet of embodiment 1 and 2 preparations.
Table 1: embodiment 1 and 2 tablet are in the release profile of phosphate buffer/900ml/USP apparatus II/50rpm of pH6.8
| Time (hour) | The drug release percentage ratio (%) of the tablet of embodiment 1 | The drug release percentage ratio (%) of the tablet of embodiment 2 |
| 0.5 | 23 | 21 |
| 1.0 | 33 | 30 |
| 2.0 | 46 | 45 |
| 4.0 | 63 | 66 |
| 6.0 | 76 | 79 |
| 8.0 | 85 | 87 |
| 10.0 | 91 | 95 |
| 12.0 | 94 | 96 |
Embodiment 3
| Composition | Weight (milligram)/tablet |
| Metformin | 1000.00 |
| Sodium carboxymethyl cellulose | 25.00 |
| Microcrystalline Cellulose | 36.50 |
| Hydroxypropyl emthylcellulose | 325.00 |
| Magnesium stearate | 3.00 |
| Colloidal silica | 15.5 |
| Water | 45.00 |
| Altogether | 1450.00 |
Step: the step given as embodiment 1.
Embodiment 4
| Composition | Weight (milligram)/tablet |
| Metformin | 1000.00 |
| Dicalcium phosphate | 205.00 |
| Hydroxypropyl emthylcellulose | 175.00 |
| Magnesium stearate | 5.00 |
| Colloidal silica | 10.00 |
| Talcum | 5.00 |
| Water | 20.00 |
| Altogether | 1420.00 |
Step: the step given as embodiment 1.
Table 2 provides the release profile according to the tablet of embodiment 3 and 4 preparations.
Table 2: embodiment 3 and 4 tablet are in the release profile of phosphate buffer/900ml/USP apparatus II/50rpm of pH6.8
| Time (hour) | The drug release percentage ratio (%) of the tablet of embodiment 3 | The drug release percentage ratio (%) of the tablet of embodiment 4 |
| 0.5 | 18 | 21 |
| 1.0 | 28 | 31 |
| 2.0 | 41 | 47 |
| 4.0 | 59 | 67 |
| 6.0 | 70 | 80 |
| 8.0 | 79 | 90 |
| 10.0 | 86 | 94 |
| 12.0 | 88 | 96 |
In addition, expect any single feature of invention as herein described change or the combination of optional feature, can get rid of clearly outside the invention of being protected, so be described as negative restriction.Therefore, the present invention is limited by appended claim.
Claims (61)
1. dimethyldiguanide tablet that continue to discharge comprises:
The metformin of a. about 500-1000 milligram,
B.5-25% the control rate aggregation thing of w/w and
C. other pharmaceutically acceptable excipient.
2. continuous release tablet as claimed in claim 1 is characterized in that, it comprises 850 gram metformin.
3. continuous release tablet as claimed in claim 1 is characterized in that, it comprises 1000 gram metformin.
4. continuous release tablet as claimed in claim 1 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.
5. continuous release tablet as claimed in claim 4 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.
6. continuous release tablet as claimed in claim 5 is characterized in that wherein pharmaceutically acceptable salt is a hydrochlorate.
7. continuous release tablet as claimed in claim 1, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.
8. continuous release tablet as claimed in claim 7 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.
9. continuous release tablet as claimed in claim 8, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.
10. continuous release tablet as claimed in claim 9 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.
11. continuous release tablet as claimed in claim 1 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.
12. continuous release tablet as claimed in claim 11, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.
13. continuous release tablet as claimed in claim 11 is characterized in that, described diluent is a microcrystalline Cellulose.
14. continuous release tablet as claimed in claim 11 is characterized in that, described lubricant is a magnesium stearate.
15. continuous release tablet as claimed in claim 11 is characterized in that, described fluidizer is a colloidal silica.
16. continuous release tablet as claimed in claim 1 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.
17. continuous release tablet as claimed in claim 1 is characterized in that, described tablet controllably discharged metformin in 12 hours.
18. continuous release tablet as claimed in claim 1 is characterized in that, described tablet discharged metformin in 24 hours.
19. continuous release tablet as claimed in claim 1, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.
20. a method for preparing the dimethyldiguanide tablet that continues to discharge comprises:
A. mix the control rate aggregation thing of metformin, 5-25% w/w and other pharmaceutically acceptable excipient,
B. compacting/compacting,
C. the material of compacting/compacting in the step (b) is ground or pulverize into granule and
D. lubricate and suppress described granule and form tablet.
21. method as claimed in claim 20 is characterized in that, described continuous release tablet contains 850 milligrams of metformin.
22. method as claimed in claim 20 is characterized in that, described continuous release tablet contains 1000 milligrams of metformin.
23. method as claimed in claim 20 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.
24. method as claimed in claim 23 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.
25. method as claimed in claim 24 is characterized in that, wherein pharmaceutically acceptable salt is a hydrochlorate.
26. method as claimed in claim 20, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.
27. method as claimed in claim 26 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.
28. method as claimed in claim 27, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.
29. method as claimed in claim 28 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.
30. method as claimed in claim 20 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.
31. method as claimed in claim 30, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.
32. method as claimed in claim 30 is characterized in that, described diluent is a microcrystalline Cellulose.
33. method as claimed in claim 30 is characterized in that, described lubricant is a magnesium stearate.
34. method as claimed in claim 30 is characterized in that, described fluidizer is a colloidal silica.
35. method as claimed in claim 20 is characterized in that, described tablet prepares by compacting.
36. method as claimed in claim 20 is characterized in that, described tablet prepares by the roller compacting.
37. method as claimed in claim 20 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.
38. method as claimed in claim 20 is characterized in that, described tablet controllably discharged metformin in 12 hours.
39. method as claimed in claim 20 is characterized in that, described tablet discharged metformin in 24 hours.
40. method as claimed in claim 20, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.
41. the dimethyldiguanide tablet of the lasting release of a monoblock comprises:
The metformin of a. about 500-1000 milligram,
B.5-25% the control rate aggregation thing of w/w and
C. other pharmaceutically acceptable excipient.
42. continuous release tablet as claimed in claim 41 is characterized in that, it comprises 850 gram metformin.
43. continuous release tablet as claimed in claim 41 is characterized in that, it comprises 1000 gram metformin.
44. continuous release tablet as claimed in claim 41 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.
45. continuous release tablet as claimed in claim 44 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.
46. continuous release tablet as claimed in claim 45 is characterized in that, wherein pharmaceutically acceptable salt is a hydrochlorate.
47. continuous release tablet as claimed in claim 41, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.
48. continuous release tablet as claimed in claim 47 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.
49. continuous release tablet as claimed in claim 48, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.
50. continuous release tablet as claimed in claim 49 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.
51. continuous release tablet as claimed in claim 41 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.
52. continuous release tablet as claimed in claim 51, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.
53. continuous release tablet as claimed in claim 51 is characterized in that, described diluent is a microcrystalline Cellulose.
54. continuous release tablet as claimed in claim 51 is characterized in that, described lubricant is a magnesium stearate.
55. continuous release tablet as claimed in claim 51 is characterized in that, described fluidizer is a colloidal silica.
56. continuous release tablet as claimed in claim 41 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.
57. continuous release tablet as claimed in claim 41 is characterized in that, described tablet controllably discharged metformin in 12 hours.
58. continuous release tablet as claimed in claim 41 is characterized in that, described tablet discharged metformin in 24 hours.
59. continuous release tablet as claimed in claim 41, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.
60. the patient for the needs treatment provides the method for the diabetes of the non--insulin dependency of treatment, described method comprises the dimethyldiguanide tablet that continues release, and described tablet comprises:
A. more than 500 milligrams metformin,
B.5-25% the control rate aggregation thing of w/w and
C. other pharmaceutically acceptable excipient.
61. method as claimed in claim 60, it is characterized in that described tablet also can comprise one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN805/DEL/2003 | 2003-06-16 | ||
| IN805DE2003 | 2003-06-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1805738A true CN1805738A (en) | 2006-07-19 |
Family
ID=33548811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800167682A Pending CN1805738A (en) | 2003-06-16 | 2004-06-14 | Extended-release tablets of metformin |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1646374A1 (en) |
| CN (1) | CN1805738A (en) |
| WO (1) | WO2004110422A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102711739A (en) * | 2009-11-13 | 2012-10-03 | 百时美施贵宝公司 | bilayer tablet |
| CN111939135A (en) * | 2020-09-02 | 2020-11-17 | 苏州东瑞制药有限公司 | Sustained-release tablet of metformin hydrochloride medicament and preparation method thereof |
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| KR100772980B1 (en) * | 2004-04-01 | 2007-11-02 | 한미약품 주식회사 | Sustained-release preparations for oral administration of metformin |
| US8192761B2 (en) * | 2005-04-26 | 2012-06-05 | Dainippon Sumitomo Pharma Co., Ltd. | Granular preparation containing biguanide compound |
| JOP20180109A1 (en) * | 2005-09-29 | 2019-01-30 | Novartis Ag | New Formulation |
| CA2632607A1 (en) * | 2005-12-09 | 2007-06-21 | Metaproteomics, Llc | Anti-inflammatory botanical products for the treatment of metabolic syndrome and diabetes |
| US8703191B2 (en) | 2006-07-25 | 2014-04-22 | Intelgenx Corp. | Controlled-release pharmaceutical tablets |
| US7674479B2 (en) | 2006-07-25 | 2010-03-09 | Intelgenx Corp. | Sustained-release bupropion and bupropion/mecamylamine tablets |
| CA2681092A1 (en) * | 2007-03-15 | 2008-09-18 | Nectid, Inc. | Anti-diabetic combinations comprising a slow release biguanide composition and an immediate release dipeptidyl peptidase iv inhibitor composition |
| US8551524B2 (en) | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
| US20120294936A1 (en) * | 2009-11-13 | 2012-11-22 | Astrazeneca Uk Limited | Reduced mass metformin formulations |
| US10610528B2 (en) | 2009-12-08 | 2020-04-07 | Intelgenx Corp. | Solid oral film dosage forms and methods for making same |
| US20110136815A1 (en) | 2009-12-08 | 2011-06-09 | Horst Zerbe | Solid oral film dosage forms and methods for making same |
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| US9211263B2 (en) | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
| EA039943B1 (en) | 2011-01-07 | 2022-03-30 | Анджи Фарма (Юс) Элэлси | Method for lowering blood glucose levels in a subject |
| US8796338B2 (en) | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9572784B2 (en) | 2011-01-07 | 2017-02-21 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US11759441B2 (en) | 2011-01-07 | 2023-09-19 | Anji Pharmaceuticals Inc. | Biguanide compositions and methods of treating metabolic disorders |
| BR112014016808B1 (en) | 2012-01-06 | 2022-01-11 | Anji Pharma (Us) Llc | USE OF A BIGUANIDE COMPOUND FOR THE MANUFACTURE OF A DRUG TO LOWER BLOOD GLUCOSE LEVELS AND FOR THE TREATMENT OF A DISORDER OF GLUCOSE METABOLISM |
| KR102231554B1 (en) | 2012-01-06 | 2021-03-23 | 앤지 파마 유에스 엘엘씨 | Compositions and methods for treating metabolic disorders |
| WO2015183794A1 (en) | 2014-05-27 | 2015-12-03 | City Of Hope | Tgr5 agonist complexes for treating diabetes and cancer |
| WO2016042567A1 (en) * | 2014-09-16 | 2016-03-24 | Suresh Pareek | Extended release formulation of metformin |
| TW201938147A (en) * | 2017-12-18 | 2019-10-01 | 德商拜耳廠股份有限公司 | Fixed dose combination tablet formulation of acarbose and metformin and process for producing the same |
| JP7376582B2 (en) * | 2018-10-22 | 2023-11-08 | イーオーイー オレオ ゲーエムベーハー | Additive for powder materials for compression into compacts |
| EP4045520A1 (en) | 2019-10-16 | 2022-08-24 | Bayer Aktiengesellschaft | Methods for the improved formation of acarbose |
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| DE4432757A1 (en) * | 1994-09-14 | 1996-03-21 | Boehringer Mannheim Gmbh | Pharmaceutical preparation containing metformin and process for its preparation |
| US6117451A (en) * | 1998-08-25 | 2000-09-12 | Pharmalogix, Inc. | Direct compression metformin hydrochloride tablets |
| JP2004510716A (en) * | 2000-10-02 | 2004-04-08 | ユーエスヴイ リミテッド | Metformin-containing sustained-release pharmacological composition and method for producing the same |
| HUP0402328A2 (en) * | 2001-09-28 | 2005-02-28 | Sun Pharmaceutical Industries Limited | Pharmaceutical composition for treatment of diabetes mellitus |
| IN192180B (en) * | 2001-09-28 | 2004-03-06 | Ranbaxy Lab | |
| EA200400628A1 (en) * | 2001-11-06 | 2004-12-30 | Рэнбакси Лабораториз Лимитед | METFORMINE TABLETS WITH CONTROLLED DELIVERY OF THE ACTIVE COMPONENT |
| US6667054B2 (en) * | 2001-12-05 | 2003-12-23 | Bernard Charles Sherman | Metformin hydrochloride tablets |
-
2004
- 2004-06-14 WO PCT/IB2004/050901 patent/WO2004110422A1/en not_active Ceased
- 2004-06-14 CN CNA2004800167682A patent/CN1805738A/en active Pending
- 2004-06-14 EP EP04736789A patent/EP1646374A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102711739A (en) * | 2009-11-13 | 2012-10-03 | 百时美施贵宝公司 | bilayer tablet |
| CN102711739B (en) * | 2009-11-13 | 2015-12-16 | 阿斯利康(瑞典)有限公司 | Bilayer tablet |
| CN105193761A (en) * | 2009-11-13 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Bilayer tablet formulations |
| CN105193761B (en) * | 2009-11-13 | 2019-12-06 | 阿斯利康(瑞典)有限公司 | Bilayer tablet |
| CN111939135A (en) * | 2020-09-02 | 2020-11-17 | 苏州东瑞制药有限公司 | Sustained-release tablet of metformin hydrochloride medicament and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1646374A1 (en) | 2006-04-19 |
| WO2004110422A1 (en) | 2004-12-23 |
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