CN101229172B - Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof - Google Patents
Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof Download PDFInfo
- Publication number
- CN101229172B CN101229172B CN2007100605288A CN200710060528A CN101229172B CN 101229172 B CN101229172 B CN 101229172B CN 2007100605288 A CN2007100605288 A CN 2007100605288A CN 200710060528 A CN200710060528 A CN 200710060528A CN 101229172 B CN101229172 B CN 101229172B
- Authority
- CN
- China
- Prior art keywords
- solid dispersion
- active component
- mesh sieves
- adjuvant
- add
- 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.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a solid dispersion containing glycyrrhetinic acid 30-amide derivative active component and a preparation method thereof. The solid dispersion consists of active components and carrier materials with the weight percentage of 1: 0.5 to 1: 50. The preparation method can adopt one of the following methods: melting method, solvent method, melting-solvent method, grinding method, spray drying method or freeze-drying method. The solid dispersion can form the medical combination with one or more pharmaceutical acceptable carriers, excipient or diluents; the invention is applied in treatments of anti-inflammatory, anti-gastric ulcer, anti-colitis, analgesia, anti-tussive, liver protection and so on.
Description
The invention belongs to field of pharmaceutical preparations, relate to a kind of solid dispersion that contains enoxolone 30-amide derivatives active component and its production and use in particular.
Background technology
Enoxolone has all many-sided effect such as antiinflammatory, analgesia, antiallergic, antiulcer, antiviral, human body immunity improving power, the liver protecting.But use this class medicine often with intending the side effect of aldosterone sample clinically in a large number, cause that sodium retention, potassium excretion increase, and cause a series of side effect such as edema, hypertension, hypokalemia.In order to overcome the side effect of enoxolone, Wang Jianwu etc. have synthesized the 30-amide derivatives (CN200510015371.8) of novel enoxolone, have antiinflammatory, analgesia isoreactivity preferably through determination of activity.Yet because the molecule of enoxolone own is bigger, molecule further strengthens behind the derivatization, dissolves and absorb relatively poor, may hinder it to become the medicine that can use clinically.In order to overcome the lower deficiency of 30-amide derivatives absolute bioavailability of enoxolone, we have carried out the research of solid dispersion technology.
Summary of the invention
An object of the present invention is overcoming the shortcoming and defect of above-mentioned prior art, provide a kind of good stability, bioavailability height and production cost low a kind of solid dispersion that contains enoxolone 30-amide derivatives active component.
Another object of the present invention provides a kind of preparation method that contains the solid dispersion of enoxolone 30-amide derivatives active component.
A further object of the present invention provides a kind of enoxolone 30-amide derivatives active component that contains as effective ingredient; and the Pharmaceutical composition of one or more pharmaceutically acceptable carriers, excipient or diluent, and in the application of aspects such as antiinflammatory, anti-gastric-ulcer, resistive connection enteritis, analgesia, antitussive, the liver protecting.
Now summary of the invention is specifically described in conjunction with purpose of the present invention.
(1) solid dispersion of the present invention is that a kind of enoxolone 30-amide derivatives active component and carrier material are prepared into solid dispersion.Its active component and carrier material weight ratio are 1: 0.5-1: 50, preferred 1: 3-1: 20; Described carrier material is one or more the compositions of polyvidone, Polyethylene Glycol, cholesterol, lecithin, beta-schardinger dextrin-and derivant thereof, lactose, mannitol, Tris, glycerol, CREMOPHORE EL, polyoxyethylene castor oil RH40, the poly-hydrocarbon oxygen ester 35 of Oleum Ricini, Polyethylene Glycol-12-hydroxy stearic acid ester, cholesterol, polyoxyethylene laurate, silicon dioxide, poloxamer, carboxymethylstach sodium, cross-linked carboxymethyl cellulose sodium;
Wherein, enoxolone 30-amide derivatives (being called for short TY501 series compound thing) comprising:
| Code name | The chemical compound title |
| TY501-G1 | N[(3-p-hydroxybenzene-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G2 | N[(3-p-methylphenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| Code name | The chemical compound title |
| TY501-G3 | N[(3-is to fluorine-based phenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G4 | The adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G5 | N[(3-p-methoxyphenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G6 | N[(3-o-methoxyphenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G7 | N[(3-methyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G8 | 18-α, N[(3-is to chloro phenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G9 | N[(3-p-trifluoromethyl phenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-G10 | N[(3-phenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide |
| TY501-DG1 | N[(3-p-hydroxybenzene-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG2 | N[(3-p-methylphenyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG3 | N[(3-is to fluorine-based phenyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG4 | The adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG6 | N[(3-o-methoxyphenyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG7 | N[(3-methyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG8 | Chloro phenyl-isoxazole-5-base between N[(3-) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG9 | N[(3-is to acetylphenyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
| TY501-DG10 | 18-α, N[(3-Chloro-O-Phenyl-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide |
(2) preparation method of solid dispersion of the present invention is as follows:
It is active ingredient that the present invention adopts a certain of TY-501 series compound, adds carrier material, adopts fusion method, fusion-solvent method, polishing, solvent method, solvent spray seasoning, solvent freeze-drying to prepare its solid dispersion respectively.
A, fusion method
Carrier material can be selected polyethylene glycol 6000, Macrogol 4000, poloxamer 188, Polyoxyethylene Sorbitan Monooleate, glycerol, polyoxyethylene laurate, carboxymethylstach sodium, cross-linked carboxymethyl cellulose sodium etc. for use.Get carrier material and active ingredient mixing, be heated to fusion or homodisperse, vigorous stirring, direct encapsulated molding or drip and to make drop pill; Or put and be cooled to solid dispersion in the ice-water bath rapidly, put 0.5-24h in the household freezer again, fully to solidify, drying is ground, and crosses the 50-300 mesh sieve, promptly gets solid dispersion of the present invention.
B, polishing
Carrier material can be selected the one or more combination thing of Macrogol 4000, polyethylene glycol 6000, microcrystalline Cellulose (PH102, PH301, PH302 etc.), beta-schardinger dextrin-and derivant, polyvidone class and lactose, galactose, silicon dioxide, lecithin, cholesterol, carboxymethylstach sodium for use.Get carrier material and active ingredient mixing, put altogether in the mortar, grind rotating speed 100-600rpm, milling time 10min-240min.Take out, cross the 50-300 order, promptly get solid dispersion of the present invention.
C, solvent method
Active ingredient is dissolved in the appropriate solvent, or adds appropriate solubilizing agent and make it to dissolve fully, again carrier material is dissolved in the appropriate solvent.With both mix homogeneously, boil off solvent and make medicine and carrier material separate out drying simultaneously; Or, boil off an amount of solvent with both mix homogeneously, and fully to solidify, drying is ground, and crosses the 50-300 mesh sieve and makes into solid dispersion, promptly gets solid dispersion of the present invention.
Quantity of solvent is 5-200 a times of active ingredient weight.Described carrier material can be selected one or more compositions of Macrogol 4000, polyethylene glycol 6000, poloxamer 188, galactose, mannitol, polyvidone, dextrose, sorbitol, sucrose, cholesterol, lecithin, beta-schardinger dextrin-and derivant thereof for use.Described solvent can be the one or more combination thing of water, acetone, ethanol, ethylene glycol, propanol, propylene glycol, isopropyl alcohol.Described solubilizing agent can be a sodium lauryl sulphate, Tris, glycerol, CREMOPHORE EL, the poly-hydrocarbon oxygen ester 35 of Oleum Ricini, Polyethylene Glycol-12-hydroxy stearic acid ester etc.
D, solvent-spray drying method
Active ingredient is dissolved in makes it dissolving in the appropriate solvent, or add appropriate solubilizing agent and make it to dissolve fully.Again carrier material is dissolved in the appropriate solvent.With both mix homogeneously, spray drying eliminates solvent or boils off an amount of solvent then, through intensive drying, grinds, and crosses the 50-300 mesh sieve and makes into solid dispersion, promptly gets solid dispersion of the present invention.
Quantity of solvent is 5-200 a times of active ingredient weight.Described carrier material can be selected one or more compositions of Macrogol 4000, polyethylene glycol 6000, poloxamer 188, galactose, mannitol, polyvidone, dextrose, sorbitol, sucrose, cholesterol, lecithin, beta-schardinger dextrin-and derivant thereof for use.Described solvent can be the one or more combination thing of water, acetone, ethanol, ethylene glycol, propanol, propylene glycol, isopropyl alcohol.Described solubilizing agent can be a sodium lauryl sulphate, Tris, glycerol, CREMOPHORE EL, the poly-hydrocarbon oxygen ester 35 of Oleum Ricini, Polyethylene Glycol-12-hydroxy stearic acid ester etc.
E, solvent-freeze-drying
Get active ingredient and add carrier material, add distilled water, make dissolving or/and appropriate amount of organic stirs, lyophilization, freeze-drying time is 8-50h.Grind again, cross the 50-200 mesh sieve, promptly get solid dispersion.
The ratio of the distillation water yield and organic solvent is 5: 1-100: 1, and the total amount of solvent is the heavy 3-30 of active ingredient times.Described carrier material also can be selected one or more compositions of Macrogol 4000, polyethylene glycol 6000, poloxamer 188, polyvidone class, lactose, mannitol, gelatin hydrolysate, cellulose family, polyacrylic resin class, citric acid, dextrose, galactose, cholic acid, sorbitol, sucrose, cholesterol, lecithin, beta-schardinger dextrin-and derivant thereof for use.
F, solvent-fusion method
Get active ingredient and be dissolved in earlier in the appropriate solvent, this solution is directly added stir in the melting carrier material, put and be cooled to solid in the ice-water bath rapidly, fully solidify, drying is ground, and sieves, and promptly gets solid dispersion of the present invention.
Carrier material can be selected polyethylene glycol 6000, Macrogol 4000, Polyethylene Glycol-12-hydroxy stearic acid ester, poloxamer 188, Polyoxyethylene Sorbitan Monooleate, glycerol, CREMOPHORE EL etc. for use.
(3) preparation of the pharmaceutical composition of solid dispersion of the present invention and preparation thereof:
Solid dispersion of the present invention can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, excipient or diluent.This pharmaceutical composition can be made solid orally ingestible.Described solid orally ingestible comprises: suitable dosage forms such as tablet, dispersible tablet, oral cavity disintegration tablet, chewable tablet, capsule, semi-solid capsule, granule, dry suspension.
The preparation method of described solid orally ingestible may further comprise the steps: with active component and carrier and optionally with a disintegrate additive composition mixture; make the aqueous solution of this mixture and binding agent then; alcohol or aqueous alcohol solution carry out granulating in suitable device; dried particles, the disintegrating agent, lubricant and the antiplastering aid that add other subsequently are pressed into appropriate formulations.
Can adopt lactose or starch carrier as described solid orally ingestible; Use gelatin, methylcellulose, polyvinylpyrrolidone etc. are as binding agent; Use starch, sodium carboxymethyl cellulose or microcrystalline Cellulose as disintegrating agent; Use Pulvis Talci, santocedl, tristerin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.
(4) solid dispersion dissolution determination method of the present invention
According to two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine, be dissolution medium with 0.5% sodium dodecyl sulfate solution 250ml, 75 rev/mins of rotating speeds, operation in the time of 60 minutes, is got solution 3ml respectively in accordance with the law, filters, and gets subsequent filtrate 1ml as need testing solution.It is an amount of that other gets reference substance, adds solution that an amount of ultrasonic dissolution of mobile phase and dilution make 50 μ g/ml product solution in contrast.Get reference substance solution and need testing solution respectively,, calculate peak area by external standard method, promptly according to high effective liquid chromatography for measuring.The HPLC condition determination is: immobile phase: ODSC-18 post, 10u filler, 200 * 4.6mm.Mobile phase: methanol: water=90: 10.30 ℃ of column temperatures.Detect: UV 230nm.Sample introduction 20ul.
(5) absolute bioavailability of solid dispersion of the present invention or its preparation is measured in the following manner:
Key instrument: HP 1100 LC-MSD liquid chromatograph-mass spectrometers: U.S. Agilent company.
Rat: healthy Wistar kind, male, body weight 150～200g, hygienic conditions Institute for Medical Research of Military Medical Science Institute provides.
Chromatographic condition mobile phase: methanol-water (97: 3, v/v), through 0.45 μ m filtering with microporous membrane, the online degassing, flow velocity 1.2ml/min does not shunt; Chromatographic column: XDB C18 post (5 μ m, 4.6 * 250mm); Column temperature: 25 ℃; Sample size 10 μ l.
Mass spectrum condition acquisition mode: selectivity ion detection (SIM); Ion polarity: negative ion mode; Ionizing mode: electro-spray ionization (AP-ESI); Detected object: molecular ion peak; Aerochamber pressure: 40psi; Protection throughput: 10L/minN2; Capillary voltage: 4000V; Ion source temperature: 100 ℃; Fragment transmission range voltage: 220V.
Healthy Wistar rat is got in dosage regimen and blood specimen collection, by the body weight random packet, gives different samples respectively, and oral dose is 100mg/kg, orally gets the blood time and is respectively before the medicine and behind the medicine 0,0.5,1,2,4,6,8,12,24 and 36h.Get blood, separation of serum from eye socket endosphere rear vein beard.In the 1.5ml plastic centrifuge tube, accurate adding plasma sample 100 μ l to be measured, vortex is even, adds ethyl acetate 1ml, vortex 3min, in the centrifugal 10min of 4000r/min, get 800 μ l supernatant in another centrifuge tube, dry up with nitrogen current in 50 ℃ of water-baths, 160 μ l second eyeballs redissolve, 10 μ l sample introductions, external standard method blood drug level.
(5) activity of solid dispersion of the present invention is measured in the following manner:
(i) antiinflammatory action
Select male and healthy ICR kind mice for use, body weight 20～24g behind the fasting 12h, is divided into model control group by body weight, positive controls (diclofenac, 40mg/kg dosage), solid dispersion group (in active component, 40mg/kg dosage), 10 every group before the experiment at random.Animal is used etherization, and in auris dextra two sided coatings Oleum Tiglii mixing proinflammatory agent 0.03ml/ only, left ear is left intact.After causing scorching 0.5h, each administration group is pressed 0.2ml/10g volume gastric infusion, and model control group gives with the blank solvent of volume.Behind the administration 2.5h, animal is taken off cervical vertebra put to death, cut ears immediately and lay round auricle at the same position of auris dextra and left ear respectively, on electronic balance, weigh with the card punch of 6mm diameter.Every Mus auris dextra sheet total amount deducts left auricle total amount and is the swelling degree, and the swelling degree of matched group and administration group is carried out statistical procedures, and calculates the suppression ratio of medicine to inflammation.Laboratory temperature is more than 25 ℃, and humidity is more than 50%.
(ii) analgesic activity
Healthy ICR kind mice, body weight 18-22 gram, male and female dual-purpose.Test lumbar injection 0.6% acetic acid the previous day, 0.2ml/ only screen and turn round the mice of body number of times in the 10-50 underrange, and knob body number of times is divided into model group, positive drug matched group and solid dispersion group at random, 10 every group.Positive drug is a diclofenac, and dosage is the 50mg/kg body weight.
More than the preceding fasting 12h of experiment, gastric infusion, model group gives isodose 1%CMCNa.Behind the administration 2h, lumbar injection 0.6% acetic acid 0.2ml/, mouse writhing number of times in the opening entry 15min behind the 5min, and calculate the suppression ratio of medicine in view of the above to writhing response.
(iii) antitussive effect
Get healthy ICR mice, body weight 18-22g, the male and female dual-purpose is divided into model group, positive drug matched group and solid dispersion group at random by body weight, 10 every group.The positive control medicine is a codeine phosphate, and dosage is the 50mg/kg body weight.
More than the preceding fasting 12h of each group experiment, gastric infusion, model group waits dosage 1%CMCNa.Behind the administration 2h, begin test, mice is placed the 500ml container, add the cotton balls that contains 0.3ml ammonia, cause cough, observe the number of times of cough in the 5min.
(iv) anti-gastric-ulcer effect
Healthy male SD rat fasting is divided into model group, positive drug matched group and solid dispersion group by body weight, 8 every group more than 24 hours at random.Positive control drug is a sofalcone.The difference oral administration, model group waits the 1%CMC-Na solution of capacity.Water is prohibited in fasting after the administration, and oral administration gavage dehydrated alcohol 7.5ml/kg after 3 hours dissected after 2 hours, got stomach behind ligation Gui Men and the pylorus.Inject 10% formalin to gastric, drop in the formalin of same concentrations fixedly 30min then, cut off and observe the pathological changes situation along greater gastric curvature.The order of severity according to pathological changes is divided into Pyatyi: 1 grade: no ulcer, and 2 grades: ulcer length＜6cm, 3 grades: ulcer length＜12cm, 4 grades: ulcer length＜18cm, 5 grades: ulcer length＞18cm, active with the graded index statistics.
(v) resistive connection enteritis effect
Healthy male SD rat fasting is divided into model group, positive drug matched group and solid dispersion group by body weight, 8 every group more than 24 hours at random.Positive control drug is a dexamethasone, and dosage is the 50mg/kg body weight.The difference oral administration, model group waits the 1%CMC-Na solution of capacity.Modeling immediately after the administration is promptly inserted special polyethylene tube from the rat anus and is injected 2ml 10% acetic acid solution, stops 15s, uses the 5ml normal saline flushing then.Dissect next day and get colon observation lesion degree.Grade scale is: 1 grade: whole 10cm intestinal tube does not have the visible inflammation of naked eyes; 2 grades: mild inflammation, slight congested; 3 grades: moderate inflammation, discontinuous hyperemia, the fine hair moderate is rubescent; 4 grades: serious inflammation, serious congested, fine hair severe is rubescent.Active with the graded index statistics.
(vi) hepatoprotective effect
Get healthy ICR mice, body weight 18-22g, the male and female dual-purpose is divided into blank group, model group, positive drug matched group and solid dispersion group, 10 every group at random by body weight.The positive control medicine is a silibinin, and dosage is the 50mg/kg body weight.The difference oral administration, once a day, continuous 4 days, inject 0.1% carbon tetrachloride oil solution 10ml/kg in administration pneumoretroperitoneum for the third time, fasting last administration in 12 hours after the modeling was plucked eyeball in 2 hours behind the medicine and got blood, and is centrifugal, separation of serum is measured the activity of alanine aminotransferase in the serum then with automatic biochemical analyzer.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
Get TY-501-DG4 sample 2g, add mixture (1: the 8) 20g of Polyethylene Glycol 1000 and polyethylene glycol 6000, put in the beaker, heating in water bath makes fusion, adds glycerol 2g again, and Oleum Ricini gathers hydrocarbon oxygen ester 351g, stir, directly the encapsulating capsule promptly gets the solid dispersion composite capsule.
Embodiment 2
Get TY-501-G1 sample 2g, add mixture (1: the 8) 40g of Polyethylene Glycol 1000 and polyethylene glycol 6000, put in the beaker, heating in water bath makes fusion, add glycerol 2g again, Oleum Ricini gathers hydrocarbon oxygen ester 351g, stirs, rapidly cooling curing, drying is pulverized, and crosses 80 mesh sieves, gets solid dispersion.
Embodiment 3
Get TY-501-DG6 sample 5g, add Polyethylene Glycol 6000 25g and put in the beaker, heating in water bath makes fusion.Add poloxamer 188 1g, glycerol 2g, carboxymethylstach sodium 0.5g stirs, and directly the encapsulating capsule promptly gets the solid dispersion composite capsule.
Embodiment 4
Get TY-501-G6 1g, add Polyethylene Glycol 6000 47g and put in the beaker, heating in water bath makes fusion.Add Polyoxyethylene Sorbitan Monooleate 1g, polyoxyethylene laurate 2g stirs.Put 0.5-24h in the household freezer, fully solidify, drying is ground, and crosses 100 mesh sieves, promptly gets solid dispersion of the present invention.
Embodiment 5
TY-501-DG8 crosses 120 mesh sieves, and is standby.Take by weighing PEG-6000 80g, PEG-4000 20g, heat 80-90 ℃ and make it to be fused into liquid; Add 5g medicine and an amount of CREMOPHORE EL, cross-linked carboxymethyl cellulose sodium and stir, make dissolving or even suspendible, place the system of dripping in the drop pill device, storage liquid instrument temperature is 85 ℃, regulating piston to proper speed is 60/min, the distance of 6cm, and the water dropper diameter is 1.3mm, splash into (the control temperature is 5-10 ℃) in the dimethicone, the system of dripping finishes, and leaves standstill half an hour, collects drop pill, inhale the condensed fluid that removes to adhere to drop pill with paper, be drying to obtain drop pill.
Embodiment 6
Get TY-501-DG10 sample 2g, add cholic acid 1g, lecithin 20g, put in the mortar, grind, rotating speed 100rpm ground 180 minutes, added microcrystalline Cellulose and crossed 80 mesh sieves, promptly got solid dispersion.
Embodiment 7
Get TY-501-G8 sample 2g, add beta-schardinger dextrin-40g, put in the mortar, grind, rotating speed 600rpm ground 240 minutes, crossed 200 mesh sieves, promptly got solid dispersion.
Embodiment 8
Get TY-501-G6 sample 2g, add silicon dioxide 5g, polyethylene glycol 6000 35g, put in the mortar, grind, rotating speed 300rpm ground 120 minutes, crossed 120 mesh sieves, promptly got solid dispersion.
Embodiment 9
Get TY-501-DG7 sample 2g, add silicon dioxide 5g, polyvidone 12PF 15g, put in the mortar, grind, rotating speed 200rpm ground 30 minutes, crossed 200 mesh sieves, promptly got solid dispersion.
Embodiment 10
Get TY-501-DG4 sample 5g, add lactose 5g, put in the mortar, grind, rotating speed 300rpm ground 60 minutes, crossed 120 mesh sieves, promptly got solid dispersion.
Embodiment 11
Take by weighing Macrogol 4000 10g, polyethylene glycol 6000 10g and be dissolved in 150ml 95% ethanol, get TY-501-G4 sample 2g, add sodium lauryl sulphate 0.5g, after thermal agitation made dissolving fully, stir about 3-4h boiled off solvent.After the residue dried, grind, cross 80 mesh sieves and promptly get solid dispersion.
Embodiment 12
Take by weighing Macrogol 4000 10g, polyethylene glycol 6000 30g and be dissolved in 200ml 95% ethanol, get TY-501-G1 sample 2g, after heated and stirred made dissolving fully, stir about 3-4h boiled off solvent.After the residue dried, grind, cross 80 mesh sieves and promptly get solid dispersion.
Embodiment 13
Take by weighing polyvidone (RF12) 15g and be dissolved in the 200ml ethanol, add TY-501-DG4 sample 2g, after 80 ℃ of oil bath heating were fully stirred and made dissolving fully, stir about 3-4h boiled off ethanol, after the residue dried, grinds, and crosses 200 mesh sieves and promptly gets solid dispersion.
Embodiment 14
Take by weighing polyvidone (RF12) 30g and be dissolved in the 200ml ethanol, add TY-501-DG1 sample 2g, after 80 ℃ of oil bath heating were fully stirred and made dissolving fully, stir about 3-4h boiled off ethanol, after the residue dried, grinds, and crosses 200 mesh sieves and promptly gets solid dispersion.
Embodiment 15
Take by weighing polyvidone (RF14) 20g and be dissolved in 180ml 80% ethanol, add TY-501-G2 sample 2g and add polyoxyethylene laurate 1g, 80 ℃ of oil bath heating make dissolving, behind the stir about 2-3h, boil off solvent, after the residue dried, grind, cross 120 mesh sieves and promptly get solid dispersion.
Embodiment 16
Taking by weighing polyvidone (RF17) 30g is dissolved in 120ml 80% ethanol, add TY-501-DG2 sample 1g, Polyethylene Glycol-12-hydroxy stearic acid ester 1g, after 80 ℃ of oil bath heated and stirred make dissolving fully, after stirring 2-3h, boil off solvent, after the residue dried, grind, cross 80 mesh sieves and promptly get solid dispersion.
Embodiment 17
Take by weighing beta-schardinger dextrin-10g and add in the 70ml water, 80 ℃ of oil bath heated and stirred make dissolving fully.TY-501-DG3 sample 1g is dissolved in the 70ml ethanol, adds CREMOPHORE EL 2g,, 80 ℃ of oil bath heated and stirred make dissolving fully.After the two mix homogeneously continues stir about 3-4h, boil off solvent after, residue dried is ground, and crosses 200 mesh sieves and promptly gets solid dispersion.
Embodiment 18
Take by weighing TY-50-G3 sample 5g, add each 500ml of acetone and water, heating makes dissolving, the 100g polyethylene glycol 6000 is dissolved in wherein again, add sodium lauryl sulphate 1g, behind the stir about 2-3h, boil off solvent, after the residue dried, grind, cross 100 mesh sieves and promptly get solid dispersion.
Embodiment 19
Take by weighing TY-501-G5 sample 5g, add each 500ml of water and acetone, be heated to about 80 ℃, lecithin 60g is dissolved in wherein again, it is an amount of to add cholesterol, behind the stir about 2-3h, boils off solvent, after the residue dried, grinds, and crosses 80 mesh sieves and promptly gets solid dispersion.
Embodiment 20
Take by weighing polyvidone 15g and be dissolved in the 150ml ethanol, add TY-501-G9 sample 2g, mannitol 3g, heating directly after the spray drying, is ground after fully stirring and making dissolving fully, crosses 120 mesh sieves and promptly gets solid dispersion.
Embodiment 21
Take by weighing polyvidone 30g and be dissolved in the 100ml isopropyl alcohol, add 50ml water, add TY-501-DG9 sample 2g, lactose 5g, heating directly after the spray drying, is ground after fully stirring and making dissolving fully, crosses 120 mesh sieves and promptly gets solid dispersion.
Embodiment 22
Take by weighing hydroxypropyl 10g and be dissolved in the 100ml water, add TY-501-G5 sample 2g, lactose 2g, poloxamer 2g, after heated and stirred made dissolving fully, lyophilization was ground after 16 hours, crossed 200 mesh sieves and promptly got solid dispersion.
Embodiment 23
Take by weighing polyethylene glycol 6000 10g, TY-501-G10 sample 1g adds ethanol 50ml, heated and stirred makes dissolving; Add water 50ml again, sorbitol 4g, mannitol 4g, heating makes dissolving; After the lyophilization 16 hours, grind, cross 120 mesh sieves and promptly get solid dispersion.
Embodiment 24
Take by weighing polyethylene glycol 6000 20g, poloxamer 1g, 80 ℃ of oil bath heated and stirred make dissolving fully.Other claims TY-501-DG4 sample 1g to add ethanol 20ml, and heated and stirred makes dissolving.To contain medicinal liquid and add mix homogeneously in the melting carrier material, stir about 0.5-1h puts and is cooled to solid in the ice-water bath rapidly, fully solidifies, and drying is ground, and crosses 80 mesh sieves.
Embodiment 25
Take by weighing Polyethylene Glycol-12-hydroxy stearic acid ester 15g, poloxamer 1g, 80 ℃ of oil bath heated and stirred make dissolving fully.Other claims TY-501-G4 sample 1g to add isopropyl alcohol 20ml, and heated and stirred makes dissolving.To contain medicinal liquid and add mix homogeneously in the melting carrier material, stir about 0.5-1h puts and is cooled to solid in the ice-water bath rapidly, fully solidifies, and drying is ground, and crosses 100 mesh sieves.
Embodiment 26
Take by weighing polyethylene glycol 6000 20g, Macrogol 4000 20g, glycerol 5g, 80 ℃ of oil bath heated and stirred make dissolving fully.Other claims TY-501-DG4 sample 1g to add ethanol 20ml, and heated and stirred makes dissolving.To contain medicinal liquid and add mix homogeneously in the melting carrier material, stir about 0.5-1h puts and is cooled to solid in the ice-water bath rapidly, puts to keep 0.5-24h in the household freezer, fully solidifies, and drying is ground, and crosses 200 mesh sieves, promptly gets solid dispersion of the present invention.
Embodiment 27
Tablet formulation (100 amounts)
Embodiment 2 solid dispersion 25g
Lactose 10g
Pregelatinized Starch 4g
Microcrystalline Cellulose 4g
Polyvinylpolypyrrolidone 3g
10% starch slurry q.s
Magnesium stearate q.s
Preparation technology:
It is standby that adjuvant is crossed 80 mesh sieves respectively.Take by weighing the abundant mixing of adjuvant of recipe quantity earlier, the solid dispersion of embodiment 1 is added in the adjuvant, make it and the abundant mixing of adjuvant.10% an amount of starch slurry joined make soft material in the compound, cross 20 mesh sieves and granulate, dry 2h in 55 ℃ of ventilated drying ovens, dried granule cross 18 mesh sieve granulate, measure intermediate content, tabletting.
Example 28:
Chewable tablet prescription (100 amounts)
Embodiment 13 solid dispersion 30g
Mannitol 70g
Microcrystalline Cellulose 15g
Xylitol 0.5g
10% polyvidone (water is joined) q.s
Magnesium stearate q.s
Preparation technology is with embodiment 27.
Example 29:
Orally disintegrating tablet prescription (100 amounts)
Embodiment 10 solid dispersion 10g
Mannitol 25g
Microcrystalline Cellulose 10g
Polyvinylpolypyrrolidone 6g
The sweet 0.2g of A Siba
Apple essence 0.1g
2% hyprolose q.s
Sodium lauryl sulphate 1.5g
Magnesium stearate q.s
Preparation technology is with embodiment 27.
Example 30:
Dispersible tablet prescription (100 amounts)
Embodiment 11 solid dispersion 40g
Lactose 10g
Microcrystalline Cellulose 10g
Carboxymethyl starch sodium 5g
The sweet 0.1g of A Siba
Orange flavor essence 0.05g
Citric acid 0.05g
2% hypromellose (30% ethanol is joined) q.s
Magnesium stearate q.s
Preparation technology is with embodiment 27.
Example 31:
Granule prescription (100 bag amount)
Embodiment 15 solid dispersion 100g
Mannitol 60g
Lactose 35g
Sodium carboxymethyl cellulose 5g
Stevioside 0.3g
Orange flavor essence 0.5g
2% hypromellose (30% ethanol is joined) q.s
Preparation technology:
It is standby that adjuvant is crossed 80 mesh sieves respectively.Take by weighing the abundant mixing of adjuvant of recipe quantity earlier.Embodiment 15 is added in the adjuvant the abundant mixing of messenger drug and adjuvant.2% hypromellose (30% ethanol is joined) joined make soft material in the compound, cross 16 mesh sieves and granulate, dry 2-3h in 55 ℃ of ventilated drying ovens, dried granule cross 12 mesh sieve granulate, measure intermediate content, pack.
Example 32:
Dry suspension prescription (100 bag amount)
Embodiment 18 solid dispersion 80g
Mannitol 40g
Lactose 30g
Carboxymethyl cellulose 5g
The sweet 1g of A Siba
Fructus Citri Limoniae essence 0.5g
10% polyvidone (water is joined) q.s
Preparation technology:
It is standby that adjuvant is crossed 80 mesh sieves respectively.Earlier with the abundant mixing of the adjuvant of recipe quantity.Embodiment 18 solid dispersions are added in the adjuvant the abundant mixing of messenger drug and adjuvant.5% polyvidone (water is joined) joined make soft material in the compound, cross 30 mesh sieves and granulate, dry 2-3h in 55 ℃ of ventilated drying ovens, dried granule cross 24 mesh sieve granulate, measure intermediate content, pack.
Example 33:
Embodiment 24 solid dispersion 20g
Microcrystalline Cellulose 5g
Carboxymethyl starch sodium 5g
Magnesium stearate 2g
Preparation technology:
It is standby that adjuvant is crossed 80 mesh sieves respectively.Take by weighing the abundant mixing of adjuvant of recipe quantity earlier, embodiment 24 solid dispersions are added in the adjuvant, the abundant mixing of messenger drug and adjuvant.Measure content and be sub-packed in capsule No. 0.
The measurement result of solid dispersion of the present invention 60 minutes dissolution (%) is as follows:
| Raw material dissolution (%) | Solid dispersion dissolution (%) | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 embodiment 9 embodiment 10 embodiment 11 embodiment 12 embodiment 13 embodiment 14 embodiment 15 embodiment 16 embodiment 17 embodiment 18 embodiment 19 embodiment 20 embodiment 21 embodiment 22 embodiment 23 embodiment 24 embodiment 25 embodiment 26 | ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 ＜10 | 41.5 58.7 37.9 62.5 82.1 78.6 65.7 76.8 87.6 67.6 89.2 83.5 88.1 97.6 94.2 93.6 72.7 90.8 80.3 93.5 92.9 87.4 89.3 90.5 76.4 94.8 |
The measurement result of solid dispersion bioavailability of the present invention is as follows:
| Group | Cmax(mg/L) | AUC(mg·h/L) | Degree of absorption improves multiple |
| TY501-DG4 raw material embodiment 2 solid dispersion embodiment 10 solid dispersion embodiment 13 solid dispersions | 0.8750 1.4414 0.8299 5.3359 | 13.6 33.8 18.4 80.0 | 1 2.49 1.35 5.88 |
Solid dispersion determination of activity result of the present invention is as follows:
Oleum Tiglii is caused the effect of mice ear inflammatory model
| Group | Dosage (mg/kg) | Swelling degree (Δ mg) |
| Model control group diclofenac TY501-DG4 raw material embodiment 2 solid dispersion embodiment 10 solid dispersion embodiment 13 solid dispersions | -- 40 40 40 40 40 | 7.52±1.81 4.78±1.31** 5.61±2.13 4.88±1.84** 5.22±0.99** 4.24±1.18** |
Annotate: compare * * p＜0.01, * p＜0.05 with model group.
Effect to mice acetic acid twisting pain model
| Group | Dosage (mg/kg) | Turn round the body number of times |
| Model control group diclofenac TY501-DG4 raw material embodiment 2 solid dispersion embodiment 10 solid dispersion embodiment 13 solid dispersions | -- 50 50 50 50 50 | 21.8±12.7 2.6±5.5** 5.1±11.1** 4.4±7.7** 6.2±6.1** 1.7±3.3** |
The antitussive effect result
| Group | Dosage (mg/kg) | The cough number of times |
| Model control group codeine TY501-DG4 raw material embodiment 2 solid dispersion embodiment 10 solid dispersion embodiment 13 solid dispersions | -- 50 50 50 50 50 | 31.5±12.7 5.6±5.5** 21.1±12.1** 14.4±9.6** 16.3±8.5** 11.5±8.2** |
The anti-gastric-ulcer exercising result
| Group | Dosage mg/kg | Average lesion degree |
| Model TY501-DG4 raw material sofalcone embodiment 11 solid dispersion embodiment 13 solid dispersions | --- 100 100 100 100 | 3.8 2.43 2.67 2.23 1.83 |
Resistive connection enteritis result
| Group | Dosage mg/kg | Average lesion degree |
| Model positive drug TY501-DG4 raw material embodiment 11 solid dispersion embodiment 13 solid dispersions | --- 50 50 50 50 | 3.2 1.67 2.21 2.03 1.95 |
The hepatoprotective effect result
| Group | Dosage mg/kg | GPT(u/ml) |
| Blank model silibinin TY501-DG4 raw material embodiment 2 solid dispersion embodiment 13 solid dispersions | - - 50 50 50 50 | 53.07±19.20 234.2±74.8 147.8±99.8* 173.1±88.1* 143.8±87.6* 136.3±68.7* |
Claims (9)
1. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Get N[(3-p-hydroxybenzene-isoxazole-5-base) methyl]-Radix Glycyrrhizae time amide sample 2g, add the mixture 40g of Polyethylene Glycol 1000 and polyethylene glycol 6000, the two ratio is 1: 8, put in the beaker, heating in water bath makes fusion, adds glycerol 2g again, and Oleum Ricini gathers hydrocarbon oxygen ester 351g, stir, rapid cooling curing, drying is pulverized, cross 80 mesh sieves, get solid dispersion.
2. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Get the adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide sample 5g, add lactose 5g, put in the mortar, grind, rotating speed 300rpm ground 60 minutes, crossed 120 mesh sieves, promptly got solid dispersion.
3. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Taking by weighing Macrogol 4000 10g, polyethylene glycol 6000 10g is dissolved in 150ml 95% ethanol, get the adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide sample 2g, add sodium lauryl sulphate 0.5g, after thermal agitation makes dissolving fully, stir 3-4h, boil off solvent, after the residue dried, grind, cross 80 mesh sieves and promptly get solid dispersion.
4. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Taking by weighing polyvidone RF1215g is dissolved in the 200ml ethanol, add the adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide sample 2g, after 80 ℃ of oil bath heating are fully stirred and are made dissolving fully, stir 3-4h, boil off ethanol, after the residue dried, grind, cross 200 mesh sieves and promptly get solid dispersion.
5. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Taking by weighing polyvidone RF1420g is dissolved in 180ml 80% ethanol, add N[(3-p-methylphenyl-isoxazole-5-bases) methyl]-Radix Glycyrrhizae time amide sample 2g, add polyoxyethylene laurate 1g, 80 ℃ of oil bath heating make dissolving, after stirring 2-3h, boil off solvent, after the residue dried, grind, cross 120 mesh sieves and promptly get solid dispersion.
6. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Take by weighing polyethylene glycol 6000 20g, poloxamer 1g, 80 ℃ of oil bath heated and stirred make dissolving fully; Other claims the adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide sample 1g adds ethanol 20ml, and heated and stirred makes dissolving; To contain medicinal liquid and add mix homogeneously in the melting carrier material, and stir 0.5-1h, and put and be cooled to solid in the ice-water bath rapidly, and fully solidify, drying is ground, and crosses 80 mesh sieves.
7. a solid dispersion that contains enoxolone 30-amide derivatives active component is characterized in that being made by weight by active component and carrier material, and concrete composition and preparation method are:
Take by weighing polyethylene glycol 6000 20g, Macrogol 4000 20g, glycerol 5g, 80 ℃ of oil bath heated and stirred make dissolving fully; Other claims the adjacent chloro phenyl of N[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time amide sample 1g adds ethanol 20ml, and heated and stirred makes dissolving; To contain medicinal liquid and add mix homogeneously in the melting carrier material, and stir 0.5-1h, and put and be cooled to solid in the ice-water bath rapidly, and put and keep 0.5-24h in the household freezer, and fully solidify, drying is ground, and crosses 200 mesh sieves, promptly.
8. a tablet that contains enoxolone 30-amide derivatives class is characterized in that being made by weight by solid dispersion and adjuvant, and 100 amounts consist of:
The described solid dispersion 25g of claim 1
Lactose 10g
Pregelatinized Starch 4g
Microcrystalline Cellulose 4g
Polyvinylpolypyrrolidone 3g
10% starch slurry q.s
Magnesium stearate q.s
Preparation technology:
It is standby that adjuvant is crossed 80 mesh sieves respectively; Take by weighing the abundant mixing of adjuvant of recipe quantity earlier, the described solid dispersion of claim 1 is added in the adjuvant, make it and the abundant mixing of adjuvant; 10% an amount of starch slurry joined make soft material in the compound, cross 20 mesh sieves and granulate, dry 2h in 55 ℃ of ventilated drying ovens, dried granule cross 18 mesh sieve granulate, measure intermediate content, tabletting.
9. a granule that contains enoxolone 30-amide derivatives class is characterized in that being made by weight by solid dispersion and adjuvant, and 100 bag amounts consist of:
The described solid dispersion 100g of claim 5
Mannitol 60g
Lactose 35g
Sodium carboxymethyl cellulose 5g
Stevioside 0.3g
Orange flavor essence 0.5g
2% hypromellose q.s of 30% ethanol preparation
Preparation technology:
It is standby that adjuvant is crossed 80 sieves respectively; Take by weighing the abundant mixing of adjuvant of recipe quantity earlier, the described solid dispersion of claim 5 is added in the adjuvant, the abundant mixing of messenger drug and adjuvant; 2% hypromellose of 30% ethanol preparation joined make soft material in the compound, cross 16 mesh sieves and granulate, dry 2-3h in 55 ℃ of ventilated drying ovens, dried granule cross 12 mesh sieve granulate, measure intermediate content, pack.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100605288A CN101229172B (en) | 2007-12-28 | 2007-12-28 | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100605288A CN101229172B (en) | 2007-12-28 | 2007-12-28 | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101229172A CN101229172A (en) | 2008-07-30 |
| CN101229172B true CN101229172B (en) | 2010-10-27 |
Family
ID=39896188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100605288A Expired - Fee Related CN101229172B (en) | 2007-12-28 | 2007-12-28 | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101229172B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813662A (en) * | 2011-06-09 | 2012-12-12 | 天津药物研究院 | New application of glycyrrhetinic acid-30-amined derivative |
| CN102813661B (en) * | 2011-06-09 | 2014-04-09 | 天津药物研究院 | Application for glycyrrhetinic acid derivatives |
| CN103102382A (en) * | 2011-11-14 | 2013-05-15 | 天津药物研究院 | Crystal form B of glycyrrhetinic acid-30-amide derivative and preparation method thereof |
| CN103102383A (en) * | 2011-11-14 | 2013-05-15 | 天津药物研究院 | Crystal form A of glycyrrhetinic acid-30-amide derivative and preparation method thereof |
| CN105616428A (en) * | 2014-10-31 | 2016-06-01 | 天津药物研究院有限公司 | Novel application of compound |
| CN106265692A (en) * | 2015-05-22 | 2017-01-04 | 天津药物研究院有限公司 | A kind of transdermal formulation of enoxolone 30-amide derivatives and its production and use |
| CN111374968A (en) * | 2018-12-27 | 2020-07-07 | 山东鲁抗医药股份有限公司 | Composition containing dapagliflozin and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1762967A (en) * | 2004-09-17 | 2006-04-26 | 山东绿叶制药有限公司 | Enoxolone derivative, preparation method and uses |
| CN1879647A (en) * | 2006-04-29 | 2006-12-20 | 杭州创新中药标准化研究所有限公司 | Solid dispersion of protopanaxadiol and preparation method thereof |
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
-
2007
- 2007-12-28 CN CN2007100605288A patent/CN101229172B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1762967A (en) * | 2004-09-17 | 2006-04-26 | 山东绿叶制药有限公司 | Enoxolone derivative, preparation method and uses |
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN1879647A (en) * | 2006-04-29 | 2006-12-20 | 杭州创新中药标准化研究所有限公司 | Solid dispersion of protopanaxadiol and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 毕殿洲.药剂学 4.人民卫生出版社,2001,114-117. |
| 毕殿洲.药剂学 4.人民卫生出版社,2001,114-117. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101229172A (en) | 2008-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101229172B (en) | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof | |
| ES2711935T3 (en) | Conjugates of rhein, method of preparing them and their uses in the production of drugs to treat diabetic nephrosis, intestinal adhesion and osteoarthritis | |
| CN105142633A (en) | Oral administration preparation with masked bitterness of silodosin | |
| CN102631377A (en) | Cordyceps sinensis freeze-dried nano powder tablet and preparation method thereof | |
| CN101889987A (en) | Method for preparing novel cefixime tablets and cefixime capsules | |
| JP2016539955A (en) | Drug composition, method for producing the same, and use | |
| WO2015081703A1 (en) | Solid dispersion containing desmodium styracifolium (osb.) merr. flavonoids, method of preparing same, and use thereof | |
| CN101181224B (en) | Solid dispersion of entecavir, pharmaceutical composition and preparation method as well as uses thereof | |
| CN1965836B (en) | Oral solid formulation and its preparation method | |
| CN101703588A (en) | Shuanghuanglian in situ gel preparation and preparation method thereof | |
| CN100536832C (en) | Hemostatic notoginseng chewing tablet and preparation method thereof | |
| CN102178658B (en) | Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof | |
| CN101375834A (en) | Solid dispersion of Ailamode and preparation method thereof and medicament application | |
| KR101086254B1 (en) | Soild dispersion composition of pranlukast with improved bioavailability and the method of preparing the solid dispersion | |
| CN1899277B (en) | Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating diabetic nephrosis | |
| CN106692715A (en) | Hangover-alleviating effervescent tablets and preparation method thereof | |
| CN101224211A (en) | Entecavir solid dispersoid, medicine compounds and preparing method and applications thereof | |
| CN102145049A (en) | Preparation method of Yiqing granules | |
| CN101292981A (en) | Solid dispersion, composition of rimonabant, preparation and medicament application thereof | |
| CN1899275B (en) | Use of composition of rheinic acid or rheinic acid compounds in preparing medicine for treating osteoarthritis | |
| CN112569190B (en) | Oral administration preparation of pulsatilla chinensis saponin B4 and preparation method thereof | |
| CN103961455A (en) | Heat-clearing and detoxifying traditional Chinese medicine compound preparation and preparation method thereof | |
| CN100420471C (en) | Oral taking preparation of Chinese traditional medicine for nourishing the kidney and the lung | |
| CN102406897B (en) | Xingnaojing solid medicinal composition and preparation method thereof | |
| CN103536632A (en) | Self-microemulsifying brucea javanica oil oral granules and preparation method thereof |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101027 Termination date: 20171228 |