CN102379858A - Osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof - Google Patents
Osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof Download PDFInfo
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- CN102379858A CN102379858A CN2011103077092A CN201110307709A CN102379858A CN 102379858 A CN102379858 A CN 102379858A CN 2011103077092 A CN2011103077092 A CN 2011103077092A CN 201110307709 A CN201110307709 A CN 201110307709A CN 102379858 A CN102379858 A CN 102379858A
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Abstract
The invention provides an osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof. The preparation tablet core is a single layer tablet, including a medicament, an absorption promoting agent, a penetration enhancer, an absorbent, a disintegrating agent, an adhesive polymer and lubricant, wherein the medicament is dissolved in the absorption promoting agent, uniformly mixed with the penetration enhancer, the absorbent, the disintegrating agent and the adhesive polymer, and is granulated; and the lubricant is added after the mixture is baked, and the mixture is tabletted to obtain the tablet core. A coating film is coated outside the tablet core, and a pore is formed on any side of the coating film. The adhesive polymer is hydroxyethyl cellulose, which can disperse the medicament uniformly when the dose of the hydroxyethyl cellulose in the prescription is 3 percent, and the medicament is released durably and stably, so that the aim of loading slightly-soluble medicaments in the osmotic pump tablets in large dose is realized. The absorption effect of the slightly-soluble medicaments is remarkably improved by adding the absorption promoting agent. The medicine content of the preparation can be 500mg, so that the medicament is controlled to release in a constant speed, the drug action is durable and stable, the number of administration is small, and the toxic and side effects are slight. The osmotic pump tablet has the advantages of more in-vivo absorption, high bioavailability and the like.
Description
Technical field
The present invention relates to medical technical field, particularly a kind ofly load heavy dose of insoluble drug and promote osmotic pump tablet of its absorption and preparation method thereof.
Background technology
Data according to statistics; Poorly water soluble drugs accounts for 40% of world's medicine total amount; Drug absorption situation diversity factor is big in individual and between individuality; Lack dose-effect relationship between blood drug level and the drug dose, the bioavailability difference is the common problem that these medicines exist, and this has caused a great difficult problem for the development and use to them.
Insoluble drug; It is made osmotic pump tablet certain difficulty is arranged; Because (Cs) is lower for its dissolubility; In the microenvironment of label, be difficult to form higher concentration and osmotic pressure is kept effective drug release rate, perhaps will keep lasting constant osmotic pressure needs a large amount of osmotic pressure promoter (having surpassed the heavy scope of normal sheet), so insoluble drug is taked double layer osmotic pump (or being called the push-pull type osmotic pumps) preparation technique usually; Make medicine and medicated layer macromolecule released drug release hole by boosting floor height molecule, reach the purpose of constant speed release medicine with the suspension form.We can say that the double layer osmotic pump preparation technique is that present insoluble drug is processed the osmotic pump type preparation method of maturation, optimum suitability for industrialized production the most.
But, comparing with primary osmotic pump, it is comparatively loaded down with trivial details that the preparation technology of double layer osmotic pump preparation then seems: at first, use suitable macromolecular material (adopting polyethylene glycol oxide usually) compacting to have the double-layer tablet of medicated layer and boosting layer; Subsequently label is carried out coating; Because medicated layer will form the suspension of macromolecule and medicine in drug release process; Aqueous solution is big usually for its viscosity, and therefore required release power is higher than elementary elementary osmotic pump, for the thickness that guarantees the required coating membrane of safe and effective release (preventing that the clothing film rupture from causing medicine to be dashed forward and releasing) also will be higher than elementary elementary osmotic pump; This has just caused the tediously long of art for coating operation, also possibly cause release initial stage " time lag " long problem simultaneously; In drill process to coated tablet; Owing to there is the two-sided identification problem of double-layer coating plate; So at first to discern before the drilling laser instrument institute to unilateral whether be medicated layer, this has just caused the further loaded down with trivial details of technological operation, also the order of accuarcy of identification apparatus is had higher requirement simultaneously.And double-layer tablet both contained medicine layer and also contained the boosting layer, and the dose that can load is limited, generally is lower than 200mg.So; Although the double layer osmotic pump release steadily, (the zero-order release mark can reach more than 90%) fully because it is more to influence the factor of double layer osmotic pump preparation drug release behavior, preparation technology is loaded down with trivial details; Performance requirement to production equipment is higher, and these have all restricted it and have used on a large scale, widely.
The invention provides a kind of mono-layer osmotic pump sheet that loads heavy dose of insoluble drug and promote its absorption.With a kind of water dissolvable and can form the macromolecular compound compressed single label of suitable viscosity, the outside encapsulates semipermeability clothing film, and punches with insoluble drug.This osmotic pump tablet is dropped in the aqueous environments, and under the osmotic pressure effect, moisture gets into coyote hole, and macromolecular compound dissolves gradually, forms solution and the uniform suspension of the common formation of insoluble drug powder with suitable viscosity.The imbibition pressure and the osmotic pressure that produce when utilizing the macromolecular compound dissolving, the suspension of insoluble drug can discharge through small delivery aperture.
Influence the factor that this type insoluble drug elementary osmotic pump sheet discharges; Except that the factors such as size of coating membrane material character and thickness, label prescription and drug release hole; Pay special attention to select the proper polymer chemical compound to make adjuvant; This macromolecular compound should be able to dissolve rapidly, volume should not overinflation in order to avoid coating membrane breaks, also to produce suitable viscosity simultaneously.Research shows that under the not disruptive situation of coating membrane, the amount that this type of macromolecular compound adds is many more, and the suspension viscosity of formation is big more, and drug powder is not easy sedimentation more, and stability is high more; The macromolecular compound addition is many more, and imbibition pressure and osmotic pressure that dissolving produces are big more, and the drug release rate of medicine is fast more.But the increase of this type of compound amount can make the amount of drug loading reduce relatively.For loading heavy dose of insoluble drug, the present invention adopts hydroxyethyl-cellulose as the stickiness polymer.The result shows, when polymer volume was merely sheet and weighs 3%, medicine can effective suspendible; Again can constant release, polymer volume significantly reduces, and the drug loading amount obviously improves; Make the drug loading amount can reach 500mg at most, realized that primary osmotic pump loads the purpose of heavy dose of insoluble drug.
The present invention adds short absorbent in primary osmotic pump, can promote the absorption of insoluble drug, thereby the realization elementary osmotic pump both can be loaded heavy dose of insoluble drug, can promote the purpose that insoluble drug absorbs again.
Summary of the invention
The purpose of this invention is to provide a kind of bioavailability height, convenient drug administration, stable curative effect, heavy dose of medicine single layer osmotic pump regulated-release preparations that toxic and side effects is little.It is characterized in that it is made up of the semi permeability film coating of pastille label with the band drug release hole,
Described label weight consists of:
Medicine 3%-70%,
Stickiness polymer 3%-10%,
Short absorbent 5%-20%,
Penetration enhancer 5%-25%,
Absorbent 5%-30%,
Disintegrating agent 6%-10%,
Lubricant 0.1%-10%,
Each component sum equals 100%;
Described semi permeability film coating liquid consists of:
Coating material: 3% (w/v, g/ml),
Plasticizer: 0.6%-0.9% (w/v, g/ml);
The film coating weightening finish is the heavy 8%-12% of sheet,
Described drug release hole is in label one side laser boring.
Method for preparing: medicine and adjuvant are crossed 100 mesh sieves respectively.Take by weighing the recipe quantity medicine dissolution in short absorbent, penetration enhancer and absorbent, disintegrating agent, the adding of stickiness polymer of mix homogeneously are urged in the absorbent, fully mix homogeneously is granulated, and oven dry adds the lubricant tabletting and gets label.Semipermeable membrane coating material and plasticizer porogen are dissolved in the mixed solvent of acetone-water, and label places the coating pan coating, and art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm.After the coating weightening finish reaches predetermined value coated tablet is put dry 12h in 36 ℃ of baking ovens.Adopt laser boring one side in office to beat diameter 0.4-1.0mm aperture dried coated tablet, wherein best with 0.9mm aperture release effect.
Short absorbent in the above-mentioned said tablet is made up of Polyethylene Glycol glyceryl laurate ester, poloxamer 188, PEG400, and the ratio between them is the Polyethylene Glycol glyceryl laurate ester: poloxamer 188: PEG400 (35: 45: 20).
The above-mentioned described osmotic pump type controlled release preparation that loads heavy dose of insoluble drug and promote its absorption is characterized in that the stickiness polymer of being selected for use comprises hydroxyethyl-cellulose (Natrasol 250H; Natrasol 250HH; Natrasol 250M; Natrasol 250L); Carbomer (940; 934); Hypromellose (K100M, E50LV, E15LV, E5LV); 30 POVIDONE K 30 BP/USPs 30 etc., wherein best with hydroxyethyl-cellulose 250H effect, consumption is 3%-10%.
Penetration enhancer in the above-mentioned said tablet is sodium chloride, sorbitol, and disintegrating agent is a polyvinylpolypyrrolidone, and the absorbent of being selected for use is a beta-schardinger dextrin-, and lubricant is Pulvis Talci and magnesium stearate.
The coating material of being selected for use in the above-mentioned said tablet is a cellulose acetate, and the plasticizer of being selected for use is a Macrogol 4000, and the coating solvent is the mixed system of acetone and water.
The drilling method of being selected for use in the above-mentioned said tablet adopts laser boring, and the aperture is 0.4-1.0mm, and is wherein best with 0.9mm aperture releasing effect.
The dissolution in vitro method: getting the osmotic pump controlled release tablet that can load heavy dose of insoluble drug and promote its absorption, adopt the three therapeutic methods of traditional Chinese medicine in the dissolution method (2000 editions two appendix XC of Chinese Pharmacopoeia), is dissolution medium with 250ml pH8.5 phosphate buffer, and rotating speed is 75rpm; Operation in accordance with the law, 1,2,4; Got dissolution fluid 5ml in 6,8,10,12 hours respectively; With 1: 1 breakdown of emulsion of ethanol, 0.45 μ m filtering with microporous membrane, and in time in process container, replenish dissolution medium 5ml of the same race.
Description of drawings
Fig. 1 is the stripping curve figure of the osmotic pump controlled release tablet of the heavy dose of insoluble drug sildenafil citrate of loading.
Fig. 2 is the stripping curve figure of the osmotic pump controlled release tablet of the heavy dose of insoluble drug gliclazide of loading.
Fig. 3 is the stripping curve figure of the osmotic pump controlled release tablet of the heavy dose of insoluble drug G004 of loading.
Fig. 4 is the stripping curve figure that loads heavy dose of insoluble drug G004 and promote the osmotic pump controlled release tablet of its absorption.
The specific embodiment
Embodiment 1
The label preparation:
Former, adjuvant is crossed 100 mesh sieves respectively, take by weighing sildenafil citrate and sorbitol, hyprolose, the abundant mix homogeneously of hyetellose of recipe quantity, add recipe quantity magnesium stearate mixing again.The tablet machine tabletting gets label.
Coating fluid prescription:
Cellulose acetate 66.7%
Macrogol 4000 33.3%
Art for coating:
Semipermeable membrane coating material and plasticizer porogen are dissolved in the mixed solvent of acetone-water, and label places the coating pan coating, and art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm.After the coating weightening finish reaches 8%-12% the coated tablet sheet is put dry 12h in 36 ℃ of baking ovens.Adopt laser boring one deck in office to beat diameter 0.9mm aperture dried coated tablet, get product.
The drug loading of sildenafil citrate is 468mg in the present embodiment, and every content of dispersion of ordinary tablet can reach 100mg at most, so present embodiment is for loading the osmotic pump tablet of heavy dose of insoluble drug.
The label preparation:
Former, adjuvant is crossed 100 mesh sieves respectively, take by weighing gliclazide and sodium chloride, hyprolose, the abundant mix homogeneously of hyetellose of recipe quantity, add recipe quantity magnesium stearate mixing again.The tablet machine tabletting gets label.
Coating fluid prescription:
Cellulose acetate 66.7%
Macrogol 4000 33.3%
Art for coating:
Semipermeable membrane coating material and plasticizer porogen are dissolved in the mixed solvent of acetone-water, and label places the coating pan coating, and art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm.After the coating weightening finish reaches 8%-12% the coated tablet sheet is put dry 12h in 36 ℃ of baking ovens.Adopt laser boring one deck in office to beat diameter 0.9mm aperture dried coated tablet, get product.
The drug loading of gliclazide is 320mg in the present embodiment, and every content of dispersion of ordinary tablet can reach 80mg at most, so present embodiment is for loading the osmotic pump tablet of heavy dose of insoluble drug.
Embodiment 3
The label preparation:
Former, adjuvant is crossed 100 mesh sieves respectively, take by weighing G004 and sodium chloride, hyprolose, the abundant mix homogeneously of hyetellose of recipe quantity, add recipe quantity Pulvis Talci mixing again.The tablet machine tabletting gets label.
Coating fluid prescription:
Cellulose acetate 83.3%
Macrogol 4000 16.7%
Art for coating: semipermeable membrane coating material and plasticizer porogen are dissolved in the mixed solvent of acetone-water, and label places the coating pan coating, and art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm.The coating weightening finish will after reaching 8%-12%
The coated tablet sheet is put dry 12h in 36 ℃ of baking ovens.Adopt laser boring one deck in office to beat diameter 0.9mm aperture dried coated tablet, get product.
The drug loading of G004 is 100mg in the present embodiment, and every content of dispersion of ordinary tablet can reach 10mg at most, so present embodiment is for loading the osmotic pump tablet of heavy dose of insoluble drug.
The label preparation:
Medicine and adjuvant are crossed 100 mesh sieves respectively.Take by weighing the recipe quantity medicine dissolution in short absorbent, penetration enhancer and absorbent, disintegrating agent, the adding of stickiness polymer of mix homogeneously are urged in the absorbent, fully mix homogeneously is granulated, and oven dry adds the lubricant tabletting and gets label.
Coating fluid prescription:
Cellulose acetate 83.3%
Macrogol 4000 16.7%
Art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm.After the coating weightening finish reaches 8%-12% the coated tablet sheet is put dry 12h in 36 ℃ of baking ovens.Adopt laser boring one deck in office to beat diameter 0.9mm aperture dried coated tablet, get product.
Present embodiment is identical with embodiment 3 dosage, but has added short absorbent in the prescription.
Embodiment 5
Get osmotic pump tablet label and the osmotic pump tablet label among the embodiment 4 among the embodiment 3, through rat the body intestinal reflux experiment relatively they in the systemic difference of rat intestine
(1) rat anesthesia
Rat is made intraperitoneal injection of anesthesia with pentobarbital sodium solution (40mg/kg), and back of the body position is fixed on the fixed station.
(2) small intestinal two ends intubate
Along abdominal part median line hara kiri (about 3cm), respectively insert one of thin glass tube at duodenal cap and ileum bottom, and tighten insertion end with surgical thread, the other end connects rubber tube respectively
(3) washing intestinal tube
37 ℃ of normal saline are slowly injected intestinal tube through the duodenal cap glass-tube, and flush away intestinal tube content is sent into air cleaning mixture is flow to end as far as possible behind the thorough washing.
(4) intestinal tube refluxes
Carry out intestinal tube backflow experiment.The osmotic pump tablet label and the osmotic pump tablet label among the embodiment 4 that are about among the embodiment 3 are positioned over respectively in an amount of Krebs-Ringer buffer, are uniformly dispersed.Draw two kinds of solution 50ml respectively and put in the reservoir, start constant flow pump and circulate, medicinal liquid is gone into intestinal tube from duodenal cap, flows in the reservoir through the ileum bottom.With the flow velocity backflow 10min of 5ml/min, be 2.5ml/min with flow rate regulation then earlier, recirculation flow 120min.
(5) sampling
Refluxing begins back 10min, from two parts of reservoir samplings, and a 1ml, another part 0.5ml is respectively as medicine and phenol red zero-time sample.Thereafter every separated 10min also takes a sample two parts equally, should replenish 1.5ml phenol red solution (20 μ g/ml) immediately after each sampling.Stop to reflux after being sampled to 120min.Measure G004 and phenol red concentration in the appearance liquid, thus long-pending the and G004 surplus of computation cycles liquid.
The result shows that the surplus of the label rat intestine backflow experiment G004 of embodiment 3 is 88.4mg, and absorbtivity is 11.6mg, and the surplus of the label rat intestine backflow experiment G004 of embodiment 4 is 75.9mg, and absorbtivity is 24.1mg.Above-mentioned data show that embodiment 4 labels absorbtivity in rat intestine is more than embodiment 3 labels absorbtivity in rat intestine, are systemic 2.08 times of rat intestines among the embodiment 3.Embodiment 4 can promote the absorption of medicine.
Claims (8)
1. the osmotic pump type controlled release preparation that can promote that heavy dose of insoluble drug absorbs is characterized in that it is made up of the semi permeability film coating of pastille label with the band drug release hole,
Described label weight consists of:
Medicine 3%-70%,
Stickiness polymer 3%-10%,
Short absorbent 5%-20%,
Penetration enhancer 5%-25%,
Absorbent 5%-30%,
Disintegrating agent 6%-10%,
Lubricant 0.1%-10%,
Each component sum equals 100%;
Described semi permeability film coating liquid consists of:
Coating material: 3% (w/v, g/ml),
Plasticizer: 0.6%-0.9% (w/v, g/ml);
The film coating weightening finish is the heavy 8%-12% of sheet,
Described drug release hole is in label one side laser boring.
2. the osmotic pump type controlled release preparation that the heavy dose of insoluble drug of raising according to claim 1 absorbs; It is characterized in that described medicine is a slightly solubility, comprise glibenclamide, glipizide, gliquidone, glimepiride, gliclazide, G004 (chemical formula is 1-{4-[2-(4-bromobenzene sulfoamido) ethyl] benzene sulfonyl }-3-(anti--the 4-methylcyclohexyl) urea), sildenafil citrate, Sertraline etc.
3. the osmotic pump type controlled release preparation that loads heavy dose of insoluble drug and promote its absorption according to claim 1 is characterized in that the stickiness polymer of being selected for use comprises hydroxyethyl-cellulose (Natrasol 250H; Natrasol 250HH; Natrasol 250M; Natrasol 250L); Acritamer 940; Carbomer 934; Hypromellose (K100M, E50LV, E15LV, E5LV); 30 POVIDONE K 30 BP/USPs 30 etc., wherein best with hydroxyethyl-cellulose 250H effect, consumption is 3%-10%.
4. the osmotic pump tablet that loads heavy dose of insoluble drug and promote its absorption according to claim 1; It is characterized in that: the best prescription that a large amount of experiments of process draw short absorbent is by the Polyethylene Glycol glyceryl laurate ester; Poloxamer 188; PEG400 is formed, and the ratio between them is the Polyethylene Glycol glyceryl laurate ester: poloxamer 188: PEG400 (35: 45: 20).
5. the osmotic pump tablet that loads heavy dose of insoluble drug and promote its absorption according to claim 1; It is characterized in that the penetration enhancer of being selected for use is sodium chloride and sorbitol; The absorbent of being selected for use is a beta-schardinger dextrin-; The disintegrating agent of being selected for use is a polyvinylpolypyrrolidone, and the lubricant of selecting for use is magnesium stearate and Pulvis Talci.
6. the osmotic pump tablet that loads heavy dose of insoluble drug and promote its absorption according to claim 1 is characterized in that the coating material of being selected for use is a cellulose acetate, and the plasticizer of being selected for use is a Macrogol 4000.
7. the osmotic pump tablet that loads heavy dose of insoluble drug and promote its absorption according to claim 1 is characterized in that adopting laser boring, and the aperture is 0.4-1.0mm, and is wherein best with aperture 0.9mm effect.
8. the osmotic pump tablet that loads heavy dose of insoluble drug and promote its absorption according to claim 1 is characterized in that may further comprise the steps:
1) medicine and adjuvant are crossed 100 mesh sieves respectively; Take by weighing the recipe quantity medicine dissolution in short absorbent, penetration enhancer and absorbent, disintegrating agent, the adding of stickiness polymer of mix homogeneously are urged in the absorbent, fully mix homogeneously; 30 orders are granulated; 36 ℃ of oven dry, 24 order granulate add the lubricant tabletting and get label;
2) semipermeable membrane coating material and plasticizer porogen are dissolved in the mixed solvent of acetone-water, label places the coating pan coating, and art for coating is following: the coating solution flow velocity is 2.5ml/min, 30 ℃ of coating kettle temperatures, rotating speed 8-10rpm;
3) coated tablet is put dry 12h in 36 ℃ of baking ovens;
4) adopt laser boring one side in office to beat diameter 0.4-1.0mm aperture dried coated tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110307709 CN102379858B (en) | 2011-10-12 | 2011-10-12 | Osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110307709 CN102379858B (en) | 2011-10-12 | 2011-10-12 | Osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102379858A true CN102379858A (en) | 2012-03-21 |
| CN102379858B CN102379858B (en) | 2013-06-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110307709 Expired - Fee Related CN102379858B (en) | 2011-10-12 | 2011-10-12 | Osmotic pump tablet capable of loading large-dose slightly-soluble medicaments and promoting absorption thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1579370A (en) * | 2004-05-18 | 2005-02-16 | 杭州康特尔医药科技有限公司 | Single-layer-core seeping pump sheet for medicine difficult to ressolve and making method |
| CN1625388A (en) * | 2002-02-01 | 2005-06-08 | 辉瑞产品公司 | Osmotic delivery system |
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2011
- 2011-10-12 CN CN 201110307709 patent/CN102379858B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625388A (en) * | 2002-02-01 | 2005-06-08 | 辉瑞产品公司 | Osmotic delivery system |
| CN1579370A (en) * | 2004-05-18 | 2005-02-16 | 杭州康特尔医药科技有限公司 | Single-layer-core seeping pump sheet for medicine difficult to ressolve and making method |
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| CN102379858B (en) | 2013-06-19 |
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