CN102267959B - Repaglinide crystal, preparation method thereof, and solid oral preparation containing same - Google Patents
Repaglinide crystal, preparation method thereof, and solid oral preparation containing same Download PDFInfo
- Publication number
- CN102267959B CN102267959B CN 201110188700 CN201110188700A CN102267959B CN 102267959 B CN102267959 B CN 102267959B CN 201110188700 CN201110188700 CN 201110188700 CN 201110188700 A CN201110188700 A CN 201110188700A CN 102267959 B CN102267959 B CN 102267959B
- Authority
- CN
- China
- Prior art keywords
- repaglinide
- parts
- crystal
- preparation
- solid orally
- 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.)
- Active
Links
Images
Abstract
The invention relates to a repaglinide crystal, a preparation method thereof, and a solid oral preparation containing the same. The particle size of the crystal is 1 to 5 mu m. The solid oral preparation is a tablet prepared from repaglinide, compressible starch, microcrystalline cellulose calcium hydrogen phosphate, polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, glycerin, poloxamer, meglumine, iron oxide and magnesium stearate. Raw materials and accessories for the tablet are safe and easily available; the prepared tablet has good dissolvability and a good dissolution rate and enables stable plasma concentration; prepared repaglinide tablets have the function characteristics of rapid absorption, fast action, a fast clearance speed in vivo and a short half life and can be used for treating 2 type diabetes. Prescription for the repaglinide cystals is reasonable; the repaglinide cystals have stable and reliable quality and good disintegration time and dissolution rates; repaglinide tablets are prepared through a direct compression process, which enables a simple process, a short production period and low production cost; therefore, industrial production of the repaglinide tablets is easy to realize.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of repaglinide crystal, its preparation method and contain the solid orally ingestible of this crystal.
Background technology
Repaglinide, English name: repaglinide, its chemical name is: S (+)-2-oxyethyl group-4-{2-[(3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino]-the 2-oxoethyl } phenylformic acid, molecular formula: C
27H
36N
2O
4, molecular weight: 452.6, structural formula is as follows:
Being white in color under the repaglinide normal temperature or the yellow-white powder, is a kind of novel fugitive oral insulin secretion accelerating antidiabetic drug with non-sulfourea insulin secretion accelerating of amino acid structure.By (moral) Boehringer Ingelheim company development, the exploitation of Novo Nordisk company and in April, 1998 in U.S.'s Initial Public Offering, go on the market in Britain October in the same year.Repaglinide stimulating pancreas uelralante reduces glucose level rapidly, this effect depends on the β of function cell in the pancreas islet, from other oral insulin secretion accelerating antidiabetic drug different be repaglinide by with different receptors bind to close ATP one dependent potassium channel in the B cytolemma, it makes the β cell depolarization, open calcium channel, the inflow of calcium is increased, this process is induced the secretion of Regular Insulin in the β cell.
Repaglinide is a kind of new oral antidiabetic drug, its hypoglycemic mechanism mainly is by closing the potassium channel of ATP sensitivity, and stimulate insulin secretion, because it absorbs fast, the onset in rear 15 minutes of taking medicine, reaching blood medicine peak times is 1 hour, metabolism is rapid, transformation period is 1 hour, at once takes before each dinner, can simulate the physiological insulin secretion, reach blood sugar reducing function, that the title that " blood sugar regulator used during user having meals " arranged, repaglinide absorb is rapid, rapid-action, removing speed in vivo also relatively very fast, the transformation period is short, has the effect characteristics of " open soon-speed close ".
Although the repaglinide structure is different from sulfonephthalein arteries and veins class, also can with B cell on the ATP sensitivity the potassium channel receptors bind and cause insulin secretion.No matter on an empty stomach or take during feed and all absorb well repaglinide reaches plasma peaks after 30～60 minutes, and is that tachymetabolism is nonactive thing by the CYP3A4 enzyme in liver, most ofly removes plasma half life approximately 1 hour with bile.Hepatic disorder person plasma drug level is higher.Plasma insulin concentration raises with serum Chinese traditional medicine concentration to be increased, and generally is returned to again basal level before having meal next time.
The people such as Yang Huazhang have delivered the progress (Chinese practical internal medicine journal the 4th phase of the 20th volume April in 2000) of hypoglycemic new drug repaglinide, its civilian described repaglinide can obviously improve plasma insulin level, lowering blood glucose, glycolated hemoglobin (HbA1c) level, its effect power depends on blood sugar concentration height and dosage in the body, the blood sugar of hypoglycemia and Tai Gao all can reduce the ability of repaglinide insulin secretion accelerating, the mechanism that it stimulates insulin secretion is similar with sulfonylurea drugs: is combined by the specific receptors on the beta Cell of islet film, thus the ATP dependency K on the promotion islet cells film
+Pathway closure suppresses K
+From the β cell drain, make the cytolemma depolarize, thus the Ca that open voltage relies on
2+Passage makes extracellular Ca
2+Enter in the cell, promote to store insulin secretion.But the site of repaglinide and β Cell binding and sulfonylurea drugs are also different, also do not have sulfonylurea drugs can directly cause the effect of Regular Insulin exocytosis.The repaglinide cell (such as 1 type patient's islet cells) impaired to function can not play a role, and re paglinide is very little on the ionic channel impact of cardiac muscle and skeletal muscle.Conclusion: repaglinide can improve diabetes B patient's different blood glucose levels, its curative effect is better than or reaches the standard of sulfonylurea drugs, but security is apparently higher than such medicine, there is not severe side effect, can adjust dose according to meal time and dining number of times flexibly, diabetic subject's compliance is better.Repaglinide is by the secretion of imitation physiological Regular Insulin, can control regularly full-time average blood sugar level, avoid postprandial hyperglycemia and hypoglycemia afterreaction hyperglycemia, the generation of controlling and slowing down complication long term to diabetes, reduce case fatality rate, the life quality that improves the patient has positive meaning.Can be used as a line medication for the treatment of diabetes B.
The people such as Chen Yan have delivered pharmacological action and the clinical application (China Dispensary the 8th phase of the 12nd volume calendar year 2001) of hypoglycemic new drug repaglinide, repaglinide (repaglinide, RGLN) be a kind of hypoglycemic new drug of non-sulfonylurea insulin secretion accelerating, RGLN can be used as type ii diabetes first-line treatment medicine.This paper makes a summary with regard to pharmacological action and the clinical application of RGLN.The clinical blood sugar for control type ii diabetes patient of RGLN, curative effect reaches or is better than sulfonylureas, but security is apparently higher than the latter.Clinically can adjust dosage according to meal time and dining number of times.RGLN is by the secretion of simulation physiology Regular Insulin; can control more regularly average blood sugar level every day; avoid postprandial hyperglycemia or hypoglycemia afterreaction hyperglycemia, to control in long term of diabetes and slow down generation, the protection pancreas islet of complication the normal beta cell, reduce mortality ratio, improve all important in inhibitings of Quality of Life.
The people such as Li Lingwei have delivered the effectiveness study of repaglinide, and (February 2011, Vol.9, No.6 Guide o f China Medicine), its objective is that the observation repaglinide is to the action effect of diabetes B patient fasting plasma glucose (FBG), postprandial blood sugar (PBG), glycolated hemoglobin (HbA1c), blood fat; Method is to adopt open research, observes 30 routine diabetes B patients, own control before and after the treatment; The result: repaglinide can make fasting plasma glucose and postprandial blood sugar descend, and the latter descends more remarkable; Glycolated hemoglobin, triacylglycerol are significantly descended; Conclusion is that repaglinide can effectively reduce on an empty stomach and postprandial blood sugar, finally reduces glycolated hemoglobin and triacylglycerol, reduces the generation of its chronic complicating diseases.And have the advantages that F.F. goes out soon, make the patient have good conformability, and do not find serious adverse reaction.Discuss: repaglinide is a kind of insulin secretion stimulant, observe by 30 routine patients being continued the medication in 12 weeks, can find out that repaglinide can make the level of FBG, PBG significantly descend, and the wherein reduction of HbA1c, prompting patient's the clinical state of an illness is controlled, thereby plays the effect that improves diabetic vascular complications.Show that simultaneously repaglinide has played the effect that reduces the TG level.Repaglinide is rapid because of onset, and the time length is short, goes out soon characteristics and have unique F.F., can have meal and take medicine, and does not have meal and does not take medicine, and can increase patient's conformability, hypoglycemia occurs without 1 example simultaneously, and hepatic and renal function is had no significant effect, and has embodied security.In a word, repaglinide is as blood sugar regulator used during user having meals, can effectively reduce postprandial hyperglycemia, have meal simultaneously and take medicine, do not have meal and do not take medicine, increased the handiness of medication, make things convenient for the patient to take, be a kind of effective and safe, the medicine that conformability is fabulous plays the effect that improves diabetes B patient prognosis by effective hypoglycemic and minimum hypoglycemia.
The people such as Xie Zibin have delivered the Study on relative bioavailability (Central-South pharmacy 2009 year September 7th volume 9th phase) of repaglinide dispersible tablet in healthy human body, research repaglinide dispersible tablet and the relative bioavailability of repaglinide in Chinese male healthy volunteer body, oral test preparation repaglinide dispersible tablet, the reference preparation repaglinide, reaching a conclusion is to be subjected to test preparation and reference preparation to have bioequivalence.
The people such as Ding Gang have delivered preparation and the quality standard research (ACAD J GCP of repaglinide, 2009,25 (6)), this determines that best prescription is combined as the MCC of 74mg, 5mgPVP-K30, the CCNa of 20mg, the solubleness of repaglinide is low, bioavailability is poor, so mainly considers how to improve its dissolution rate during Formulation.In the literary composition, cross-linked carboxymethyl cellulose is received and can be made the instantaneous disintegration of tablet as disintegrating agent, thereby improves dissolution rate; MCC has larger specific surface area, excellent adsorption, and chance water rapidly disintegration forms uniform stickiness suspension, increases dissolution rate; The aqueous solution of tamanori PVP2K30 can make the hydrophobic particle surface hydrophilicity increase, and accelerates disintegration and stripping.
Zheng Xin has delivered repaglinide and has treated new diagnosed type 2 diabetic 20 routine clinical analysiss (Proceeding of Clinical Medicine, Feb.2009, Vol 19 No.2A), state repaglinide as a kind of novel blood sugar regulator used during user having meals, be a kind of safely and effectively medicine, can significantly reduce postprandial blood sugar and fasting plasma glucose, few side effects, patient compliance is good, is the ideal chose of the new diagnosed type 2 diabetic patients of China.
The people such as Hu Jinhong have delivered repaglinide pharmacokinetics and pharmacodynamic studies (journal 2002Apr of The 2nd Army Medical College in Chinese visible human; 23 (4)), reach a conclusion: the repaglinide onset is rapid, and acting duration is short, is applicable to mealtime blood sugar and regulates, and can be used for treating diabetes B.
CN101548972A has announced a kind of solid composite medicament of repaglinide, and its existence form can be dispersible tablet, orally disintegrating tablet, capsule, is used for the treatment of the diabetes B that dietary control and motion exercise can not effectively be controlled hyperglycemia.
CN101695491A has announced a kind of sustained release preparation of repaglinide, its invention relates to sustained release preparation of repaglinide and preparation method thereof, mainly be the problem that solves insoluble drug repaglinide slowly-releasing, as slow-release material repaglinide made slow release formulation with Vltra tears, Rikemal B 200, ethyl cellulose, acrylic resin, Ka Bopu, stearyl alcohol, hexadecanol, stearic acid, Xylo-Mucine, sodium alginate etc.
Because the solubleness of repaglinide is low, bioavailability is poor, mainly considers how to improve its dissolution rate during above-mentioned Formulation.The inventor is devoted for years in the research of bulk drug repaglinide, ultrasonic wave is introduced in the crystallisation process of bulk drug repaglinide, obtained the very little repaglinide crystal of a kind of granularity, find more pleasantly surprisedly that in the research of the solid orally ingestible that carries out subsequently the solid orally ingestible dissolution rate that adopts this repaglinide crystal and pharmaceutical excipient to be prepared from has also obtained obvious improvement, thereby finished the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of repaglinide crystal.
The second purpose of the present invention is to provide a kind of preparation method of repaglinide crystal, and the method is introduced ultrasonic wave in the crystallisation process of bulk drug repaglinide, has obtained the very little repaglinide crystal of a kind of granularity.
The 3rd purpose of the present invention is to provide a kind of solid orally ingestible, and this solid orally ingestible contains the crystal that repaglinide crystal of the present invention and described preparation method make.Solid orally ingestible solvability provided by the present invention is good, has good dissolution rate, and Plasma Concentration is steady, absorbs the effect characteristics that removing speed rapid, rapid-action, in vivo is fast, the transformation period is short, can be used for treating diabetes B; Its preparation technology is simple, convenient, feasible, favorable reproducibility.
For realizing the first purpose of the present invention, the present invention adopts following technical scheme:
A kind of repaglinide crystal, wherein, described repaglinide crystal uses that characteristic peak is 4.8 °, 13.6 °, 14.9 °, 15.2 °, 16.0 °, 19.1 °, 21.2 ° and 24.1 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Cu-K alpha-ray measures.
According to aforesaid repaglinide crystal, wherein, the particle diameter of described repaglinide crystal is 1～5 μ m.
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of repaglinide crystal, the method comprises the steps:
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 2-ethylhexyl succinate sodium sulfonate solution as dispersion medium;
3) under ultrasonic field, with microsyringe disperse phase solution is joined in the dispersion medium, continue ultrasonic, centrifugation goes out the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying namely gets the repaglinide crystal.
The concentration of the 2-ethylhexyl succinate sodium sulfonate solution according to aforesaid preparation method, wherein, step 2) is 0.05～0.3molL
-1The power of ultrasonic field step 3) is 0.1～0.3KW, described ultrasonic be ultrasonic 1～3 minute, described centrifugal be at 9000～11000rmin
-1Condition under centrifugal, described washing centrifugally operated is repeated washing centrifugally operated 2～4 times, described vacuum-drying is vacuum-drying 8～12h.
For realizing the 3rd purpose of the present invention, the present invention adopts following technical scheme:
A kind of solid orally ingestible, wherein, described solid orally ingestible contains the repaglinide crystal of repaglinide crystal of the present invention or preparation method of the present invention preparation.
According to aforesaid solid orally ingestible, wherein, described solid orally ingestible comprises repaglinide, amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, Luo Shamu, glycerine, meglumine, ferric oxide and Magnesium Stearate.
According to aforesaid solid orally ingestible, wherein, described solid orally ingestible is by repaglinide crystal 0.5-3 part, 10～100 parts of amylum pregelatinisatums, 10～80 parts of Microcrystalline Celluloses, 10～35 parts of secondary calcium phosphates, 10～50 parts of polyvinylpyrrolidones, 10～50 parts of croscarmellose sodiums, 10～30 parts of poloxamers, 10～30 parts of glycerine, 10～30 parts of meglumines, 10～30 parts of ferric oxide and 1～3 part of repaglinide of making of Magnesium Stearate.
According to aforesaid solid orally ingestible, wherein, described solid orally ingestible is by 2 parts of repaglinides, 80 parts of amylum pregelatinisatums, 60 parts of Microcrystalline Celluloses, 20 parts of secondary calcium phosphates, 28 parts of polyvinylpyrrolidones, 35 parts of croscarmellose sodiums, 10 parts of poloxamers, 10 parts of glycerine, 10 parts of meglumines, 10 parts of ferric oxide and 1 part of repaglinide of making of Magnesium Stearate.
According to aforesaid solid orally ingestible, wherein, the preparation method of described repaglinide is as follows:
1) auxiliary material amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, Luo Shamu, glycerine, meglumine, ferric oxide and Magnesium Stearate are carried out pre-treatment, for subsequent use;
2) take by weighing the repaglinide crystal by described consumption and above-mentioned auxiliary material except Magnesium Stearate for subsequent use adopts the equivalent method of progressively increasing to carry out mixing, add again Magnesium Stearate, mixing, and the control mixing time obtains powder mix in 5min;
3) sampling detects;
4) detect and resulting mixed powder to be carried out direct pressed powder after qualified, namely get described repaglinide.
According to aforesaid solid orally ingestible, wherein, described pre-treatment was dried by the fire 2～3 hours under 60～80 ℃ of conditions for first auxiliary material being pulverized again, and then crossed 60～80 mesh sieves.
Below describe the present invention in detail:
Repaglinide is almost insoluble in water, and the solubleness in water is 0.005mg/mL only, causes the vitro Drug dissolution rate poor, causes its bioavailability low.
The inventor is devoted for years in the research of bulk drug repaglinide, ultrasonic wave is introduced in the crystallisation process of bulk drug repaglinide, has obtained the very little repaglinide crystal of a kind of granularity, and primary and foremost purpose of the present invention just is to provide this crystal.
Specifically, repaglinide crystal provided by the present invention uses that characteristic peak is 4.8 °, 13.6 °, 14.9 °, 15.2 °, 16.0 °, 19.1 °, 21.2 ° and 24.1 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Cu-K alpha-ray measures.
The particle diameter of this crystal is 1～5 μ m.
Medicine in vivo absorption rate is usually determined by the speed of dissolving, medicine in the solid preparation is before being absorbed, must and dissolve the process that then transfers solution to through disintegration, if medicine is difficult for discharging from preparation or the dissolution rate of medicine is very slow, then the absorption rate of said preparation Chinese traditional medicine or degree just might have problems, on the other hand, some pharmacological action is violent, safety index is little, the medicine dissolution rate is too fast rapidly if absorb, and may produce obvious untoward reaction, and the time of keeping drug effect also will shorten, in this case, the dissolution rate of preparation of traditional Chinese medicine be should give control.Among the present invention, repaglinide is water-soluble hardly, therefore adopts common repaglinide and pharmaceutical excipient to make common tablet and can exist repaglinide just to be difficult for the defective that discharges from preparation.Among the present invention, the repaglinide that provides is that a kind of particle diameter is the superfine microcrystal of 1～5 μ m, can significantly improve the solvability of repaglinide, repaglinide can be discharged from preparation with speed faster, thus improve medicine dissolution rate, improve its bioavailability.And the granularity of repaglinide crystal provided by the present invention is very little, and reduces the onset time that granularity is conducive to shorten medicine, improves the dissolution rate of medicine and improves its bioavailability.
The present invention also provides the preparation method of described repaglinide crystal, and the method comprises the steps:
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 2-ethylhexyl succinate sodium sulfonate solution as dispersion medium;
3) under ultrasonic field, with microsyringe disperse phase solution is joined in the dispersion medium, continue ultrasonic, centrifugation goes out the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying namely gets the repaglinide crystal.
It is the repaglinide superfine microcrystal of 1～5 μ m that the present invention has prepared particle diameter easily with the method for ultrasonic wave and microemulsion compound use, and in the preparation process, can realize easily the isolation and purification of repaglinide micro mist and tensio-active agent, tensio-active agent and organic solvent also can be recycled easily.
The concentration of the 2-ethylhexyl succinate sodium sulfonate solution in the aforesaid method, step 2) is 0.05～0.3molL
-1The power of ultrasonic field step 3) is 0.1～0.3KW, described ultrasonic be ultrasonic 1～3 minute, described centrifugal be at 9000～11000rmin
-1Condition under centrifugal, described washing centrifugally operated is repeated washing centrifugally operated 2～4 times, described vacuum-drying is vacuum-drying 8～12h.
In the research of the preparation that carries out subsequently, find to adopt the dissolution rate of the solid orally ingestible that this repaglinide crystal and pharmaceutical excipient be prepared to obtain obvious improvement more pleasantly surprisedly.Therefore, the present invention also aims to the solid orally ingestible that provides this repaglinide crystal and pharmaceutical excipient to make.
Described solid orally ingestible is acceptable oral dosage form on the pharmaceutics, and its composition comprises repaglinide, amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, Luo Shamu, glycerine, meglumine, ferric oxide and Magnesium Stearate.
Preferably make repaglinide by the material of following weight part:
1～3 part of repaglinide 0.5-3 part, 10～100 parts of amylum pregelatinisatums, 10～80 parts of Microcrystalline Celluloses, 10～35 parts of secondary calcium phosphates, 10～50 parts of polyvinylpyrrolidones, 10～50 parts of croscarmellose sodiums, 10～30 parts of poloxamers, 10～30 parts of glycerine, 10～30 parts of meglumines, 10～30 parts of ferric oxide and Magnesium Stearate
More preferably, make repaglinide by 1 part of 2 parts of repaglinides, 80 parts of amylum pregelatinisatums, 60 parts of Microcrystalline Celluloses, 20 parts of secondary calcium phosphates, 28 parts of polyvinylpyrrolidones, 35 parts of croscarmellose sodiums, 10 parts of poloxamers, 10 parts of glycerine, 10 parts of meglumines, 10 parts of ferric oxide and Magnesium Stearate.
Repaglinide of the present invention adopts direct compression process, if auxiliary material is selected and consumption is incorrect, can make the tablet at short notice can not disintegration and dissolving, therefore a generation sand type in making mouthful.The present invention adopts amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, poloxamer, glycerine, meglumine, ferric oxide and Magnesium Stearate as auxiliary material.
Microcrystalline Cellulose (MCC) compressibility is good, have concurrently bonding, help the effects such as stream, be applicable to direct compression process.The tablet that contains MCC has the characteristic that disintegration is fast, hardness is large and fragility is low, because a little less than its swelling behavior, general and strong auxiliary material such as the low-substituted hydroxypropyl cellulose (L-HPC) of other swelling behaviors united use.
Croscarmellose sodium has stronger wetting ability, swelling property and water absorbability, meet water-soluble swollenly and do not dissolve, its particle surface has crude structure, can strengthen medicinal powder and intergranular tessellation, have simultaneously larger surface-area and porosity, compressibility is strong, easily is shaped, and the compressed tablet outward appearance is neat and artistic, hardness is large and disintegration is rapid, dissolution rate is high, is good disintegrating agent and tamanori, and consumption is generally 2%～5%.
Polyvinylpyrrolidone (PVPP) has efficient capillary effect and significant hydration, and disintegration is effective.Studies show that, when the content of PVPP was 5%～8%, wetting time was short, and between 8%～15%, wetting time prolongs on the contrary.When PVPP content is about 8%, can obtain best disintegrating property.Wu Yisheng has carried out the preparation research of oral cavity quick disintegrating slice, finds that hardness is 5kgf when selecting 8%PVPP as disintegrating agent, and blank fast disintegrating tablet had the shortest disintegration time when sheet directly was 8mm.
MCC is good disintegrating agent and weighting agent, and compressibility is good, and has bonding concurrently, helps the effects such as stream, but swelling property is poor; L-PHC has very strong absorptive and swelling property, and both couplings have preferably disintegration effect, but the MCC grittiness is stronger, so consumption is too much unsuitable; PVPP has stronger capillary action and hydratability, and water absorbability is strong, and disintegration is rapid.The three has complementary advantages, and makes the disintegration of tablet effect better.
Experimental result shows: adopt this prescription, technique can successfully prepare repaglinide, this tablet has following characteristics: the supplementary material that 1. adopts is easy to get safely; 2. the constant product quality of making, rapidly disintegration and dissolving, rapid-action, good mouthfeel is without sand type; 3. absorb rapid, rapid-action; 4. in vivo removing speed is fast, the transformation period is short; 5. technique is simple, and cost is low, and is profitable.
The present invention also further provides the preparation method of described repaglinide, and the method comprises the steps:
1) auxiliary material amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, Luo Shamu, glycerine, meglumine, ferric oxide and Magnesium Stearate are carried out pre-treatment, for subsequent use;
2) take by weighing the repaglinide crystal by described consumption and above-mentioned auxiliary material except Magnesium Stearate for subsequent use adopts the equivalent method of progressively increasing to carry out mixing, add again Magnesium Stearate, mixing, and the control mixing time obtains powder mix in 5min;
3) sampling detects;
4) detect and resulting mixed powder to be carried out direct pressed powder after qualified, namely get described repaglinide.
Among the above-mentioned preparation method, described pre-treatment was dried by the fire 2～3 hours under 60～80 ℃ of conditions for first auxiliary material being pulverized again, and then crossed 60～80 mesh sieves.
Among the preparation method of the present invention, first auxiliary material is carried out pre-treatment, can be so that the abundant mixing of main ingredient composition and can Uniform Dispersion, so that this tablet has good stability, has preferably disintegration and dissolution rate.
Among the preparation method of the present invention, step 2) in, first that other material is mixed, mix with Magnesium Stearate more at last, and the control mixing time can be avoided the generation of hydrophobic effect in 5min.
Among the preparation method of the present invention, step 3) sampling described in detects mainly carries out main content inspection and Weight loss on drying detection, and for the ease of control moisture, the technique means that this commonly uses for this area is for conventionally known to one of skill in the art.
Compared with prior art, the present invention has following advantage:
(1) repaglinide crystal provided by the present invention can significantly improve the solvability of repaglinide, thereby improves the dissolution rate of medicine, improves bioavailability;
(2) method of ultrasonic wave and microemulsion compound use has been prepared particle diameter easily is the repaglinide superfine microcrystal of 1～5 μ m in the present invention, and in the preparation process, can realize easily the isolation and purification of repaglinide micro mist and tensio-active agent, tensio-active agent and organic solvent also can be recycled easily;
(3) solid orally ingestible provided by the present invention, owing to containing repaglinide crystal of the present invention or adopting the prepared repaglinide crystal of the inventive method, this crystal can discharge with speed faster repaglinide from preparation, thus improve medicine dissolution rate, improve its bioavailability.And the granularity of repaglinide crystal provided by the present invention is very little, and reduces the onset time that granularity is conducive to shorten medicine, improves the dissolution rate of medicine and strengthens drug effect.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of the prepared repaglinide crystal of the embodiment of the invention 1;
Fig. 2 is repaglinide accumulation stripping curve comparison diagram.
Embodiment
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The preparation of [embodiment 1] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 2-ethylhexyl succinate sodium sulfonate solution as dispersion medium;
3) under ultrasonic field, with microsyringe disperse phase solution is joined in the dispersion medium, continue ultrasonic, centrifugation goes out the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying namely gets the repaglinide crystal.
The particle diameter of prepared repaglinide crystal is 1 μ m, and the middle characteristic peak of the X-ray powder diffraction pattern (seeing Fig. 1) that uses the Cu-K alpha-ray to measure is 4.8 °, 13.6 °, 14.9 °, 15.2 °, 16.0 °, 19.1 °, 21.2 ° and 24.1 ° of demonstrations at 2 θ.
The preparation of [embodiment 2] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 0.05molL
-12-ethylhexyl succinate sodium sulfonate solution is as dispersion medium;
3) be under the ultrasonic field of 0.1KW at power, with microsyringe disperse phase solution joined in the dispersion medium, continued ultrasonic 1 minute, at 9000rmin
-1Condition under high speed centrifugation isolate the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated 2 times, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying 8h namely gets the repaglinide crystal.
The particle diameter of gained repaglinide crystal is 5 μ m, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 3] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 0.3molL
-12-ethylhexyl succinate sodium sulfonate solution is as dispersion medium;
3) be under the ultrasonic field of 0.3KW at power, with microsyringe disperse phase solution joined in the dispersion medium, continued ultrasonic 3 minutes, at 11000rmin
-1Condition under high speed centrifugation isolate the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated 4 times, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying 12h namely gets the repaglinide crystal.
The particle diameter of gained repaglinide crystal is 3 μ m, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 4] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 0.2molL
-12-ethylhexyl succinate sodium sulfonate solution is as dispersion medium;
3) be under the ultrasonic field of 0.2KW at power, with microsyringe disperse phase solution joined in the dispersion medium, continued ultrasonic 3 minutes, at 10000rmin
-1Condition under high speed centrifugation isolate the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated 3 times, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying 10h namely gets the repaglinide crystal.
The particle diameter of gained repaglinide crystal is 4 μ m, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 5] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 0.1molL
-12-ethylhexyl succinate sodium sulfonate solution is as dispersion medium;
3) be under the ultrasonic field of 0.15KW at power, with microsyringe disperse phase solution joined in the dispersion medium, continued ultrasonic 1.5 minutes, at 9800rmin
-1Condition under high speed centrifugation isolate the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated 3 times, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying 11h namely gets the repaglinide crystal.
The particle diameter of gained repaglinide crystal is 2 μ m, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 6] repaglinide crystal
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 0.25molL
-12-ethylhexyl succinate sodium sulfonate solution is as dispersion medium;
3) be under the ultrasonic field of 0.2KW at power, with microsyringe disperse phase solution joined in the dispersion medium, continued ultrasonic 2 minutes, at 10000rmin
-1Condition under high speed centrifugation isolate the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated 3 times, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying 9h namely gets the repaglinide crystal.
The particle diameter of gained repaglinide crystal is 5 μ m, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
[preparation 1] repaglinide
Preparation technology:
1) auxiliary material amylum pregelatinisatum, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Xylo-Mucine and Magnesium Stearate are carried out pre-treatment, for subsequent use;
2) take by weighing by described consumption and implement 1 repaglinide crystal and the above-mentioned auxiliary material employing equivalent method of progressively increasing except Magnesium Stearate for subsequent use and carry out mixing, add again Magnesium Stearate, mixing, and control mixing time in 5min, obtain powder mix;
3) sampling detects;
4) detect and resulting mixed powder to be carried out direct pressed powder after qualified and obtain repaglinide;
Below be example of formulations 2-6, supplementary material title and consumption see the following form 1, wherein the used repaglinide crystal of example of formulations is the prepared repaglinide crystal of corresponding embodiment, be corresponding embodiment 2 prepared repaglinide crystal such as example of formulations 2 used repaglinide crystal, concrete preparation method sees example of formulations 1.
Table 1
Test example 1
This test example detects content, related substance and the dissolution rate of the prepared repaglinide of the present invention, and it the results are shown in Table 2:
Table 2, assay
Test example 2
1 object and method
1.1 case is selected
Choose 2009 60 routine diabetes B patients so far all meet WHO clinical criteria in 1998.Male 30 examples wherein, woman's 30 examples, year mean age (50.0 ± 5.6), be and accept the diet exercise therapy, and used the treatment of biguanides or other sulfonylureas, but glycemic control is still undesirable, fasting plasma glucose (FBG)＞8.0mmol/L, postprandial blood sugar (PBG)＞11.0mmol/L is not taken lipid-regulation medicine simultaneously and is surpassed more than 4 weeks.
1.2 method
Adopt open research, own control before and after the patient treatment.Medicine in inactive other sulfonylurea of all cases when entering research, all the other treatment plans are constant.During the research beginning 60 routine patients are divided into two groups, every group of 30 examples (male 15 examples, women 15 examples) add respectively the repaglinide 0.5mg with NovoNorm (repaglinide) and example of formulations of the present invention 1,3 times/d; 19 routine patient's Postprandial glucose control gastrointestinal disease patients wherein, corresponding dose before the meal is added to 1.0mg, 1.5mg or 2.0mg.Add 0.5mg when snack is arranged, oral before the meal, treatment is totally 12 weeks.Before and after treatment, look into respectively FBG, PBG2h, glycolated hemoglobin (HbA
1C), TG, CHOL, HDL.
1.3 statistical method
Data represent with mean ± standard deviation, each index before and after relatively treating.
2 results
2.1 the blood sugar reducing function of repaglinide
Repaglinide in treatment of patients is after 12 weeks, patient FBG, PBG, HbA
1C treats front remarkable improvement, illustrate that repaglinide has good blood sugar reducing function to diabetes B, and repaglinide blood sugar reducing function of the present invention is more obvious, the results are shown in Table 3.
The blood sugar reducing function of table 3, repaglinide
| Project | The example number | Sex (example) | FBG | PBG2h | Glycolated hemoglobin | |
| Before taking medicine | 60 | Man | 30 |
＞8.0mmol/L | ＞11.0mmol/L | 8.0±0.2 |
| NovoNorm | 30 examples | Man 15 woman 15 | 5.5±0.6 | 7.5±0.8 | 6.0±0.6 | |
| The |
30 examples | Man 15 woman 15 | 5.0±0.6 | 7.1±0.8 | 5.5±0.6 |
2.2 repaglinide is on the impact of blood fat
In lowering blood glucose, the Repaglinide in treatment of patients in 12 weeks still can make diabetes B patient's serum triglyceride level reduce, and the effect of repaglinide of the present invention is more obvious, but little on cholesterol and high-density lipoprotein (HDL) impact.The results are shown in Table 4.
Lipid before and after table 4, the Repaglinide in treatment of patients
| Project | Triacylglycerol | Cholesterol | High-density lipoprotein (HDL) |
| Before taking medicine | 2.3±0.6 | 6.4±0.2 | 1.1±0.3 |
| NovoNorm | 1.2±0.2 | 6.3±0.9 | 1.1±0.1 |
| The present invention | 1.0±0.2 | 6.2±0.9 | 1.0±0.1 |
2.3 untoward reaction
The 30 routine patients that receive treatment all occur without hypoglycemia and liver and kidney dysfunction occurs.
The repaglinide prepared to other example of formulations of the present invention also carried out above-mentioned test, and the result of its acquisition is similar.
Comparative example 1
Get 6 of repaglinides, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), with 0.1molL
-1Hydrochloric acid soln 100mL is dissolution medium, rotating speed 50rmin
-1, operation is taken a sample during 30min in accordance with the law, filters to get trial-product liquid; Get the repaglinide reference substance an amount of, add 0.1molL
-1Hydrochloric acid soln preparation reference substance solution (5 μ gmL
-1); " 23.2 " chromatographic condition in " preparation of repaglinide and quality standard research " (ACAD J GCP, 2009,25 (6)) of delivering according to people such as Ding Gang is measured, and calculates the dissolution rate of repaglinide 30min.Simultaneously, carry out the prepared repaglinide of the embodiment of the invention 1, reference substance 1 (adopts prescription and preparation method's preparation of example of formulations 1 of the present invention, difference is that used repaglinide is the repaglinide bulk drug, provided by Zhejiang Haixiang Pharmaceutical Co., Ltd., lot number: 30032071, content 100.4%), reference substance 2 (" preparation of repaglinide and quality standard research " (ACAD J GCP that the people such as Ding Gang delivers, 2009,25 (6)) the self-control repaglinide that relates in) with the listing product (inspire confidence in and come enlightening) respectively 2,5,8,11,15, take a sample during 30min, measure content, carry out the contrast of stripping curve, the results are shown in Figure 2.The embodiment of the invention 1 prepared repaglinide, reference substance 1, reference substance 2 has similar stripping curve to the listing product, and the accumulation stripping quantity that adopts the corresponding time point of the prepared repaglinide of prescription of the present invention and technique (reference substance 1) is higher than reference substance 2 and listing product, and the accumulation stripping quantity of the corresponding time point of repaglinide of the repaglinide crystal preparation of the employing embodiment of the invention 1 is higher than reference substance 1 again.
The repaglinide prepared to other example of formulations of the present invention also carried out identical comparison test, and the result of its acquisition is similar.
Claims (10)
1. repaglinide crystal, it is characterized in that, characteristic peak is 4.8 °, 13.6 °, 14.9 °, 15.2 °, 16.0 °, 19.1 °, 21.2 ° and 24.1 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that described repaglinide crystal use Cu-K alpha-ray measures.
2. repaglinide crystal according to claim 1 is characterized in that, the particle diameter of described repaglinide crystal is 1～5 μ m.
3. the preparation method of a claim 1 or 2 described repaglinide crystal, the method comprises the steps:
1) the repaglinide powder is dissolved in is made into repaglinide solution in the ethanol as disperse phase;
2) 2-ethylhexyl succinate sodium sulfonate is dissolved in octane-iso and is made into 2-ethylhexyl succinate sodium sulfonate solution as dispersion medium;
3) under ultrasonic field, with microsyringe disperse phase solution is joined in the dispersion medium, continue ultrasonic, centrifugation goes out the super powder of repaglinide, go supernatant liquor to add octane-iso washing centrifugally operated, to remove the 2-ethylhexyl succinate sodium sulfonate of repaglinide surface adsorption, vacuum-drying namely gets the repaglinide crystal.
4. preparation method according to claim 3 is characterized in that step 2) described in the concentration of 2-ethylhexyl succinate sodium sulfonate solution be 0.05～0.3molL
-1The power of ultrasonic field step 3) is 0.1～0.3KW, described ultrasonic be ultrasonic 1～3 minute, described centrifugal be at 9000～11000rmin
-1Condition under centrifugal, described washing centrifugally operated is repeated washing centrifugally operated 2～4 times, described vacuum-drying is vacuum-drying 8～12h.
5. a solid orally ingestible is characterized in that, described solid orally ingestible contains the repaglinide crystal of claim 1 or 2 described repaglinide crystal or claim 3 or 4 described preparation method's preparations.
6. solid orally ingestible according to claim 5, it is characterized in that, described solid orally ingestible comprises repaglinide, amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, poloxamer, glycerine, meglumine, ferric oxide and Magnesium Stearate.
7. solid orally ingestible according to claim 6, it is characterized in that, described solid orally ingestible is by repaglinide crystal 0.5-3 part, 10～100 parts of amylum pregelatinisatums, 10～80 parts of Microcrystalline Celluloses, 10～35 parts of secondary calcium phosphates, 10～50 parts of polyvinylpyrrolidones, 10～50 parts of croscarmellose sodiums, 10～30 parts of poloxamers, 10～30 parts of glycerine, 10～30 parts of meglumines, 10～30 parts of ferric oxide and 1～3 part of repaglinide of making of Magnesium Stearate.
8. solid orally ingestible according to claim 7, it is characterized in that, described solid orally ingestible is by 2 parts of repaglinides, 80 parts of amylum pregelatinisatums, 60 parts of Microcrystalline Celluloses, 20 parts of secondary calcium phosphates, 28 parts of polyvinylpyrrolidones, 35 parts of croscarmellose sodiums, 10 parts of poloxamers, 10 parts of glycerine, 10 parts of meglumines, 10 parts of ferric oxide and 1 part of repaglinide of making of Magnesium Stearate.
9. according to claim 7 or 8 described solid orally ingestibles, it is characterized in that, the preparation method of described repaglinide is as follows:
1) auxiliary material amylum pregelatinisatum, Microcrystalline Cellulose, secondary calcium phosphate, polyvinylpyrrolidone, croscarmellose sodium, poloxamer, glycerine, meglumine, ferric oxide and Magnesium Stearate are carried out pre-treatment, for subsequent use;
2) take by weighing the repaglinide crystal by described consumption and above-mentioned auxiliary material except Magnesium Stearate for subsequent use adopts the equivalent method of progressively increasing to carry out mixing, add again Magnesium Stearate, mixing, and the control mixing time obtains powder mix in 5min;
3) sampling detects;
4) detect and resulting mixed powder to be carried out direct pressed powder after qualified, namely get described repaglinide.
10. solid orally ingestible according to claim 9 is characterized in that, described pre-treatment was dried by the fire 2～3 hours under 60～80 ℃ of conditions for first auxiliary material being pulverized again, and then crosses 60～80 mesh sieves.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110188700 CN102267959B (en) | 2011-07-06 | 2011-07-06 | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110188700 CN102267959B (en) | 2011-07-06 | 2011-07-06 | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102267959A CN102267959A (en) | 2011-12-07 |
| CN102267959B true CN102267959B (en) | 2013-05-01 |
Family
ID=45050440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110188700 Active CN102267959B (en) | 2011-07-06 | 2011-07-06 | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102267959B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584743A (en) * | 2011-12-28 | 2012-07-18 | 中国药科大学 | Dimethylaminopyridine repaglinide eutectic |
| CN103040772B (en) * | 2012-06-20 | 2015-05-20 | 江苏豪森药业股份有限公司 | Repaglinide dispersible tablet and preparation method thereof |
| CN103610677B (en) * | 2013-11-14 | 2016-06-01 | 海南华益泰康药业有限公司 | A kind of Repaglinide tablet and its preparation method |
| CN103690498A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | Preparation method capable of improving stability of repaglinide tablets |
| CN104434840A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Repaglinide tablet and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068820A (en) * | 1991-06-21 | 1993-02-10 | 卡尔·托马有限公司 | (S) (+)-2-oxyethyl group-4-[N-[1-(2-piperidino-phenyl)-3-methyl isophthalic acid-butyl] amino carbonyl methyl] phenylformic acid, contain pharmaceutical composition of this compound and preparation method thereof |
| WO2004018442A1 (en) * | 2002-08-23 | 2004-03-04 | Dr. Reddy's Laboratories Limited | Crystalline and amorphous forms of (s) -repaglinide and the processes for preparation thereof |
| CN1571769A (en) * | 2001-09-25 | 2005-01-26 | 兰贝克赛实验室有限公司 | Process for the preparation of repaglinide |
| CN101481363A (en) * | 2008-01-10 | 2009-07-15 | 江苏豪森药业股份有限公司 | Method for preparing repaglinide |
| CN102002021A (en) * | 2010-12-07 | 2011-04-06 | 合肥华方医药科技有限公司 | Novel method for synthesizing repaglinide |
-
2011
- 2011-07-06 CN CN 201110188700 patent/CN102267959B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068820A (en) * | 1991-06-21 | 1993-02-10 | 卡尔·托马有限公司 | (S) (+)-2-oxyethyl group-4-[N-[1-(2-piperidino-phenyl)-3-methyl isophthalic acid-butyl] amino carbonyl methyl] phenylformic acid, contain pharmaceutical composition of this compound and preparation method thereof |
| CN1571769A (en) * | 2001-09-25 | 2005-01-26 | 兰贝克赛实验室有限公司 | Process for the preparation of repaglinide |
| WO2004018442A1 (en) * | 2002-08-23 | 2004-03-04 | Dr. Reddy's Laboratories Limited | Crystalline and amorphous forms of (s) -repaglinide and the processes for preparation thereof |
| CN101481363A (en) * | 2008-01-10 | 2009-07-15 | 江苏豪森药业股份有限公司 | Method for preparing repaglinide |
| CN102002021A (en) * | 2010-12-07 | 2011-04-06 | 合肥华方医药科技有限公司 | Novel method for synthesizing repaglinide |
Non-Patent Citations (2)
| Title |
|---|
| 唐鹤等.瑞格列奈的合成.《中国医药工业杂志》.2008,第39卷(第10期),727-730，特别是729右栏最后一段. |
| 瑞格列奈的合成;唐鹤等;《中国医药工业杂志》;20081231;第39卷(第10期);727-730，特别是729右栏最后一段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102267959A (en) | 2011-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104981240B (en) | It is used to treat composition, method and the purposes of diabetes and associated disease by control blood glucose level | |
| CN102267959B (en) | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same | |
| CN101590007A (en) | A kind of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions and preparation thereof | |
| CN101181373B (en) | Cortex moutan valid target pharmaceutical combination, preparation method and application thereof | |
| WO2022062518A1 (en) | Application of oxyberberine in preparation of drugs for metabolic diseases, and pharmaceutical composition comprising oxyberberine | |
| CN103622946A (en) | Medical application of anhydroicaritin | |
| CN105213335A (en) | Glipizide tablet and preparation method thereof and application | |
| CN106110310A (en) | A kind of compound for reducing blood suger containing pioglitazone and preparation method thereof | |
| CN103055176B (en) | Traditional Chinese medicine for treating diabetes mellitus and preparation method thereof | |
| CN102228457B (en) | Pharmaceutical composition for treating diabetes and complication thereof | |
| CN101524353B (en) | Oral anti-allergy compound pharmaceutical composition | |
| CN103230594A (en) | Medicine composition of alpha-glucosidase inhibitor and vitamin B | |
| CN100490808C (en) | Gliquilone slow-releasing preparation | |
| CN106822014A (en) | Gliclazide gastric floating tablet and preparation method thereof | |
| CN101829271A (en) | Chinese medicinal compound with function of treating diabetes and preparation method and application thereof | |
| CN101537102A (en) | Medical and edible dual-purpose composition for treating sugar diabetes and preparation method thereof | |
| CN104208034A (en) | Glimepiride pharmaceutical composition tablet and its preparation method and use | |
| CN101347511B (en) | Medicament composition with function for reducing blood sugar | |
| CN108703956A (en) | A kind of solid composite medicament containing Bosentan | |
| CN102274514B (en) | Medicinal composition for preventing and treating type-II diabetes and complications thereof | |
| CN102657626B (en) | Medicinal composite tablet of pioglitazone medicine | |
| CN102218062B (en) | Medicine composition for treating diabetes mellitus | |
| CN100455279C (en) | Oral administered sustained release lozenge composition and its preparation method | |
| CN105079793A (en) | Liraglutide and metformin hydrochloride compound preparation applicable to oral administration | |
| CN103006656A (en) | Antitussive and expectorant compound chemical drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: Hainan Jinrui Pharmaceutical Co., Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: Hainan Jinrui Pharmaceutical Co., Ltd. |