CN101168059A - Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof - Google Patents
Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof Download PDFInfo
- Publication number
- CN101168059A CN101168059A CNA2007100928301A CN200710092830A CN101168059A CN 101168059 A CN101168059 A CN 101168059A CN A2007100928301 A CNA2007100928301 A CN A2007100928301A CN 200710092830 A CN200710092830 A CN 200710092830A CN 101168059 A CN101168059 A CN 101168059A
- Authority
- CN
- China
- Prior art keywords
- glimepiride
- cellulose
- pharmaceutical composition
- layer
- release layer
- 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
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a stable oral solid medicinal composition and process for preparing the stable oral solid medicinal composition, wherein the stable medicinal composition contains biguanide, sulfonylurea and hiazolidinedione. The stable medicinal composition are composed of three layers of a sustained release layer which is composed by containing the biguanide and rate control materials, an interlayer which is composed by containing the hiazolidinedione and one or more vehicles, and an immediate release layer which is composed of the sulfonylurea and one or more vehicles. The composition is capable of enabling biguanides to interact with sulfonylureas, thereby increasing the therapeutic effect and stability of the composition.
Description
Technical field
The invention belongs to formulation art, be specifically related to a kind of stable oral solid drug composition that contains biguanide, sulfonylureas and thiazolidinedione and preparation method thereof, this stable pharmaceutical composition is formed by following three layers: the immediate release layer that contains slow release layer that biguanide and rate controlled material form, contains intermediate layer that thiazolidinedione and one or more excipient form, is made up of sulfonylureas and one or more excipient.Said composition can be avoided the interaction of biguanides and sulfonylureas medicine, improves the therapeutic effect and the stability of compositions.
Technical background
Diabetes are one group, and to increase with chronic blood sugar level be the metabolic disease group of feature.Hyperglycemia be owing to defect of insulin secretion and (or) the insulin action defective causes.Except that carbohydrate, protein is still arranged, lipid metabolism is unusual.Prolonged illness can cause the multisystem infringement, causes the chronic progressive external pathological changes of tissues such as eye, kidney, nerve, heart, blood vessel, causes functional defect and depletion.Be in a bad way or stress the time acute metabolism disorder can take place, as ketoacidosis, hyperosmolar coma etc.
Diabetes generally can be divided into insulin dependent diabetes mellitus (IDDM) (IDDM, type i diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, type ii diabetes), and wherein, type ii diabetes accounts for more than 95% of this disease group.The generation of type ii diabetes is divided into two kinds of situations: the pancreatic secretion insulin reduces (insulin definitely lacks) and the sensitivity decline (insulin relative lacks) of patient to insulin.
Glimepiride is a third generation sulfonylurea oral hypoglycemic, it is developed by German Hochst Mariom Roussel (HMR) company, nineteen ninety-five, JIUYUE went on the market with trade name Amaryl in Sweden first, entered American market through FDA approval in 1996, it is present internationally recognized type 2 diabetes mellitus choice drug, it also is unique sulfonylurea hypoglycemic agent thing that can use with insulin combination of U.S. FDA approval, its hypoglycemic activity mechanism is to stimulate the beta Cell of islet excreting insulin, and part improves the sensitivity of surrounding tissue to insulin.Commercially available glimepiride tablet is 1mg, 2mg and 4mg tablet, and give once every day.
Metformin is the biguanides antidiabetic drug, go on the market in the U.S. in nineteen ninety-five, its slow releasing tablet takes the lead in by (the 100 o'clock Mei-Shi Guibao) succeed in developing of U.S. Bristol-MyersSquibb company, go on the market through the FDA approval in October, 2000, become diet and the out of contior type ii diabetes patient's of motion first-selected prescription drug.The blood sugar lowering mechanism of action of metformin is different with sulfonylureas, it can not impel insulin from pancreatic secretion, it is by improving the insulin active in the peripheral tissues, suppresses gluconeogenesis and reduces liver glucose output, and reduce and come blood sugar regulation from the intestinal absorption glucose.Biguanides is the effective oral hypoglycemic thing of generally recognized as safe in the world, for also being that Chinese adult type ii diabetes human gets oral prescription antidiabetic drug at most in the world at present.Commercially available metformin hydrochloride tablet is 500mg, 850mg or 1000mg specification, and recommending maximal dose is 2500mg/ days.Yet its action time is short, needs every day and take secondary or three times.
Pioglitazone is the thiazolidinediones antidiabetic drug, and this medicine is researched and developed successfully by Japan military field drugmaker, after clinical research, obtains drugs approved by FDA in July, 1999, unites the introduction American market by Wu Tian company and Li Lai company.Traditional Chinese Medicine Research ﹠ Development Center and Beijing Tai Yang Pharmaceutical obtain the first class national new drug certificate, trade name Ai Ting after developing jointly.Pioglitazone is an euglycemic agent of new generation, and the main mechanism of action of this medicine is to activate the PPAR nuclear receptor of tissues that insulin acts on such as fat, skeletal muscle and liver, thereby regulates insulin replies gene transcription, the generation of blood sugar control, transhipment and utilization.The specification of commercially available pioglitazone hydrochloride sheet is 15mg and 30mg, and is once a day oral, and maximum recommended dosage is 45mg.
For the type ii diabetes patient, glycemic control is a progressive process: the oral hypoglycemic thing blood sugar control of the type ii diabetes patient at initial stage at first being selected single component; Development along with the state of an illness, the medicine of single component is effective blood sugar control, need the complementary two kinds of oral hypoglycemic things of the mechanism of action to jointly control blood glucose, be that three kinds of oral hypoglycemic things jointly control blood glucose at last, when the therapeutic alliance of three kinds of oral hypoglycemic things all can not fine blood sugar control, can adopt insulinize.
Because the mechanism of action complementation of pioglitazone, glimepiride and metformin, drug combination can produce synergism, brings into play hypoglycemic effect better, so its exploitation is become compound preparation; Again owing to the half-life of pioglitazone and glimepiride is grown (T
1/2Be respectively 3～7 hours and 5～8 hours), usage is every day 1 time, so in compound preparation they are made immediate release layer, also can reach the effect of quick acting simultaneously; The half-life of metformin hydrochloride is lacked (T
1/20.9～2.6), need 2-3 administration every day,, reduce side effects of pharmaceutical drugs,, reach the effect of continuous action so in compound preparation, be made into slow release layer in order to increase the compliance that patient takes medicine.And metformin is a slow release layer in this product, compares with common metformin hydrochloride tablet (taking every day 2～3 times), make slow release after, drug slow discharges, steadily blood sugar lowering is taken number of times and is reduced to once a day, improves patient's compliance, side effect obviously reduces.The metformin hydrochloride ordinary tablet (GLUCOPHAGE) of BMS company accounts for 6% because of what drowsiness side effect discontinued medication, and slow releasing tablet only is 0.6%; Diarrhoea reduces to 9.6% by 53.2% of ordinary tablet after making slow releasing tablet; The side effect of feeling sick, vomitting reduces to 6.5% by 25.5% of ordinary tablet.And compound preparation does not increase in side effect to some extent than single preparations of ephedrine, so this product more has superiority on hypoglycemic activity than the single preparations of ephedrine of pioglitazone, glimepiride and metformin.
About the compound preparation of glimepiride and metformin, relate generally to the content of following several respects in the disclosed patent documentation:
This patent of WO04045622 (corresponding Chinese patent is CN1729005) relates to a kind of compound preparation, comprise biguanides (comprising metformin) slow release layer and sulfonylureas medicine (comprising glimepiride) release layer, in this patent dependent claims, mention " this dosage form also comprises glitazone, comprising pioglitazone ".This patent relates to the double-layer tablet that contains glimepiride, pioglitazone and metformin, and all embodiment in this patent carry out coating to glimepiride, but do not have open prescription and the embodiment that specifically contains sulfonylureas such as glimepiride, glitazone such as pioglitazone and biguanides such as metformin compound preparation, specifically do not disclose its three-layer tablet preparation and preparation technology thereof yet.
The inventor is when the quality of research biguanides (comprising metformin), glitazone (comprising pioglitazone) and sulfonylureas medicine (comprising glimepiride) compound medicament composition preparation, it is unexpected that the discovery biguanides exist interaction when contacting with the sulfonylureas medicine, biguanides (as 40 degree, 60 degree) under hot conditions promotes sulfonylureas drug degradation, related substance to raise, and proves that biguanides directly contacts the stability that influences this compound medicament composition with the sulfonylureas medicine.Be the combination preparation and the stability problem thereof that solve this three medicine, the inventor has finished the present invention for this reason.
Summary of the invention
The invention provides a kind of stable oral solid drug composition that contains biguanide, sulfonylureas and thiazolidinedione, this stable pharmaceutical composition is formed by following three layers: the immediate release layer or the title release layer (the 3rd layer) that contain slow release layer (ground floor) that biguanide and rate controlled material form, contain the immediate release layer that thiazolidinedione and one or more excipient form or claim release layer (intermediate layer), be made up of sulfonylureas and one or more excipient.Preferred dosage form is a tablet.
Stable oral solid drug composition of the present invention, wherein said biguanide comprises metformin, phenformin, buformin (buformin) or their officinal salt, example hydrochloric acid salt, sulfate etc. are therefrom selected one or more, preferred metformin or its hydrochlorate; Wherein said sulfonylureas comprises glipizide, glimepiride, glibornuride, glibenclamide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide, toluene butyl urea or their officinal salt, therefrom select one or more, preferred glimepiride; Wherein said thiazolidinedione comprises troglitazone, rosiglitazone and pioglitazone or its officinal salt, and example hydrochloric acid salt, sulfate, maleate and mesylate etc. are therefrom selected one or more, preferred pioglitazone or its hydrochlorate.
The present invention adopts the immediate release layer of being made up of thiazolidinedione and one or more excipient as the intermediate layer biguanides and sulfonylureas medicine to be kept apart, avoid them to interact, prevent the degraded of sulfonylureas, thereby improve the stability of compositions, help the long term storage of said composition.This technical scheme is compared the isolation of coating method, and is more economical, simpler, more easy to operate, suitability for industrialized production preferably.Simultaneously, these three kinds of medicines are made compound preparation, for the difficult control of blood glucose, need can reduce administration number of times the sugared urea patient of triple therapy, improve the compliance and the compliance of patient's long-term prescription, and can reduce the side effect that long-term prescription causes.
Because hypoglycemic activity only needs carry out after the meal, do not need to continue hypoglycemic activity night, so we are designed to 6～16 hours with release time of metformin slow release layer.The rate of release control material can be selected from one or more following materials: cellulose derivative, pregelatinized Starch, starch derivatives, crylic acid resin, carbopol, polyvinyl alcohol, crospolyvinylpyrrolidone, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, alginate, chitosan, gelatin, carrageenin, xanthan gum, stearic acid, glyceryl monostearate, Brazil wax, vegetable oil, guar gum, octadecanol, Synthetic Spermacet, hexadecanol.
Cellulose derivative class rate of release control material comprises methylcellulose, cellulose acetate, cellulose vinegar method ester (USPNF:Gellacefate), ethyl cellulose, hydroxyethyl-cellulose, hymetellose hydroxypropyl cellulose, hydroxypropyl cellulose, hypromellose, phthalic acid hypromellose, cellulose acetate-phthalate, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose.
Crylic acid resin rate of release control material comprises EUDRAGIT NE 30 D EUDRAGIT NE 30D, dimethylaminoethyl methacrylate-neutral methacrylic acid esters copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-methyl acrylate copolymer, neutral EUDRAGIT NE 30 D EUDRAGIT NE 30D, methacrylic acid trimethylammonium ethyl ester-acrylate copolymer, methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer, methacrylic acid-methylmethacrylate copolymer, the ethoxy acrylic acid methyl ester..
Preferred rate of release control material is cellulosic polymer, especially hydroxypropyl emthylcellulose.The rate of release control material accounts for 10%～80% of slow release layer weight, and preferred 10%～60%.
Can further include one or more excipient in the biguanide slow release layer, this excipient can be diluent (filler), binding agent, fluidizer, one or more in the lubricant.Diluent can be a starch, pregelatinized Starch, calcium hydrogen phosphate, dextrin, microcrystalline Cellulose, lactose, mannitol, xylitol, one or more in the Sorbitol.Lubricant can be a Pulvis Talci, stearic acid, calcium stearate, magnesium stearate, one or more in the liquid paraffin, preferred magnesium stearate.Fluidizer can be a Pulvis Talci, silicon dioxide, one or more in the corn starch.Binding agent can be a polyvinyl pyrrole lattice alkane ketone, polyvinyl pyrrole lattice alkane ketone/vinyl acetate polymer, starch, pregelatinized Starch, dextrin, carboxymethyl cellulose, the alcohol-water mixed liquor, methylcellulose, hydroxypropyl emthylcellulose, in the sodium alginate one or more, preferably polyethylene base pyrrole lattice alkane ketone.
The intermediate layer is made up of thiazolidinediones medicine and one or more excipient.Wherein, excipient comprises diluent, disintegrating agent, binding agent, fluidizer or lubricant or their combination in any.Diluent can be a starch, pregelatinized Starch, calcium hydrogen phosphate, dextrin, microcrystalline Cellulose, lactose, mannitol, xylitol, one or more in the Sorbitol.Lubricant can be a Pulvis Talci, stearic acid, calcium stearate, magnesium stearate, one or more in the liquid paraffin.Fluidizer can be a Pulvis Talci, silicon dioxide, one or more in the corn starch.Binding agent can be a polyvinyl pyrrole lattice alkane ketone, polyvinyl pyrrole lattice alkane ketone/vinyl acetate polymer, starch, pregelatinized Starch, dextrin, carboxymethyl cellulose, alcohol-water mixed liquor, methylcellulose, hydroxypropyl emthylcellulose, one or more in the sodium alginate.
Because glimepiride is release layer, and glimepiride is insoluble drug, so its selected excipient need help the disintegrate and the stripping of glimepiride.The excipient of glimepiride and pioglitazone layer comprises diluent, disintegrating agent, binding agent, fluidizer or lubricant or their combination in any.Diluent can be a starch, pregelatinized Starch, calcium hydrogen phosphate, dextrin, microcrystalline Cellulose, lactose, mannitol, xylitol, one or more in the Sorbitol.Lubricant can be a Pulvis Talci, stearic acid, calcium stearate, magnesium stearate, one or more in the liquid paraffin.Fluidizer can be a Pulvis Talci, silicon dioxide, one or more in the corn starch.Binding agent can be a polyvinyl pyrrole lattice alkane ketone, polyvinyl pyrrole lattice alkane ketone/vinyl acetate polymer, starch, pregelatinized Starch, dextrin, carboxymethyl cellulose, alcohol-water mixed liquor, methylcellulose, hydroxypropyl emthylcellulose, one or more in the sodium alginate.
No matter glimepiride and metformin hydrochloride are that crude drug mixes the back placement or glimepiride, pioglitazone and metformin are made double-layer tablet, interaction is all arranged between two medicines, and after two interlayers add the intermediate layer, the stability of this product is significantly improved, and this technology was not only simple but also can avoid the interaction of two medicines.
Compositions of the present invention is oral 1 the present invention's on the one a slow releasing tablet, to single with sulfonylureas or single with biguanide effectively the type ii diabetes patient of blood sugar control have good hypoglycemic activity.
Purpose of the present invention also provides a kind of method that contains biguanide, row ketone and sulfonylureas compound medicament composition of the present invention for preparing, and comprises following process:
A, sulfonylureas layer:
1. in suitable batch mixer, the method that an amount of sulfonylureas and other optional excipient employing equivalent are progressively increased is mixed.
2. with binder solution the mixture in the step 1 is granulated.
3. dry and sieve granule.
4. with the dried granule of gained and other mixed with excipients, it is standby to be designated as granule 1.
B, intermediate layer:
Thiazolidinedione and one or more excipient are got by direct mixing or granulation.
C, the slow releasing layer of biguanide:
1. in suitable batch mixer, with an amount of biguanide and rate of release control material and other optional mixed with excipients.
2. with binder solution the mixture in the step 1 is granulated.
3. dry and sieve granule.
4. with the dried granule of gained and other mixed with excipients, it is standby to be designated as granule 2.
With above sulfonylureas layer, intermediate layer, the prepared granule of the slow releasing layer of biguanide, be pressed into three-layer tablet by proper method.
Perhaps, can adopt non-water granulation, directly compacting, or the dry granulation technology prepares three-layer tablet.When directly suppressing, the mixture of preparation sulfonylureas, thiazolidinedione and metformin and proper auxiliary materials is pressed into tablet then earlier.The dry granulation process can be undertaken by compacting, and the material that obtains is sieved; Hybrid lubricant and fluidizer also are pressed into three-layer tablet.
After the slow release layer granule also can adopt suitable rate controlled material heat melted again with other adjuvant and biguanide mixed pelletization and get.
Also can pass through the pressed coated prepared, that is: first one, the slow releasing piece of compacting biguanide, ball; In second step, as core, contain the intermediate layer of thiazolidinedione in its outer compacting with the slow releasing piece of biguanide, ball; The 3rd step, compacting sulfonylureas release layer on the second step basis.
In the said method, described biguanide is selected from one or more in metformin, phenformin and the buformin (buformin), preferred metformin; Described sulfonylureas is selected from one or more in glipizide, glimepiride, glibornuride, glibenclamide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide and the toluene butyl urea, glimepiride; Described thiazolidinedione comprises one or more in troglitazone, rosiglitazone and the pioglitazone, preferred pioglitazone.
Biguanide of the present invention, row ketone and sulfonylureas compound medicament composition, be specially metformin, the compound medicament composition of pioglitazone and glimepiride, more specifically for containing metformin, the slow release three-layer tablet of pioglitazone and glimepiride, wherein metformin is 0.5～1g, preferred 500mg, pioglitazone is 1～30mg, preferred 15mg, glimepiride 0.5～10mg, preferred 1mg and 2mg, day obeys once, and wherein metformin discharged (slow release) fully behind the oral administration in about 6～16 hours, preferred 8～12 hours, other two kinds of medicines were rapid release or discharge immediately.
Description of drawings
The metformin slow release release profiles of Fig. 1 embodiment 1～3
The metformin slow release release profiles of Fig. 2 embodiment 4～6
The specific embodiment mode
Further illustrate the present invention by the following examples, but be not limited to embodiment.
The comparative example 1
Glimepiride and pioglitazone hydrochloride and metformin hydrochloride crude drug exist and interact, and all do not become to mention in this former document and the patent.For better explanation the present invention, glimepiride, pioglitazone hydrochloride and metformin hydrochloride are made double-layer tablet according to prior art, wherein, glimepiride and pioglitazone are in release layer, and metformin is in slow release layer (specification: glimepiride/pioglitazone hydrochloride/metformin hydrochloride: 1mg/15mg/500mg).
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Hydroxypropyl emthylcellulose | 500 | |
| 8％PVP(K30) | In right | |
| Magnesium stearate | ||
| 10 | ||
| Release layer | Glimepiride | 1 |
| Pioglitazone hydrochloride | 15 | |
| Microcrystalline Cellulose | 120 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Low-substituted hydroxypropyl cellulose | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, transfer to mixing in the high-speed mixing granulating machine.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, the method mixing that adopts equivalent to progressively increase microcrystalline Cellulose, lactose and the carboxymethyl starch sodium of glimepiride, pioglitazone hydrochloride and the recipe quantity of recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add low-substituted hydroxypropyl cellulose and magnesium stearate mixing, promptly get the release layer granule.
3, slow release layer granule, release layer granule are pressed into double-layer tablet.
The comparative example 2～4
Prescription is formed:
| Composition | Ratio (%) or content (mg) | |
| The comparative example 2 | |
100％ |
| The comparative example 3 | Glimepiride | 1mg |
| Metformin hydrochloride | 500mg | |
| The comparative example 4 | Glimepiride | 1mg |
| Pioglitazone hydrochloride | 15mg |
Operation: the glimepiride crude drug is mixed in proportion with pioglitazone hydrochloride and metformin hydrochloride respectively.
The comparative example 5
Prescription is formed:
| Prescription | Composition | The mg/ sheet |
| Glimepiride | 1 | |
| Pioglitazone hydrochloride | 15 | |
| Microcrystalline Cellulose | 120 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 |
Operation:
1, glimepiride, pioglitazone hydrochloride, carboxymethyl starch sodium and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, mixing in the high-speed mixing granulating machine is transferred in the equivalent mixing of progressively increasing.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get granule.
2, add low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium and magnesium stearate mixing, tabletting promptly.
The comparative example 6
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Hydroxypropyl emthylcellulose | 500 | |
| 8％PVP(K30) | In right | |
| Magnesium stearate | ||
| 10 | ||
| Release layer | Glimepiride | 1 |
| Microcrystalline Cellulose | 120 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Low-substituted hydroxypropyl cellulose | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, transfer to mixing in the high-speed mixing granulating machine.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, the method mixing that adopts equivalent to progressively increase microcrystalline Cellulose, lactose and the carboxymethyl starch sodium of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add low-substituted hydroxypropyl cellulose and magnesium stearate mixing, promptly get the release layer granule.
3, slow release layer granule, release layer granule are pressed into double-layer tablet.
Embodiment 1
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Ethyl cellulose | 200 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 7 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
100 | |
| Release layer | Glimepiride | 1 |
| Microcrystalline Cellulose | 120 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the ethyl cellulose of recipe quantity are crossed 60 mesh sieves respectively, transfer to mixing in the high-speed mixing granulating machine.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, pioglitazone hydrochloride and the Celluloasun Microcrystallisatum mixing with recipe quantity promptly gets the intermediate layer granule.
3, the method mixing that adopts equivalent to progressively increase the carboxymethyl starch sodium of microcrystalline Cellulose, lactose and the Nei Jia of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the carboxymethyl starch sodium and the magnesium stearate mixing that add, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule and release layer granule are pressed into three-layer tablet.
Embodiment 2
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Hydroxypropyl emthylcellulose | 180 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 6.8 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
100 | |
| Release layer | Glimepiride | 1 |
| Microcrystalline Cellulose | 120 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 |
| 8％PVP(K30) | In right amount | |
| Low-substituted hydroxypropyl cellulose | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, transfer to mixing in the high-speed mixing granulating machine.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, will promptly get the intermediate layer behind the pioglitazone hydrochloride of recipe quantity and the lactose mixing.
3, the method mixing that adopts equivalent to progressively increase microcrystalline Cellulose, lactose and the carboxymethyl starch sodium of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add low-substituted hydroxypropyl cellulose and magnesium stearate mixing, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule and release layer granule are pressed into three-layer tablet.
Embodiment 3
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Ethyl cellulose | 150 | |
| |
30 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 6.8 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
80 | |
| |
50 | |
| |
10 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 | |
| Release layer | Glimepiride | 1 |
| |
100 |
| |
80 | |
| |
30 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 |
Operation:
1, metformin hydrochloride, ethyl cellulose and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, transfer to mixing in the high-speed mixing granulating machine.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, with pioglitazone hydrochloride, microcrystalline Cellulose, lactose, starch and the carboxymethyl starch sodium mixing of recipe quantity, with an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add low-substituted hydroxypropyl cellulose and magnesium stearate mixing, promptly get the intermediate layer granule.
3, the method mixing that adopts equivalent to progressively increase microcrystalline Cellulose, starch, lactose and the carboxymethyl starch sodium of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add low-substituted hydroxypropyl cellulose and magnesium stearate mixing, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule and release layer granule are pressed into three-layer tablet.
Embodiment 4
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Octadecanol | 150 | |
| |
30 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 6.8 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
100 | |
| Release layer | Glimepiride | 1 |
| Mannitol | 110 | |
| |
80 |
| |
30 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, after the octadecanol heat of recipe quantity is melted, add metformin hydrochloride and hydroxypropyl emthylcellulose, mixing, cooling.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, recipe quantity pioglitazone hydrochloride and Celluloasun Microcrystallisatum mixing are promptly got the intermediate layer granule.
3, the method mixing that adopts equivalent to progressively increase the carboxymethyl starch sodium of mannitol, starch, lactose and the Nei Jia of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the carboxymethyl starch sodium and the magnesium stearate mixing that add, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule and release layer granule are pressed into three-layer tablet.
Embodiment 5
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Stearic acid | 150 | |
| |
30 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 6.8 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
100 | |
| Release layer | Glimepiride | 1 |
| |
100 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride of recipe quantity and hydroxypropyl emthylcellulose are crossed 60 mesh sieves respectively, after the stearic acid heat of recipe quantity is melted, add metformin hydrochloride and hydroxypropyl emthylcellulose, mixing, cooling.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, pioglitazone hydrochloride and the microcrystalline Cellulose mixing with recipe quantity promptly gets the intermediate layer granule.
3, the method mixing that adopts equivalent to progressively increase the carboxymethyl starch sodium of microcrystalline Cellulose, lactose and the Nei Jia of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the carboxymethyl starch sodium and the magnesium stearate mixing that add, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule and release layer granule are pressed into three-layer tablet.
Embodiment 6
Prescription is formed:
| Composition | The mg/ sheet | |
| Slow release layer | Metformin hydrochloride | 500 |
| Glyceryl monostearate | 150 | |
| |
30 | |
| 8％PVP(K30) | In right amount | |
| Magnesium stearate | 6.8 | |
| The intermediate layer | Pioglitazone hydrochloride (being equivalent to pioglitazone 15mg) | 16.5 |
| |
70 | |
| |
50 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount | |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 | |
| Release layer | Glimepiride | 1 |
| |
100 | |
| |
80 | |
| Carboxymethyl starch sodium | 6 | |
| 8％PVP(K30) | In right amount |
| Carboxymethyl starch sodium | 4 | |
| Magnesium stearate | 2 |
Operation:
1, the metformin hydrochloride and the hydroxypropyl emthylcellulose of recipe quantity are crossed 60 mesh sieves respectively, after the glyceryl monostearate heat of recipe quantity is melted, add metformin hydrochloride and hydroxypropyl emthylcellulose, mixing, cooling.With 20 mesh sieve granulate.Add the magnesium stearate mixing, promptly get the slow release layer granule.
2, with the carboxymethyl starch sodium mixing of pioglitazone hydrochloride, microcrystalline Cellulose, lactose and the Nei Jia of recipe quantity, with an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the carboxymethyl starch sodium and the magnesium stearate mixing that add, promptly get the intermediate layer granule.
3, the method mixing that adopts equivalent to progressively increase the carboxymethyl starch sodium of microcrystalline Cellulose, lactose and the Nei Jia of the glimepiride of recipe quantity and recipe quantity.With an amount of 8%PVP (K30) wet granulation.Oven dry.With 20 mesh sieve granulate.Add the carboxymethyl starch sodium and the magnesium stearate mixing that add, promptly get the release layer granule.
4, slow release layer granule, intermediate layer granule pressure and release layer granule are made three-layer tablet.
The mensuration of metformin hydrochloride release
Use ZRS-4 type medicine intelligence digestion instrument, according to Chinese Pharmacopoeia version appendix in 2005 drug release determination first method (changeing the basket method) operation, with the release of metformin hydrochloride in phosphate buffer (1000 milliliters) test implementation example 1～6 tablet of pH6.8.Temperature is set at 37.5 ℃ ± 0.5 ℃, and speed setting is 100 rev/mins.With predetermined interval sampling 5mL, and supply medium.Drug release determination result such as table 1 and shown in Figure 1.The result shows that metformin has discharged basically, demonstrates slow release effect in 10 hours.
Table 1 embodiment 1～6 metformin hydrochloride release result
The glimepiride dissolution determination
Use ZRS-4 type medicine intelligence digestion instrument, according to Chinese Pharmacopoeia version appendix in 2005 the drug release determination three therapeutic methods of traditional Chinese medicine (little agar diffusion method) operation, with the dissolution of glimepiride in 0.02% Tris (100 milliliters) test implementation example, 1～6 tablet.Temperature is set at 37.5 ℃ ± 0.5 ℃, and speed setting is 75 rev/mins, sampling in 45 minutes.The dissolution determination result is as shown in table 2.
Table 2 embodiment 1～6 glimepiride dissolution result
| Embodiment | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolution (%) | 95 | 93 | 95 | 94 | 92 | 93 |
The pioglitazone hydrochloride dissolution determination
Use ZRS-4 type medicine intelligence digestion instrument, according to Chinese Pharmacopoeia version appendix in 2005 drug release determination second method (slurry method) operation, with the dissolution of pioglitazone hydrochloride in 0.1mol/lHCl 900ml test implementation example 1～6 tablet.Temperature is set at 37.5 ℃ ± 0.5 ℃, and speed setting is 50 rev/mins, sampling in 30 minutes.The dissolution determination result is as shown in table 3.
Table 3 embodiment 1～6 pioglitazone hydrochloride dissolution result
| Embodiment | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolution (%) | 97 | 98 | 96 | 96 | 98 | 99 |
Stability experiment
There are interaction in glimepiride and pioglitazone hydrochloride and metformin hydrochloride crude drug, all do not mention in document that this is former and the patent.
According to 2005 editions methods of Chinese Pharmacopoeia and the glimepiride pioglitazone metformin slow releasing tablet clinical research quality standard ordered certainly, double-layer tablet (specification: glimepiride/pioglitazone hydrochloride/metformin hydrochloride: 1/15mg/500mg) carry out influence factor's test to contrast enforcement 1, measure the related substance of glimepiride, metformin and pioglitazone respectively, the results are shown in Table 4, table 5 and table 6.
Table 4 influence factor tests related substance (%) result
| 0 |
40 |
60℃ | Illumination | RH75％ | RH95％ | ||||||
| 5 |
10 days | 5 |
10 days | 5 |
10 days | 5 |
10 days | 5 |
10 days | ||
| Glimepiride | 0.19 | 0.35 | 0.37 | 0.81 | 1.15 | 0.28 | 0.32 | 0.32 | 0.36 | 0.27 | 0.38 |
| Metformin | 0.02 | 0.03 | 0.04 | 0.03 | 0.05 | 0.03 | 0.03 | 0.03 | 0.04 | 0.04 | 0.04 |
| Pioglitazone | 0.23 | 0.25 | 0.28 | 0.27 | 0.31 | 0.26 | 0.28 | 0.25 | 0.29 | 0.28 | 0.29 |
As can be seen from Table 4: the stability of metformin hydrochloride and pioglitazone is better, and they do not interact; Glimepiride is less stable under 60 ℃ of conditions, may be because glimepiride self is responsive to temperature, also may be that glimepiride interacts with pioglitazone and metformin with this understanding, for this reason, the glimepiride crude drug is mixed back (comparative example 2～4) respectively with pioglitazone hydrochloride and metformin hydrochloride, carry out 60 ℃ of influence factor's tests simultaneously, measure the glimepiride related substance, the results are shown in Table 5.
60 ℃ of influence factors of table 5 test glimepiride related substance testing result (%)
| 5 |
10 days | |
| Comparative example 2 (glimepiride) | 0.0888 | 0.1003 |
| Comparative example 3 (glimepiride: metformin hydrochloride 1: 500) | 0.2368 | 0.3339 |
| Comparative example 4 (glimepiride: pioglitazone hydrochloride 1: 15) | 0.1675 | 0.2314 |
As can be seen from Table 5: under 60 ℃ of conditions, the stability of glimepiride better; Glimepiride and pioglitazone hydrochloride and metformin hydrochloride all have interaction.
In order further to investigate the degree of glimepiride and pioglitazone hydrochloride and metformin hydrochloride effect, glimepiride and pioglitazone hydrochloride are made ordinary tablet (specification 1mg/15mg) (comparative example 5), glimepiride and metformin hydrochloride make double-layer sustained release tablets (glimepiride release layer wherein, metformin hydrochloride is at slow release layer, specification: 1mg/500mg) (comparative example 6) carry out accelerated test under 30 ℃ and the 40 ℃ of conditions, investigate the related substance of glimepiride, the results are shown in Table 6:
Table 6 accelerated test glimepiride related substance testing result (%)
| 0 |
30 |
40℃ | |||||||
| January | February | March | June | January | February | March | June | ||
| The comparative example 5 | 0.15 | 0.18 | 0.21 | 0.22 | 0.29 | 0.29 | 0.46 | 0.65 | 0.94 |
| The comparative example 6 | 0.17 | 0.25 | 0.39 | 0.52 | 0.82 | 0.59 | 0.86 | 1.35 | 1.98 |
As can be seen from Table 6: glimepiride interacts less with pioglitazone hydrochloride under 30 ℃ of conditions; And glimepiride and metformin hydrochloride have interaction equally under 30 ℃ of conditions.By table 5 and table 6 as can be known, metformin is bigger to the stability influence of glimepiride, and pioglitazone is less to the stability influence of glimepiride, therefore, glimepiride and metformin hydrochloride are separated, simultaneously, pioglitazone hydrochloride is added in the intermediate layer, reduce being in contact with one another of glimepiride and pioglitazone hydrochloride, thereby reduce the interaction of glimepiride and pioglitazone hydrochloride.
Glimepiride is dispersed in release layer, pioglitazone hydrochloride is dispersed in the intermediate layer, metformin hydrochloride is dispersed in slow release layer, make three-layer tablet (specification: 1mg/15mg/500mg) (embodiment 1～6), optional embodiment 1 sample carries out 60 ℃ of influence factor's tests and accelerated test, investigate the related substance of glimepiride, the results are shown in Table 7 and table 8:
60 ℃ of influence factors of table 7 test glimepiride related substance testing result (%)
| Embodiment 1 | 0 day | 0.21 |
| 5 days | 0.43 | |
| 10 days | 0.62 |
Table 8 accelerated test glimepiride related substance (%)
| Embodiment 1 | 0 |
30 |
40℃ | ||||||
| January | February | March | June | January | February | March | June | ||
| 0.15 | 0.17 | 0.19 | 0.20 | 0.25 | 0.20 | 0.39 | 0.59 | 0.81 | |
By table 7 and table 8 as can be seen: with the pioglitazone hydrochloride intermediate layer with glimepiride and metformin hydrochloride centre after, the stability of three-layer tablet of the present invention is significantly improved, and helps long term storage.Metformin drug release feature and glimepiride, pioglitazone hydrochloride dissolution characteristic have been kept simultaneously.
Though described some particular forms of the present invention, obviously can be under the situation of not violating the principle and scope of the present invention make various improvement and combination also belongs to scope of the present invention to the present invention.
Claims (13)
1. stable oral solid drug composition, said composition is made up of following:
Ground floor contains the slow release layer of biguanide and one or more rate of release control materials; With
The second layer contains the release layer of thiazolidinedione and one or more excipient; With
The 3rd layer, contain the release layer of sulfonylureas and optional one or more drug excipients.
2. pharmaceutical composition as claimed in claim 1, said biguanide comprise metformin, phenformin or buformin or its officinal salt.
3. pharmaceutical composition as claimed in claim 2, said biguanide are metformin or its hydrochlorate.
4. pharmaceutical composition as claimed in claim 1, said sulfonylureas comprise glipizide, glimepiride, glibornuride, glibenclamide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide, toluene butyl urea or its officinal salt.
5. pharmaceutical composition as claimed in claim 4, said sulfonylureas is a glimepiride.
6. as claim 1 described pharmaceutical composition, said thiazolidinedione comprises troglitazone, rosiglitazone, pioglitazone or its officinal salt.
7. pharmaceutical composition as claimed in claim 6, wherein, said thiazolidinedione is pioglitazone or its hydrochlorate.
8. pharmaceutical composition as claimed in claim 1, wherein, said rate of release control material accounts for 10%～80% of slow release layer weight.
9. pharmaceutical composition as claimed in claim 1, wherein said rate of release control material comprise and are selected from the following material one or more: cellulose derivative, pregelatinized Starch, starch derivatives, crylic acid resin, carbopol, polyvinyl alcohol, crospolyvinylpyrrolidone, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, alginate, chitosan, gelatin, carrageenin, xanthan gum, stearic acid, glyceryl monostearate, Brazil wax, vegetable oil, guar gum, octadecanol, Synthetic Spermacet, hexadecanol.
10. pharmaceutical composition as claimed in claim 9, wherein said cellulose derivative comprise methylcellulose, cellulose acetate, cellulose vinegar method ester (USPNF:Cellacefate), ethyl cellulose, hydroxyethyl-cellulose, hymetellose hydroxypropyl cellulose, hydroxypropyl cellulose, hypromellose, phthalic acid hypromellose, cellulose acetate-phthalate, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose.
11. pharmaceutical composition as claimed in claim 9, wherein said crylic acid resin comprises EUDRAGIT NE 30 D EUDRAGIT NE 30D, dimethylaminoethyl methacrylate-neutral methacrylic acid esters copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-methyl acrylate copolymer, neutral EUDRAGIT NE 30 D EUDRAGIT NE 30D, methacrylic acid trimethylammonium ethyl ester-acrylate copolymer, methacrylic acid trimethylammonium ethyl ester-methacrylate copolymer, methacrylic acid-methylmethacrylate copolymer or ethoxy acrylic acid methyl ester..
12. as claim 1 described pharmaceutical composition, wherein described biguanides discharged in 6～16 hours fully behind the oral administration, preferred 6～12 hours.
13. a method for preparing stable oral solid drug composition comprises following process:
A. biguanides is dispersed in one or more rate of release control materials, forms slow release mixture or granule, as ground floor;
B. thiazolidinedione is dispersed in pharmaceutically acceptable one or more excipient, forms rapid release mixture or granule, as the intermediate layer;
C. in addition sulfonylureas is dispersed in one or more drug excipients, forms rapid release mixture or granule, as the 3rd layer;
D. mixture or the granule with a step, b step and c step is pressed into three-layer tablet, or is prepared into three-layer tablet by the multilamellar pressed coated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100928301A CN101168059A (en) | 2007-10-12 | 2007-10-12 | Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100928301A CN101168059A (en) | 2007-10-12 | 2007-10-12 | Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101168059A true CN101168059A (en) | 2008-04-30 |
Family
ID=39388912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100928301A Pending CN101168059A (en) | 2007-10-12 | 2007-10-12 | Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101168059A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104208034A (en) * | 2013-12-11 | 2014-12-17 | 重庆康刻尔制药有限公司 | Glimepiride pharmaceutical composition tablet and its preparation method and use |
| CN107205969A (en) * | 2014-12-23 | 2017-09-26 | 韩德株式会社 | Treating diabetes pharmaceutical composition |
| CN112494485A (en) * | 2020-11-26 | 2021-03-16 | 北京福元医药股份有限公司 | Saxagliptin and metformin hydrochloride sustained-release tablet |
-
2007
- 2007-10-12 CN CNA2007100928301A patent/CN101168059A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104208034A (en) * | 2013-12-11 | 2014-12-17 | 重庆康刻尔制药有限公司 | Glimepiride pharmaceutical composition tablet and its preparation method and use |
| CN104208034B (en) * | 2013-12-11 | 2017-11-07 | 重庆康刻尔制药有限公司 | A kind of Glimepiride medicinal composition tablets, preparation method and applications |
| CN107205969A (en) * | 2014-12-23 | 2017-09-26 | 韩德株式会社 | Treating diabetes pharmaceutical composition |
| CN112494485A (en) * | 2020-11-26 | 2021-03-16 | 北京福元医药股份有限公司 | Saxagliptin and metformin hydrochloride sustained-release tablet |
| CN112494485B (en) * | 2020-11-26 | 2022-04-01 | 北京福元医药股份有限公司 | Saxagliptin and metformin hydrochloride sustained-release tablet |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2226396C2 (en) | Solid dosed medicinal formulation for oral using containing combination of metformin and glibenclamide | |
| EP1738751B1 (en) | Spaced drug delivery system | |
| CN105147662A (en) | Pharmaceutical composition comprising glucopyranosyl diphenylmethane derivatives, pharmaceutical dosage form thereof, process for their preparation and uses thereof for improved glycemic control in a patient | |
| CN104586834A (en) | Pharmaceutical composition of empagliflozin and metformin and preparation method thereof | |
| CN110339176A (en) | Composition of medicine and preparation method thereof comprising gigue column spit of fland and melbine | |
| CN101167731A (en) | Dispersible tablet containing metformin and glibenclamide and preparation method thereof | |
| CN102266325B (en) | Melbine crystal and medicinal composition of melbine and saxagliptin and preparation method thereof | |
| CN101990427A (en) | Combination of mitiglinide and metformin and process for preparing same | |
| KR20060096728A (en) | Sustained-release formulation and combinative sustained-release tablet with sustained-release pellets | |
| CN101168059A (en) | Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof | |
| US20040147564A1 (en) | Combinations of glimepiride and the thiazolidinedione for treatment of diabetes | |
| CN102755310B (en) | A kind of composition medicine preparation containing levodopa | |
| CN101168060B (en) | Stable medicinal composition containing biguanide and sulfonylurea and preparation method thereof | |
| CN102727894B (en) | A kind of pharmaceutical composition and application thereof for the treatment of diabetes and complication thereof | |
| CN102119931A (en) | Novel metformin hydrochloride slow-releasing tablet and preparation method thereof | |
| CN115813874B (en) | Preparation method of oral three-way combined hypoglycemic double-release tablet and preparation thereof | |
| CN109010298B (en) | Metformin and glipizide compound composition and preparation method thereof | |
| CN103417496A (en) | Method for preparing metformin hydrochloride controlled-release pellet preparation | |
| CN1331470C (en) | Method for preparing high stripping-degree hautriwaic glipizide capsule | |
| WO2005107717A2 (en) | Oral dosage form for the extended release of biguanide and sulfonylurea | |
| CN103705515B (en) | The preparation method of the pharmaceutical composition that contains Repaglinide and Metformin hydrochloride | |
| CN103505466B (en) | Solid compound preparation containing metformin hydrochloride and glimepiride and its production and use | |
| CN100490808C (en) | Gliquilone slow-releasing preparation | |
| CN101011364A (en) | Slow release preparation of metformin rosiglitazone | |
| CN103271907B (en) | Oral medicine composition consisting of berberine and melbine, and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080430 |