CN102631324A - Nimesulide self-emulsification particle and preparation method thereof - Google Patents
Nimesulide self-emulsification particle and preparation method thereof Download PDFInfo
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- CN102631324A CN102631324A CN2011100378702A CN201110037870A CN102631324A CN 102631324 A CN102631324 A CN 102631324A CN 2011100378702 A CN2011100378702 A CN 2011100378702A CN 201110037870 A CN201110037870 A CN 201110037870A CN 102631324 A CN102631324 A CN 102631324A
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Abstract
The invention discloses a nimesulide self-emulsification particle and a preparation method thereof. The nimesulide self-emulsification particle mainly comprises nimesulide, diluent, emulsifier, auxiliary emulsifier, adsorbent and solid condensing agent, and the weight ratio of the components is 1:(0-5):(0-5):(0-2):(5-10):(5-10). The specification of the nimesulide is 50mg to 200mg. According to the invention, the appropriate accessories and the nimesulide are combined, and compared with the normal nimesulide oral preparation, the nimesulide self-emulsification particle has the advantages of good dissolution rate, quick absorption and the like. The nimesulide preparation provided by the invention is safer, has equal curative effects and is controllable in preparation process quality and good in stability.
Description
Technical field
The invention belongs to medical manufacturing field, be specifically related to a kind of nimesulide self emulsifying granule and preparation method thereof.
Background technology
Nimesulide is a kind of NSAID, and the alternative cyclooxygenase II that suppresses is so have significant antiinflammatory, analgesia and refrigeration function.Have the lots of clinical documents and materials to show both at home and abroad, it is faster that nimesulide and ibuprofen, acetaminophen are compared the antipyretic effect onset, and untoward reaction is suitable.Be considered to rapid-action a, good effect, safe, NSAID with good development prospect.In addition, nimesulide also has antiallergic and antihistamine effect, therefore can not bring out aspirin asthma, can be used safely in asthmatic patients hypersensitive such as aspirin.
Nimesulide (Nimesulide) is the patented product of Switzerland Helsinn company, uses in more than 50 countries at present in Italian Initial Public Offering in 1985, and its market scale is above 1,000,000,000 dollars.Nimesulide antiinflammatory action in vivo is three times of indometacin, but the effect of vitro inhibition prostaglandin be merely indometacin 1/5 because a little less than the inhibition of Mesulid to prostaglandin, its digestive tract side effects is little than other NSAID.Be used for the multiple disease that needs anti-inflammatory treatment.Have antiinflammatory, analgesia, antipyretic effect, like rheumatism outside osteoarthritis, the joint, the pain and the inflammation of operation and acute injury, pain that the acute upper respiratory tract inflammation causes and fever, dysmenorrhea.The toleration of nimesulide is good.Heartburn, feel sick and the stomachache idol has generation, but be of short duration and slight, seldom need TD, rare case has allergic rash, dizzy report.Clinically, nimesulide is mainly used in antipyretic-antalgic, antiinflammatory, treatment rheumatalgia, headache, outer grieved, cancer pain etc., and accepted extensively by clinical because of digestive tract side effects is less, especially in the application of children's's antipyretic-antalgic agent relatively extensively.Because its this medicine of unique pharmacological mechanism once was considered to a safety good (gastrointestinal reaction is few), and the NSAID of good development prospect is arranged.
The activity of nimesulide through high selectivity inflammation-inhibiting property prostaglandin synthetase Cox-2 suppresses also to remove free radical, and the CKIs hydrolytic enzyme suppresses histamine release and reaches antiphlogistic effects.Cox-1 is not produced effect,, significantly reduced digestive tract ulcer and hemorrhage side effect, to also safety of the bronchial asthma patient of aspirin sensitive so do not influence the synthetic of gastric protectiveness prostaglandin.
Nimesulide plasma protein binding rate 99% can be replaced the medicine of taking simultaneously with it, like salicylic acid, fenofibrate, tolbutamide and furosemide etc.Mainly be distributed in extracellular fluid, apparent volume of distribution 0.19～0.9L/kg.Nimesulide is at intrahepatic metabolism, and primary product is the 4-hydroxy derivatives, and the metabolite in urine and the feces is respectively 80% and 20% of dosage, and oral back 1～2h reaches peak plasma concentration, plasma half-life 2～3h, relative bioavailability 95.0%; Effectively the treatment concentration persistent period is 6～8h.Age, sex influence not obvious to the physiological disposition of this medicine.Since at intrahepatic metabolism, RE, the careful usefulness of severe hepatic renal insufficiency person.
Nimesulide has multiple dosage forms such as granule, sheet, dispersible tablet, slow releasing tablet, oral cavity disintegration tablet, capsule, dry suspension, slow releasing capsule, gel; Will be owing to the nimesulide dissolubility to be bad, bioavailability is low, causes the dosage that reaches effective curative effect bigger; Window phase is narrow; Therefore improve the dissolubility of nimesulide, can reduce the nimesulide adverse reaction rate, nimesulide is processed the dissolution in vitro that can significantly improve nimesulide behind the self emulsifying granule.Nimesulide self emulsifying granule belongs to self-emulsifying drug delivery system (self-emulsifying drug delivery systems; SEDDS); The self-emulsifying drug delivery system is meant the mixture that all comprises medicine in the lump that is formed by diluent, surfactant and co-emulsifier; Under the situation of ambient temperature (being generally 37 ℃) and gentle agitation, because the existence of surfactant, spontaneous emulsification forms the Emulsion of particle diameter at 100～500nm.And add co-emulsifier when the higher or surfactant of hydrophilic surfactant active (HLB＞12) content; Just can under mild agitation, make meticulousr solution (particle diameter＜100nm; Be called self-micro-emulsification medicine-releasing system (self-microemulsifying durg delivery systems, SMEDDS).
Self-microemulsifying drug delivery system can be used as the carrier of hydrophobicity, difficult absorption, facile hydrolysis medicine, and oral back contacts with gastro-intestinal Fluid and forms the little emulsion droplet of medicine carrying, has increased the long-pending and dissolubility of medical surfaces;, fast distribution even at gastrointestinal tract; Surfactant can reduce surface tension, the obstacle when having overcome through the gastrointestinal tract epithelial cell film, and medicine is easy to be delivered to absorption site through the gastrointestinal wall hydrated sheath; Improve dissolution and permeability, reduced the peak/paddy ratio and the untoward reaction of drug-time curve.Self-microemulsifying drug delivery system also can absorb through lymphatic vessel and overcome first pass effect, can avoid to a certain extent medicine in gastrointestinal tract by enzyme hydrolysis, help to improve bioavailability.
Summary of the invention:
The purpose of this invention is to provide a kind of nimesulide self emulsifying granule, solve the existing not good characteristic of nimesulide preparation dissolving out capability, thereby promote absorption and the utilization of human body nimesulide.Nimesulide self emulsifying granule by nimesulide, diluent, emulsifying agent, co-emulsifier, adsorbent, coagulate agent admittedly and form, its part by weight is respectively 1: 0～5: 0～5: 0～2: 5～15: 5～20.The specification of nimesulide is 50mg～200mg.
The self-emulsifying drug delivery system requires the diluent can be with the medicine of less consumption dissolving recipe quantity, even under the cryopreservation condition, does not have also that medicine is separated out and easily by the emulsifying agent emulsifying in the prescription.Diluent comprises oleic acid, linoleic acid, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, polyglycerol fatty acid fat, hot certain herbaceous plants with big flowers acid glycerol monoesters or dibasic acid esters, hot certain herbaceous plants with big flowers acid glycerol propylene glycol dibasic acid esters; Hot certain herbaceous plants with big flowers acid glycerol three esters; Acetylated monoglyceride, olein, glyceryl linoleate; The Polyethylene Glycol glyceryl laurate ester, ethyl oleate, isopropyl myristate and composition thereof.
The general emulsifying agent that adopts high HLB of self-emulsifying drug delivery system.The self-emulsifying drug delivery system will be in gastrointestinal tract self emulsifying and keep the Emulsion state, need emulsifying agent in the prescription, but a large amount of emulsifying agents may the stimulating gastrointestinal road, so should take into full account the safety of emulsifying agent.The strongly hydrophilic of high HLB emulsifying agent is to form oil-in-water emulsion droplet and self emulsifying liquid immediately in water environment, to spread necessaryly, and it can make the self emulsifying process faster.Emulsifying agent is amphiphatic, and itself also can dissolve a large amount of relatively hydrophobic drugs, can prevent that medicine from depositing in gastrointestinal tract and the dissolved state of prolong drug molecule, and this is extremely important to effective absorption.Emulsifying agent comprises lecithin; Soybean phospholipid, turkey red oil, fatty acid glyceride, gather fatty acid oil ester, sucrose ester, tween, span, west and tell horse brother, peregal, milky white spirit, polyoxyethylene castor oil; Polyoxyethylene hydrogenated Oleum Ricini, hot certain herbaceous plants with big flowers acid polyethylene glycol glyceride, oleic acid polyethyleneglycol glyceride, Polyethylene Glycol 15 hydroxy stearic acid esters and composition thereof.
The existing hydrophilic of co-emulsifier has lipophile again, adds co-emulsifier and helps to reduce interfacial tension; Increase the flowability of interfacial film; Regulate the HLB value.Reduce simultaneously the consumption of emulsifying agent again, reduce its genotoxic potential.General long-chain alcohol or the long chain acid of using, ethylene glycol, propylene glycol, glycerol, PEG400, hexadecanol, octadecanol, TC and composition thereof all can be used as oral self-emulsifying drug delivery system's cosolvent.
Adsorbent is meant that adjuvant utilizes self intensive pore to construct and receives liquid, thereby realizes liquid curing.Comprise micropowder silica gel, microcrystalline Cellulose, cyclodextrin, dextrin, calcium hydrogen phosphate, kaolin, magnesium oxide, calcium carbonate, aluminium hydroxide, mannitol, sucrose, arabic gum, pectin, starch, polyvinylpolypyrrolidone and composition thereof.
Be meant that adjuvant utilizes self solid-liquid dual character admittedly coagulate agent, with the liquid drug congruent melting, the cooling back forms the waxy solid disperse object when high temperature, thus the realization liquid curing.Comprise Macrogol 4000, polyethylene glycol 6000, hydrogenated vegetable oil, lauric acid polyethyleneglycol glyceride, card pool nurse, poloxamer, glyceryl monostearate, polyglycereol stearate, cocoa butter, Oleum Linderae and composition thereof.
The particulate method for preparing of above-mentioned nimesulide self emulsifying: take by weighing nimesulide, diluent, emulsifying agent, co-emulsifier, coagulate the agent heated and stirred admittedly and be dissolved into solution by recipe quantity, the cooling back is pulverized and is processed granule.Perhaps take by weighing after nimesulide, diluent, emulsifying agent, co-emulsifier stirring and dissolving become solution, add adsorbent and process pressed powder, add binding agent and process granule by recipe quantity.
Beneficial effect of the present invention: after adopting the self-emulsifiable oral medicine-releasing system, get into the interior back of body nimesulide and formed the very little breast grain of particle diameter.Be distributed in digestive system rapidly equably, human body is effectively absorbed, thereby improved human bioavailability, have good economic and social benefit.
One, the particulate raw material research of nimesulide self emulsifying
Nimesulide is that yellow or light yellow crystalline powder, fusing point are 148～150 ℃, is soluble in acetone, is slightly soluble in ethanol, and is water insoluble.Water solublity is not good to be to influence the key factor that nimesulide absorbs.
Two, nimesulide self emulsifying granule prescription screening and technical study
It is that the amino alkane buffer of trihydroxy methyl is measured that surfactant is generally adopted in the external stripping behavior of domestic granule; Covered the situation of the external stripping no better than one ought to of different manufacturers granule; Other dosage forms such as tablet etc. then adopt the high alkalinity medium to measure the external stripping behavior (pH=9.0) of these article; Inconsistent with normal human's physiological environment, covered the present situation of the external stripping no better than one ought to of different dosage form indirectly.The preparation of existing list marketing, all very low at water neutralized salt acid solution dissolution in vitro, only about 5%～10%.For this reason through the solid self-emulsifying technology; Make nimesulide be dissolved in the solid dielectric or be dissolved in the liquid medium and then adsorb with adsorbent; Thereby make nimesulide form molecular solution, after nimesulide self emulsifying granule adds water, form diameter and be scattered in the water at the drop of the diluent of 100～500nm; Nimesulide then is dissolved in the drop, forms true solution.Therefore the nimesulide granule of processing with the solid self-emulsifying technology; Ni Meishu can be dissolved in the medium of any pH value; Change the external stripping behavior of nimesulide, improved the intravital absorbance of nimesulide, improved the nimesulide bioavailability.
Description of drawings
Fig. 1 is the nimesulide stripping curve figure in water (pH=5.0) in the embodiment 1-4 nimesulide self emulsifying granule.
Fig. 2 is the nimesulide stripping curve figure in hydrochloric acid (pH=1.0) in the embodiment 1-4 nimesulide self emulsifying granule.
Fig. 3 is the nimesulide stripping curve figure in phosphate buffer (pH=7.2) in the embodiment 1-4 nimesulide self emulsifying granule.
Fig. 4 is the nimesulide stripping curve figure in the amino alkane buffer of trihydroxy methyl in the embodiment 1-4 nimesulide self emulsifying granule.
The specific embodiment
Embodiment 1:
Prescription:
Nimesulide 50g
Ethyl oleate 50g
Polyoxyethylene castor oil 125g
Polyoxyethylene hydrogenated Oleum Ricini 25g
Micropowder silica gel 550g
Aspartame 5g
10% polyethylene pyrrole lattice alkane ketone alcoholic solution is an amount of
Process 1000 bags altogether
Preparation technology: take by weighing after nimesulide, ethyl oleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini mixed dissolution become settled solution by recipe quantity; The micropowder silica gel that adds recipe quantity is adsorbed, is pulverized; After adding the aspartame mix homogeneously, granulate 12 granulate with 10% polyethylene pyrrole lattice alkane ketone alcoholic solution, 24 orders; Packing, packing.
Embodiment 2:
Prescription:
Nimesulide 50g
Oleic acid 50g
Polysorbate85 100g
Sorbester p17 20g
Dextrin 400g
Micropowder silica gel 300g
Aspartame 5g
10% starch slurry is an amount of
Process 1000 bags altogether
Preparation technology: take by weighing after nimesulide, oleic acid, polysorbate85, sorbester p17 mixed dissolution become settled solution by recipe quantity, add 100 order dextrin, micropowder silica gel mixture mix homogeneously, pulverize; The aspartame that adds recipe quantity; Mix homogeneously is granulated 12 granulate with 10% starch slurry, 24 orders; Packing, packing.
Embodiment 3:
Prescription:
Nimesulide 50g
Polyethylene Glycol 15 hydroxy stearic acid ester 20g
Polyoxyethylene hydrogenated Oleum Ricini 75g
Poloxamer 800g
Carbomer 100g
Polyethylene glycol 6000 100g
Aspartame 5g
Orange flavor 10g
Process 1000 bags altogether
Preparation technology: take by weighing nimesulide, Polyethylene Glycol 15 hydroxy stearic acid esters, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, carbomer, polyethylene glycol 6000 high temperature melt by recipe quantity; Make nimesulide be dissolved into settled solution; Behind the aspartame of adding recipe quantity, the orange flavor mix homogeneously, the frozen water cooling, 16 order pulverize at low temperature become granule, 12 order granulate; Packing, packing.
Embodiment 4:
Prescription:
Nimesulide 50g
Polyoxyethylene castor oil 200g
Macrogol 4000 200g
Polyethylene glycol 6000 600g
Aspartame 10g
Orange flavor 10g
Process 1000 bags altogether
Preparation technology: take by weighing nimesulide ethyl ester, polyoxyethylene castor oil, Macrogol 4000, polyethylene glycol 6000 high temperature melt by recipe quantity; Make nimesulide be dissolved into settled solution; Behind the aspartame of adding recipe quantity, the orange flavor mix homogeneously, the frozen water cooling, 16 order pulverize at low temperature become granule, 12 order granulate; Packing, packing.
Five, the particulate dissolution of nimesulide self emulsifying is investigated
Nimesulide self emulsifying granule to processing carries out dissolution determination.
The dissolution test method:
Get nimesulide self emulsifying granule,, (take by weighing the amino alkane 12.1g of trihydroxy methyl with the amino alkane buffer of trihydroxy methyl respectively according to dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2010); Be dissolved in water and be diluted to 900ml, regulate pH value to 9.0 with dilute hydrochloric acid, thin up is to 1000ml; Promptly get), water (pH=5.0), hydrochloric acid solution (pH=1.0), phosphate buffer salt (pH=7.2) 900ml is dissolution medium; Rotating speed is that per minute 50 changes, and solution 10ml (adding equality of temperature solvent 10ml simultaneously) is got in operation during respectively at 5,10,15,30,45,60 minutes in accordance with the law; Filter, as need testing solution; Get nimesulide reference substance an amount of (about 0.01g), the accurate title, decide, and puts in the 100ml volumetric flask, adds an amount of jolting dissolving of methanol and be diluted to scale; Shake up, filter, the accurate absorption in subsequent filtrate 5ml to the 50ml volumetric flask; Thin up shakes up to scale, as reference substance solution.According to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), measure trap respectively in the 393nm wavelength, calculate every bag of accumulation stripping percentage amounts by the two absorbance ratio in each time, draw stripping curve figure.
Respectively nimesulide self emulsifying granule (example 1, example 2, example 3, example 4) is carried out dissolution determination, the result is following:
Table 1: the nimesulide in each nimesulide self-emulsification capsule is the stripping curve table in water (pH=5.0)
| Time | 5min | 10min | 15min | 30min | 45min | 60min |
| Example 1 | 78.70％ | 84.80％ | 93.80％ | 95.90％ | 96.40％ | 95.50％ |
| Example 2 | 70.10％ | 90.30％ | 95.90％ | 94.60％ | 96.80％ | 96.10％ |
| Example 3 | 75.40％ | 85.30％ | 94.30％ | 95.40％ | 96.10％ | 95.70％ |
| Example 4 | 83.60％ | 90.40％ | 98.40％ | 99.30％ | 99.10％ | 98.40％ |
Table 2: the nimesulide in each nimesulide self-emulsification capsule is the stripping curve table in hydrochloric acid solution (pH=1.0)
| Time | 5min | 10min | 15min | 30min | 45min | 60min |
| Example 1 | 81.30％ | 88.40％ | 95.20％ | 95.70％ | 96.30％ | 95.90％ |
| Example 2 | 78.30％ | 89.60％ | 92.70％ | 94.30％ | 96.90％ | 94.10％ |
| Example 3 | 81.20％ | 86.70％ | 91.60％ | 95.90％ | 98.60％ | 99.80％ |
| Example 4 | 88.20％ | 95.30％ | 98.90％ | 99.30％ | 99.70％ | 98.60％ |
Table 3: the nimesulide in each nimesulide self-emulsification capsule is the stripping curve table in phosphate buffer salt (pH=7.2)
| |
5 | 10 | 15 | 30 | 45 | 60 |
| Example 1 | 81.40％ | 90.20％ | 92.60％ | 93.40％ | 95.30％ | 98.20％ |
| Example 2 | 75.30％ | 85.00％ | 91.70％ | 94.60％ | 97.30％ | 99.70％ |
| Example 3 | 81.50％ | 88.30％ | 91.50％ | 96.30％ | 97.90％ | 99.10％ |
| Example 4 | 79.30％ | 84.50％ | 93.40％ | 94.60％ | 95.20％ | 96.30％ |
Table 4: the nimesulide in each nimesulide self-emulsification capsule is the stripping curve table in the amino alkane buffer of trihydroxy methyl
| |
5 | 10 | 15 | 30 | 45 | 60 |
| Example 1 | 92.50％ | 96.50％ | 96.70％ | 97.70％ | 97.10％ | 98.40％ |
| Example 2 | 90.40％ | 95.70％ | 95.80％ | 96.20％ | 96.90％ | 98.90％ |
| Example 3 | 93.60％ | 96.90％ | 98.90％ | 99.20％ | 99.70％ | 99.80％ |
| Example 4 | 91.60％ | 92.60％ | 92.70％ | 96.10％ | 97.90％ | 99.60％ |
Claims (8)
1. nimesulide self emulsifying granule; It is characterized in that: described nimesulide self emulsifying granule by nimesulide, diluent, emulsifying agent, co-emulsifier, adsorbent, coagulate agent admittedly and form, its part by weight is respectively: 1: 0～5: 0～5: 0～2: 5～15: 5～20.The specification of nimesulide is 50mg～200mg.
2. nimesulide self emulsifying granule according to claim 1 is characterized in that: described diluent comprises oleic acid, linoleic acid, soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, polyglycerol fatty acid fat, hot certain herbaceous plants with big flowers acid glycerol monoesters or dibasic acid esters; Hot certain herbaceous plants with big flowers acid glycerol propylene glycol dibasic acid esters, hot certain herbaceous plants with big flowers acid glycerol three esters, acetylated monoglyceride; Olein; Glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, ethyl oleate, isopropyl myristate and composition thereof.
3. nimesulide self emulsifying granule according to claim 1; It is characterized in that: described emulsifying agent comprises lecithin; Soybean phospholipid, turkey red oil, fatty acid glyceride, gather fatty acid oil ester, sucrose ester, tween, span, west and tell horse brother, peregal, milky white spirit, polyoxyethylene castor oil; Polyoxyethylene hydrogenated Oleum Ricini, hot certain herbaceous plants with big flowers acid polyethylene glycol glyceride, oleic acid polyethyleneglycol glyceride, Polyethylene Glycol 15 hydroxy stearic acid esters and composition thereof.
4. nimesulide self emulsifying granule according to claim 1 is characterized in that: describedly help emulsifying to comprise ethylene glycol, propylene glycol, glycerol, PEG400, hexadecanol, octadecanol, TC and composition thereof.
5. nimesulide self emulsifying granule according to claim 1, it is characterized in that: described adsorbent comprises micropowder silica gel, microcrystalline Cellulose, cyclodextrin, dextrin, calcium hydrogen phosphate, kaolin, magnesium oxide, calcium carbonate, aluminium hydroxide, mannitol, sucrose, arabic gum, pectin, starch, polyvinylpolypyrrolidone and composition thereof.
6. nimesulide self emulsifying granule according to claim 1 is characterized in that: describedly coagulate agent admittedly and comprise Macrogol 4000, polyethylene glycol 6000, hydrogenated vegetable oil, lauric acid polyethyleneglycol glyceride, card pool nurse, poloxamer, glyceryl monostearate, polyglycereol stearate, cocoa butter, Oleum Linderae and composition thereof.
7. nimesulide self emulsifying granule according to claim 1 is characterized in that: take by weighing nimesulide, diluent, emulsifying agent, co-emulsifier, coagulate the agent heated and stirred admittedly and be dissolved into solution by recipe quantity, the cooling back is pulverized and is processed granule.
8. nimesulide self emulsifying granule according to claim 1 is characterized in that: take by weighing after nimesulide, diluent, emulsifying agent, co-emulsifier stirring and dissolving become solution by recipe quantity, add adsorbent and process pressed powder, add binding agent and process granule.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105287429A (en) * | 2015-11-20 | 2016-02-03 | 河北科技大学 | Preparation method of brucea javanica oil solid self-emulsifying capsule |
| CN105372187A (en) * | 2014-08-29 | 2016-03-02 | 武汉光谷人福生物医药有限公司 | Method for determining dissolution rate of meisuoshuli tablets |
| CN109588376A (en) * | 2018-12-27 | 2019-04-09 | 广西融安县金鼎制丝有限责任公司 | A kind of store method of silkworm seed |
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| EP0880965A1 (en) * | 1997-05-26 | 1998-12-02 | Dompe' International S.A.M. | Topical pharmaceutical formulations containing nimesulide |
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| CN1189337A (en) * | 1996-07-23 | 1998-08-05 | 灵药生物技术有限公司 | Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105372187A (en) * | 2014-08-29 | 2016-03-02 | 武汉光谷人福生物医药有限公司 | Method for determining dissolution rate of meisuoshuli tablets |
| CN105287429A (en) * | 2015-11-20 | 2016-02-03 | 河北科技大学 | Preparation method of brucea javanica oil solid self-emulsifying capsule |
| CN109588376A (en) * | 2018-12-27 | 2019-04-09 | 广西融安县金鼎制丝有限责任公司 | A kind of store method of silkworm seed |
| CN109588376B (en) * | 2018-12-27 | 2021-09-21 | 融安县德源农业科技发展有限公司 | Silkworm egg preservation method |
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Application publication date: 20120815 |