CN102579407B - Preparation method for indapamide microsphere sustained release capsules - Google Patents
Preparation method for indapamide microsphere sustained release capsules Download PDFInfo
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Abstract
Provided is a preparation method for indapamide microsphere sustained release capsules. The indapamide microsphere sustained release capsules, especially contents, are formed by microsphere of gastrointestinal tract release medicine manufactured by indapamide and high polymer materials with high potential of hydrogen (pH) dependency. The high polymer materials comprise polyacrylate E-100, hydroxypropyl methylcellulose phthalic ester HP-55 and hydroxypropyl methylcellulose succinate HAS which are respectively manufactured into stomach dissolving microsphere, intestines dissolving microshpere and colon dissolving microsphere with the indapamide. All microspheres are combined into particle dispersing capsules according to weight parts. After taken, medicine is released in the stomach and intestines according to pH gradient, blood concentration is stable, sustained release is achieved, medicine in the microsphere is highly dispersed and dissolved out to be completely absorbed, and biological utilization of oral medicine is improved. The medicine microsphere is simple in the preparation method and equipment and suitable for industrialization.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly relate to Indapamide Sustained-release Capsules, its content is mainly combined by the indapamide location microsphere that tool pH dependency gradient discharges, oral rear medicine discharges and absorbs at full gastrointestinal, reach slow release effect, and improve the bioavailability of insoluble drug.
Background technology
Hypertension is the modal cardiovascular disease in the world, is also one of maximum epidemic diseases, often causes the complication of the internal organs such as the heart, brain, kidney, and the mankind's health in serious harm.China's hypertension ubiquity " three-hypers " that prevalence is high, mortality rate is high, disability rate is high and awareness is low, treatment rate is low, control rate is low " three is low " characteristics, and wherein treatment rate and control rate are only 24.7% and 6.1% according to survey result in 2004.China becomes one of the most serious country of high blood pressure disease harm in the world, and active development is treated hypertensive pharmaceutical preparation has safely and effectively become the important topic of medical scientific research.
The English name of indapamide is: Indapamide; Chemical formula: C
16H
16ClN
3O
3S, structural formula:
The molecular weight of indapamide (Indapamide IDP) is 365.83, and structural formula is:
Indopamide is off-white color acicular crystal or crystalline powder, and odorless is tasteless, and water-soluble and dilute hydrochloric acid, be dissolved in ethanol hardly, is soluble in acetone.
Indapamide is the new medicine of dropping blood pressure with diuresis and calcium antagonism.Indapamide vasoactive smooth muscle; the diastole small artery; can reduce peripheral vascular resistance and to the reactivity of hypertensive substance; and diuresis arranged; be applied to essential hypertension, not only but also do not cause postural hypotension, flushing and tachycardia, do not cause that also blood fat changes; to preferably with edema tendency person, kidney also there is protective effect.To have an antihypertensive effect good due to indapamide, long action time, side effect is little, but the advantages such as life-time service, especially in blood pressure lowering, blood glucose, blood fat, blood uric acid and blood electrolyte are all had no significant effect, and are the present hypertensive drug of first choices of clinical anti-all kinds, have wide market prospect and high medical value.
At present, clinical have indapamide ordinary tablet and the slow releasing tablet of using is US Patent No. 5334392.The every daily dose 2.5mg of indopamide conventional tablet, produce the blood drug level peak value after medication, cause outward potassium flow, easily causes hypokalemia.Every day, the indapamide slowly-releasing tablet of 1.5mg reduced taking dose, and can make blood drug level steady, overcame the side effect such as hypokalemia.Patent 02129461.5 and 03104699.1 has prepared Indapamide Sustained-release Capsules by the micropill technology and has reached blood drug level stably.But indopamide is insoluble in water, and slow release is delayed peak time, and peak concentration reduces, and needs to solve to bring the low problem of bioavailability.
A kind of steadily blood drug level of clinical needs, bioavailability is high, and the simple indapamide slow release preparation of preparation technology.
Summary of the invention
The purpose of this invention is to provide a kind of preparation technology simple, the Indapamide Sustained-release Capsules that bioavailability is high, by selecting different macromolecular materials, prepare the indapamide location release microsphere that tool pH dependency gradient discharges, make again the Indapamide Sustained-release Capsules that full gastrointestinal absorbs, microsphere Chinese medicine high degree of dispersion, can promote effective absorption of insoluble drug simultaneously.
In order to solve the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent are 1:4-12:3-10 obtain solution A according to weight part ratio, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 500rpm ~ 800rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 80ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 80ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the gastric solubleness microsphere,
prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent are 1:3-10:3-9 obtain solution B according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 300rpm ~ 600rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect enteric-coated microsphere,
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:2-6:3-8 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 300rpm ~ 600rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.01%-0.1%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 1 ~ 4 part of gastric solubleness microsphere, 5 ~ 9 parts of enteric-coated microspheres, 0.5 ~ 2 part of the molten microsphere of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1 ~ 1.5 mg;
In the 3rd step, be filled to capsule shells with adjuvant full, makes indapamide microsphere sustained-release capsule.
Described indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent are 1:5-8:3-10 obtain solution A according to weight part ratio;
Described indapamide, HP-55 HP-55 and the second organic solvent are 1:4-6:3-9 obtain solution B according to weight part ratio;
Described indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:3-4:3-8 obtain solution C according to weight part ratio.
The parts by weight of raw materials proportioning of described adjuvant is: 30 ~ 50 parts of microcrystalline Cellulose, 25 ~ 45 parts of lactose, 1 ~ 3 part of micropowder silica gel, 1 ~ 3 part of Pulvis Talci; Described adjuvant is the one or more combination in microcrystalline Cellulose, lactose, micropowder silica gel and Pulvis Talci.
Gastrointestinal absorption is the important prerequisite of oral drugs performance drug effect.At first, there were significant differences for each section of gastrointestinal tract pH, and people's Gastric pH on an empty stomach is 1 ~ 3, and after diet, pH increases to 3 ~ 5, and intestinal fluid pH is 6 ~ 7, and large intestine pH is 7 ~ 8.The solution absorption that the pH of gastro-intestinal Fluid changes medicine affects very greatly, and also the appropriate design for oral Preparation provides thinking.PH according to gastro-intestinal Fluid changes, and can design pH dependency preparation to improve the bioavailability of medicine.
According to the absorption dynamics research of rat at body stomach, intestinal, indapamide is 9.8% at stomach 2h PA; At full intestinal, better absorption is arranged all, in 6h, the average absorption rate is 73.3 %, and the degree of absorption between different intestinal segment is without significant difference; Absorption rate constant at colon is approximately 30% of little intestinal segment; Show that indapamide all has absorption at full gastrointestinal tract, keep for preparation oral administration system that curative effect reaches 24 h the foundation of science is provided.
The present invention is according to effect characteristics in the body of indopamide, choose and have the dependent three kinds of macromolecular materials of pH: Eudragit E-100 is that gastric solubility carrier material, HP-55 HP-55 are that enteric solubility carrier material, hydroxypropyl methylcellulose succinate HAS are colon solubleness carrier material, forms indapamide gastric solubleness microsphere, enteric-coated microsphere and the molten microsphere of colon with medicine respectively.
The present invention prepares the gastric solubleness microsphere, and the weight ratio of indapamide and Eudragit E-100 is 1: 4 ~ 12, and microsphere 2h average accumulated release amount in simulated gastric fluid can reach 82.3% ~ 99.6% in this scope.Find in test, when the weight ratio of medicine and carrier material, during lower than 1: 1,, due to the deficiency of carrier material amount, make drug encapsulation incomplete, have drug crystallization to separate out in system.Along with the increase of carrier material, the microsphere molding is better, but drug loading can reduce gradually, and the rate of release of medicine is also obviously slowed down, may be larger due to the E-100 stickiness, after its ratio increases, to the retardancy of drug release, also can increase.In sum, preferably the weight ratio of medicine and Eudragit E-100 is 1: 5 ~ 8 o'clock, and the drug accumulation release reaches 90.2% ~ 99.1% when 2h, in stomach release more complete, meet the requirements.
Prepare enteric-coated microsphere, the weight ratio of indapamide and HP-55 HP-55 is 1: 3 ~ 10, and microsphere 6h average accumulated release amount in the phosphate buffer of pH6.8 can reach 85.7% ~ 99.4% in this scope; And in simulated gastric fluid 2h almost without drug release.Find in test, along with the increase of carrier material amount, the microsphere yield increases, but drug loading reduces gradually, and the rate of release of medicine is also obviously slowed down.Consider the rate of release of drug loading and the medicine of microsphere, the weight ratio of preferred agents and HP-55 HP-55 is 1: 4 ~ 6, and the cumulative release degree of medicine reaches 92.7% ~ 99.4% when 6h.
Prepare the molten microsphere of colon, the weight ratio of indapamide and hydroxypropyl methylcellulose succinate HAS is 1: 2 ~ 6, and microsphere 6h average accumulated release amount in the phosphate buffer of pH7.8 can reach 81.3% ~ 90.7% in this scope; And 4h has a small amount of drug release in the phosphate buffer of pH6.8; 2h is almost without drug release in simulated gastric fluid.Further the weight ratio of preferred agents and HAS is 1: 3 ~ 4 o'clock, the thus obtained microsphere rounding, and good uniformity, the cumulative release degree of medicine reaches 85.1% ~ 94.6% when 4h.
Indapamide method for preparing microsphere of the present invention is: (1) gastric solubleness microsphere: indapamide and Eudragit E-100 are dissolved in the mixed solvent of acetone and dichloromethane, under certain temperature and stirring condition, this liquid is injected and contains a certain amount of emulsifying agent-lauryl sodium sulfate aqueous solution, add aqueous solution after certain hour, after spheroidal particle solidifies fully, filter, drying, collect medicine microspheres.(2) enteric-coated microsphere: indapamide and HP-55 HP-55 are dissolved in the mixed solvent of dehydrated alcohol and dichloromethane.At certain temperature and stirring condition, this liquid is injected the aqueous solution that contains a certain amount of emulsifying agent-sodium lauryl sulphate, after certain hour, add aqueous solution, after continuing to be stirred to spheroidal particle and solidifying fully, filter, drying, collect medicine microspheres.(3) the molten microsphere of colon: indapamide and hydroxypropyl methylcellulose succinate HAS are dissolved in the mixed solvent of dehydrated alcohol and dichloromethane, under certain temperature and stirring condition, this liquid is injected the aqueous solution that contains a certain amount of emulsifying agent-sodium lauryl sulphate is housed, add aqueous solution after certain hour, after continuing to be stirred to spheroidal particle and solidifying fully, filter, drying, collect medicine microspheres.
Three kinds of indapamide microspheres of the present invention adopt the one-step method pelletize, being about to three kinds of different macromolecular materials induces one in the spherocrystal granulation process, a step completes medicine and dissolves, separates out, is gathered into spherical granule with carrier material and prepares with the indapamide microsphere in solution, greatly simplified traditional granulating process, operational approach is easy, cost, and the spherocrystal granular preparation more is better than the former powder preparation of medicine.The microsphere outward appearance rounding (Fig. 1) that the present invention makes, not only improved the mobility of medicine, as the angle of repose of three kinds of microspheres
θAll, less than 30 °, shows good mobility, bring very large facility for the production of preparation, and the tablets in vitro result shows good:
(1) microsphere that makes has stronger pH dependency gradient release characteristics.The basic release of 2h in the pH1.2 medium of gastric solubleness microsphere is complete; Enteric-coated microsphere in the pH6.8 medium and the release in pH 7.8 media of the molten microsphere of colon complete, and both in the pH1.2 medium all without drug release;
(2) medicine can discharge medicine after making microsphere in vivo according to certain rules, just can reach expection medication purpose.The purpose of research microsphere drug release feature is to provide certain theoretical foundation for prediction microsphere drug release behavior in vivo.Three kinds of microspheres of the present invention carry out the release dynamics simulation test, and result shows: the dispose procedure of indapamide E-100 gastric solubleness microsphere in simulated gastric fluid meets the Higuchi model, and releasing mechanism is drug diffusion and bulk erosion combined effect; The dispose procedure of indapamide HP-55 enteric-coated microsphere in the pH6.8 medium meets Hixson-Crowel corrosion equation, and releasing mechanism is that bulk erosion plays a major role; The dispose procedure of the molten microsphere of indapamide HAS colon in the pH7.8 medium meets the First-order model, and releasing mechanism is that skeleton dissolving reconciliation is adsorbed as main first-order release;
(3) indapamide microsphere sustained-release capsule of the present invention is that the drug dose ratio of the above-mentioned three kinds microspheres that contain indapamide according to every day incapsulated.Due to the microsphere supported material of selecting, the copolymer as Eudragit E-100 is cationic methacrylate, dissolve in gastric juice; HP-55 HP-55 is insoluble to gastric juice, can dissolve fast at upper part of small intestine; Hydroxypropyl methylcellulose succinate HAS comparatively fast dissolves under the alkalescence condition, thus after this capsule oral, under the different pH condition of gastrointestinal tract, according to high molecular character make in microsphere medicine steadily and sustained release.
Indapamide microsphere sustained-release capsule of the present invention, also contain other adjuvant, as one or more in microcrystalline Cellulose, lactose, micropowder silica gel, Pulvis Talci.
Indapamide microsphere sustained-release capsule of the present invention is for having the dependent indapamide slow release preparation of pH, demonstrate good slow release effect, can not only reduce the side effect such as hypokalemia that ordinary preparation easily causes, simultaneously can keep 24 hours effective blood drug concentrations, medicine is discharged in gradient at full gastrointestinal, fully absorb, with minimum dose, reach maximum drug effect, improve the bioavailability of oral drugs.
The indapamide microsphere sustained-release capsule of the present invention's research has reached designing requirement at external release behavior, for investigating this preparation blood drug level-Time Change in vivo, the design of further checking, feedback pharmaceutical preparation and the result of study of galenic pharmacy, the present invention is take healthy dogs as subjects, take the indapamide preparation as reference preparation, investigated the drug release behavior of self-control indapamide microsphere sustained-release capsule in the dog body, compare with reference preparation, relative bioavailability is 111.14 ± 5.14%, sees Fig. 2.
Description of drawings
Fig. 1 is the electron-microscope scanning figure of three kinds of microspheres of indapamide.
Fig. 2 be in indapamide microsphere sustained-release capsule dog body blood drug level through the time curve.
The specific embodiment
Embodiment 1
The preparation of indapamide E-100 microsphere:
Indapamide 0.04g
Eudragit E-100 0.28g
Micropowder silica gel is appropriate
By above-mentioned prescription, to get principal agent indapamide and Eudragit E-100 and be dissolved in acetone and dichloromethane mixed solvent 5.2ml, then add a small amount of micropowder silica gel, vibration forms finely dispersed organic liquor; Under 24 ℃ and 600rpm stirring condition, this organic liquor is injected lauryl sodium sulfate aqueous solution 52ml, continue to stir, add commensurability aqueous solution; Continue to be stirred to spheroidal particle and solidify, filter, drying, collect the gastric solubleness microsphere.
The preparation of indapamide HP-55 microsphere:
Indapamide 0.04g
HP-55 HP-55 0.20g
By above-mentioned prescription, principal agent indapamide and HP-55 are dissolved in dehydrated alcohol and dichloromethane mixed solvent 4.0ml, form organic liquor; Under 25 ℃ and 500rpm stirring condition, this organic liquor is injected lauryl sodium sulfate aqueous solution 42ml, continue to stir, then add commensurability aqueous solution; Continue to be stirred to spheroidal particle and solidify, filter, drying, collect enteric-coated microsphere.
The preparation of indapamide HAS microsphere:
Indapamide 0.04g
Hypromellose succinate HAS 0.16g
By above-mentioned prescription, principal agent indapamide and carrier HAS are dissolved in dehydrated alcohol and dichloromethane mixed solvent 3.6ml, form organic liquor; Under 25 ℃ and 400rpm stirring condition, this organic liquor is injected sodium dodecyl sulfate solution 32ml, continue to stir, then add commensurability aqueous solution; Continue to be stirred to spheroidal particle and solidify, filter, drying, collect the molten microsphere of colon.
Embodiment 2
Indapamide Sustained-release Capsules
Gastric solubleness microsphere 1.9g
Enteric-coated microsphere 10g
The molten microsphere 1.1g of colon
Microcrystalline Cellulose 25g
Lactose 20g
Pulvis Talci 2g
Form by above-mentioned prescription, get the molten microsphere 1.1g of gastric solubleness microsphere 1.9g, enteric-coated microsphere 10g and colon with the equivalent method mix homogeneously that progressively increases; Microcrystalline Cellulose, lactose and Pulvis Talci are crossed 80 mesh sieve mix homogeneously; Microsphere and adjuvant are respectively charged into capsulae vacuus, make 1000, the heavy 60mg of every capsules, containing indapamide in every capsules is 1.5mg.
Embodiment 3
Indapamide Sustained-release Capsules
Gastric solubleness microsphere 2.5g
Enteric-coated microsphere 9.3g
The molten microsphere 1.2g of colon
Microcrystalline Cellulose 27g
Lactose 18g
Micropowder silica gel 2g
Form by above-mentioned prescription, get the molten microsphere 1.2g of gastric solubleness microsphere 2.5g, enteric-coated microsphere 9.3g and colon with the equivalent method mix homogeneously that progressively increases; 80 mesh sieve mix homogeneously are crossed in microcrystalline Cellulose, lactose and micropowder silica gel; Microsphere and adjuvant are respectively charged into capsulae vacuus, make 1000, the heavy 60mg of every capsules, containing indapamide in every capsules is 1.5mg.
Embodiment 4
Indapamide Sustained-release Capsules
Gastric solubleness microsphere 2.4g
Enteric-coated microsphere 15g
The molten microsphere 1.0g of colon
Microcrystalline Cellulose 24.6g
Lactose 15g
Micropowder silica gel 2g
Form by above-mentioned prescription, get the molten microsphere 1g of gastric solubleness microsphere 2.4g, enteric-coated microsphere 15g and colon with the equivalent method mix homogeneously that progressively increases; 80 mesh sieve mix homogeneously are crossed in microcrystalline Cellulose, lactose and micropowder silica gel; Microsphere and adjuvant are respectively charged into capsulae vacuus, make 1000, the heavy 60mg of every capsules, containing indapamide in every capsules is 1.5mg.
The cumulative in vitro drug release determination method of Indapamide Sustained-release Capsules:
Release medium: the release in vitro research of the full gastro-intestinal Fluid of Indapamide Sustained-release Capsules simulation is carried out in this test, so select the release medium of stomach in analogue body, small intestinal, the different pH value of colon: first discharge 2h in the hydrochloric acid solution 250ml of pH=1.2, then add appropriate Na
3PO
4After being adjusted to pH=6.8 release 6h, then add appropriate Na
3PO
4Be adjusted to pH=7.8 and discharge 16h.
Method for releasing: get 6 Indapamide Sustained-release Capsules and be respectively charged into bag filter, be placed in the stripping rotor that fills release medium 250ml, be to carry out release test under the 100r/min condition in 37 ℃, rotating speed, respectively at 2h, 4h, 6h, 8h, 10 h, 12h, 14h, 24h timing sampling, and add same volume release medium, after discharging the liquid filtration, in high performance liquid chromatograph, measure, calculate the medicine total release percentage.
Embodiment 5
A kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
Prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent, according to weight part ratio, be 1:12:10 obtain solution A, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:3, then at 30 ℃, under the stirring condition of 800rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 80ml, add the lauryl sodium sulfate aqueous solution of 80ml after stirring 20min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect the gastric solubleness microsphere;
Prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent, according to weight part ratio, be 1:10:9 obtain solution B, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:3, then at 30 ℃, under the stirring condition of 600rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 60ml, add the lauryl sodium sulfate aqueous solution of 60ml after stirring 20min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect enteric-coated microsphere;
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:6:8 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:3, then at 30 ℃, under the stirring condition of 600rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 60ml, add the lauryl sodium sulfate aqueous solution of 60ml after stirring 20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.1%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 4 parts of gastric solubleness microspheres, 9 parts of enteric-coated microspheres, 2 parts of molten microspheres of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1.5 mg;
In the 3rd step, be filled to capsule shells with microcrystalline Cellulose full, makes indapamide microsphere sustained-release capsule.
Embodiment 6
A kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
Prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent, according to weight part ratio, be 1:4:3 obtain solution A, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:1, then at 20 ℃, under the stirring condition of 500rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 30ml, add the lauryl sodium sulfate aqueous solution of 30ml after stirring 10min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect the gastric solubleness microsphere;
Prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent, according to weight part ratio, be 1:3:3 obtain solution B, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1, then at 20 ℃, under the stirring condition of 300rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 30ml, add the lauryl sodium sulfate aqueous solution of 30ml after stirring 10min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect enteric-coated microsphere;
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:2:3 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1, then at 20 ℃, under the stirring condition of 300rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 30ml, add the lauryl sodium sulfate aqueous solution of 30ml after stirring 10min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.01%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 1 part of gastric solubleness microsphere, 5 parts of enteric-coated microspheres, 0.5 part of the molten microsphere of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1mg;
The 3rd step, with microcrystalline Cellulose and lactose, according to the weight portion proportioning, be: 30 parts of microcrystalline Cellulose, 25 parts of mix homogeneously of lactose, be filled to capsule shells full, make indapamide microsphere sustained-release capsule.
Embodiment 7
A kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
Prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent, according to weight part ratio, be 1:5:5 obtain solution A, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:2, then at 25 ℃, under the stirring condition of 600rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 50ml, add the lauryl sodium sulfate aqueous solution of 50ml after stirring 15min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect the gastric solubleness microsphere;
Prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent, according to weight part ratio, be 1:4:7 obtain solution B, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:2, then at 25 ℃, under the stirring condition of 400rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 40ml, add the lauryl sodium sulfate aqueous solution of 40ml after stirring 15min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect enteric-coated microsphere;
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:3:5 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:2, then at 25 ℃, under the stirring condition of 400rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 50ml, add the lauryl sodium sulfate aqueous solution of 50ml after stirring 15min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.05%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 3 parts of gastric solubleness microspheres, 7 parts of enteric-coated microspheres, 1 part of the molten microsphere of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1.2 mg;
The 3rd step, with microcrystalline Cellulose, lactose, micropowder silica gel and Pulvis Talci, according to the weight portion proportioning, be: 40 parts of microcrystalline Cellulose, 35 parts of lactose, 2 parts of micropowder silica gels, 2 parts of Pulvis Talci, be filled to capsule shells full, make indapamide microsphere sustained-release capsule.
Embodiment 8
A kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
Prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent, according to weight part ratio, be 1:8:8 obtain solution A, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:1.2, then at 28 ℃, under the stirring condition of 700rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 60ml, add the lauryl sodium sulfate aqueous solution of 60ml after stirring 17min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect the gastric solubleness microsphere;
Prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent, according to weight part ratio, be 1:6:5 obtain solution B, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1.2, then at 28 ℃, under the stirring condition of 500rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 50ml, add the lauryl sodium sulfate aqueous solution of 50ml after stirring 17min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect enteric-coated microsphere;
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:4:4 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1.2, then at 28 ℃, under the stirring condition of 400rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 40ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml after stirring 17min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.06%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 2 parts of gastric solubleness microspheres, 7 parts of enteric-coated microspheres, 1.5 parts of molten microspheres of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1.3mg;
The 3rd step, with microcrystalline Cellulose, micropowder silica gel and Pulvis Talci, according to the weight portion proportioning, be: 45 parts of microcrystalline Cellulose, 2 parts of micropowder silica gels, 2 parts of Pulvis Talci, be filled to capsule shells full, make indapamide microsphere sustained-release capsule.
Embodiment 9
A kind of preparation method for indapamide microsphere sustained release capsules, carry out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon
Prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent, according to weight part ratio, be 1:6:6 obtain solution A, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:1.5, then at 24 ℃, under the stirring condition of 650rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 55ml, add the lauryl sodium sulfate aqueous solution of 55ml after stirring 16min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect the gastric solubleness microsphere;
Prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent, according to weight part ratio, be 1:5:6 obtain solution B, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1.5, then at 24 ℃, under the stirring condition of 450rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 45ml, add the lauryl sodium sulfate aqueous solution of 45ml after stirring 16min, continue to stir after spheroidal particle solidifies fully, filter, drying, collect enteric-coated microsphere;
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:3.5:5 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1.5, then at 24 ℃, under the stirring condition of 450rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 55ml, add the lauryl sodium sulfate aqueous solution of 55ml after stirring 16min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.03%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 2 parts of gastric solubleness microspheres, 6 parts of enteric-coated microspheres, 1.8 parts of molten microspheres of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1.5 mg;
The 3rd step, with lactose, micropowder silica gel and Pulvis Talci, according to the weight portion proportioning, be: 30 parts of lactose, 3 parts of micropowder silica gels, 1 part of Pulvis Talci, be filled to capsule shells full, make indapamide microsphere sustained-release capsule.
Gastric solubleness microsphere: indapamide 0.04g and polyacrylic resin Eudragit E-100 0.46g are dissolved in the mixed solvent 10ml of acetone and dichloromethane, under 30 ℃ and 500rpm stirring condition, this liquid is injected the aqueous solution 80ml that contains sodium lauryl sulphate, add the lauryl sodium sulfate aqueous solution of equivalent after the stirring certain hour, continue to stir after spheroidal particle solidifies fully, filter, drying, collect medicine microspheres;
Enteric-coated microsphere: indapamide 0.04g and HP-55 HP-55 0.30g are dissolved in the mixed solvent 9ml of dehydrated alcohol and dichloromethane.Under 30 ℃ and 300rpm stirring condition, this liquid is injected the aqueous solution 60ml that contains sodium lauryl sulphate, after stirring certain hour, add the lauryl sodium sulfate aqueous solution of equivalent, continue to be stirred to spheroidal particle and solidify fully, filtration, drying, collect medicine microspheres;
The molten microsphere of colon: indapamide 0.04g and hydroxypropyl methylcellulose succinate HAS 0.28g are dissolved in 8ml in the mixed solvent of dehydrated alcohol and dichloromethane, under 30 ℃ and 300rpm stirring condition, this liquid is injected the aqueous solution 60ml that contains sodium lauryl sulphate is housed, add the lauryl sodium sulfate aqueous solution of equivalent after certain hour, continuing to be stirred to spheroidal particle solidifies fully, filter, drying, collect medicine microspheres.
Embodiment 11
Gastric solubleness microsphere: indapamide 0.04g and polyacrylic resin Eudragit E-100 0.12g are dissolved in the mixed solvent 3ml of acetone and dichloromethane, under 20 ℃ and 800rpm stirring condition, this liquid is injected the aqueous solution 30ml that contains sodium lauryl sulphate, add the lauryl sodium sulfate aqueous solution of equivalent after the stirring certain hour, continue to stir after spheroidal particle solidifies fully, filter, drying, collect medicine microspheres;
Enteric-coated microsphere: indapamide 0.04g and HP-55 HP-55 0.12g are dissolved in the mixed solvent 3ml of dehydrated alcohol and dichloromethane.Under 20 ℃ and 600rpm stirring condition, this liquid is injected the aqueous solution 30ml that contains sodium lauryl sulphate, after stirring certain hour, add the lauryl sodium sulfate aqueous solution of equivalent, continue to be stirred to spheroidal particle and solidify fully, filtration, drying, collect medicine microspheres;
The molten microsphere of colon: indapamide 0.04g and hydroxypropyl methylcellulose succinate HAS 0.08g are dissolved in 3ml in the mixed solvent of dehydrated alcohol and dichloromethane, under 20 ℃ and 600rpm stirring condition, this liquid is injected the aqueous solution 30ml that contains sodium lauryl sulphate is housed, add the lauryl sodium sulfate aqueous solution of equivalent after certain hour, continuing to be stirred to spheroidal particle solidifies fully, filter, drying, collect medicine microspheres.
Filtration described in embodiment, drying process are prior art.
Claims (3)
1. preparation method for indapamide microsphere sustained release capsules is characterized in that carrying out according to following steps:
The first step, prepare respectively the gastric solubleness microsphere, the molten microsphere of enteric-coated microsphere and colon;
prepare the gastric solubleness microsphere: with indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent are 1:4-12:3-10 obtain solution A according to weight part ratio, described the first organic solvent is comprised of acetone and dichloromethane, described acetone and dichloromethane weight part ratio are 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 500rpm ~ 800rpm, described solution A is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 80ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 80ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the gastric solubleness microsphere,
prepare enteric-coated microsphere: with indapamide, HP-55 HP-55 and the second organic solvent are 1:3-10:3-9 obtain solution B according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 300rpm ~ 600rpm, described solution B is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect enteric-coated microsphere,
prepare the molten microsphere of colon: with indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:2-6:3-8 obtain solution C according to weight part ratio, described the second organic solvent is comprised of dehydrated alcohol and dichloromethane, described dehydrated alcohol and dichloromethane weight part ratio 1:1-3, then at 20 ℃ ~ 30 ℃, under the stirring condition of 300rpm ~ 600rpm, described solution C is injected the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml, add the lauryl sodium sulfate aqueous solution of 30ml ~ 60ml after stirring 10-20min, continue to stir after spheroidal particle solidifies fully, filter, dry, collect the molten microsphere of colon,
Described lauryl sodium sulfate aqueous solution weight percent concentration is 0.01%-0.1%;
Second step, with the gastric solubleness microsphere of above-mentioned preparation, the molten microsphere of enteric-coated microsphere and colon according to the weight portion proportioning is: 1 ~ 4 part of gastric solubleness microsphere, 5 ~ 9 parts of enteric-coated microspheres, 0.5 ~ 2 part of the molten microsphere of colon take respectively, the capsulae vacuus of packing into after mix homogeneously; In simple grain indapamide microsphere sustained-release capsule, the total content of indapamide is 1 ~ 1.5 mg;
In the 3rd step, be filled to capsule shells with adjuvant full, makes indapamide microsphere sustained-release capsule.
2. a kind of preparation method for indapamide microsphere sustained release capsules according to claim 1, is characterized in that described indapamide, polyacrylic resin Eudragit E-100 and the first organic solvent are 1:5-8:3-10 obtain solution A according to weight part ratio;
Described indapamide, HP-55 HP-55 and the second organic solvent are 1:4-6:3-9 obtain solution B according to weight part ratio;
Described indapamide, hydroxypropyl methylcellulose succinate HAS and the second organic solvent are 1:3-4:3-8 obtain solution C according to weight part ratio.
3. a kind of preparation method for indapamide microsphere sustained release capsules according to claim 1 and 2, is characterized in that the parts by weight of raw materials proportioning of described adjuvant is: 30 ~ 50 parts of microcrystalline Cellulose, 25 ~ 45 parts of lactose, 1 ~ 3 part of micropowder silica gel, 1 ~ 3 part of Pulvis Talci; Described adjuvant is the one or more combination in microcrystalline Cellulose, lactose, micropowder silica gel and Pulvis Talci.
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| CN1466945A (en) * | 2003-06-03 | 2004-01-14 | 天津药物研究院 | Slow releasing micropill containing active component of indapamide and method for preparing the same |
| CN1468598A (en) * | 2002-08-28 | 2004-01-21 | 天津开发区渤海医药贸易公司 | Slow-released indapamide capsule and its prepn process |
| CN1522695A (en) * | 2003-02-21 | 2004-08-25 | 天津太平洋制药有限公司 | Indapamide slow release capsule and preparation method |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
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| CN1468598A (en) * | 2002-08-28 | 2004-01-21 | 天津开发区渤海医药贸易公司 | Slow-released indapamide capsule and its prepn process |
| CN1522695A (en) * | 2003-02-21 | 2004-08-25 | 天津太平洋制药有限公司 | Indapamide slow release capsule and preparation method |
| CN1466945A (en) * | 2003-06-03 | 2004-01-14 | 天津药物研究院 | Slow releasing micropill containing active component of indapamide and method for preparing the same |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
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