CN102058545B - Meropenem freeze-dried preparation for injection and preparation method thereof - Google Patents
Meropenem freeze-dried preparation for injection and preparation method thereof Download PDFInfo
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- CN102058545B CN102058545B CN2010106038945A CN201010603894A CN102058545B CN 102058545 B CN102058545 B CN 102058545B CN 2010106038945 A CN2010106038945 A CN 2010106038945A CN 201010603894 A CN201010603894 A CN 201010603894A CN 102058545 B CN102058545 B CN 102058545B
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Abstract
The invention discloses a meropenem freeze-dried preparation for injection and a preparation method thereof. 1,000 milliliters of water for injection comprises the following ingredients: 2 to 15 grams of meropenem, 20 to 100 grams of oil for injection, 0 to 20 grams of stabilizing agent, 10 to 80 grams of emulsifying agent, 10 to 30 grams of glycerol and 50 to 200 grams of freeze-dried protective agent. The preparation method comprises the following steps of: dispersing the emulsifying agent into the oil for injection and adding the meropenem; adding the glycerol into the water for injection; stirring and mixing uniformly to form an aqueous phase; emulsifying and homogenizing an oil phase and the aqueous phase to obtain emulsion; and preparing freeze-dried emulsion. A meropenem lipid microsphere preparation provided by the invention can obviously reduce hydrolysis and oxidation of active ingredients and can maintain the integrity of the lipid microsphere structure so as to obviously improve the stability of medicament storage.
Description
Technical field
The invention belongs to pharmaceutical product, what relate in particular to is a kind of injection meropenem preparation and preparation method thereof.
Background technology
Meropenem (meropenem) is a kind of new carbapenem class high-efficiency broad spectrum antibiotic; Its chemical name is 3-[[5-[(dimethylamino) carbonyl]-3-pyrrolidinyl] sulfo-]-6-(1-ethoxy)-4-methyl-7-oxo-1-azabicyclo [3; 2,0] hept-2-ene"-2-carboxylic acid, molecular formula is: C
17H
25N
3O
5S, chemical structural formula is:
Meropenem is stable to extended spectrum (ESBLs); Grain-positive, gram-negative bacteria all there is stronger antibacterial activity; Mainly be applicable to responsive microbial various infection clinically, as: infection in respiratory system infection, the abdomen, urinary system and genital system infection, osteoarthrosis and skin soft-tissue infection, eye and otorhinolaryngology infection etc.Meropenem is as the new varieties of carbapenem antibiotic; Because of its has a broad antifungal spectrum, antibacterial activity by force, distinguishing feature does not quite receive clinical attention with other beta-lactam antibiotic crossing drug resistants and adverse reaction rate be low etc., becomes one of choice drug of treating severe infection and mixed infection clinically.The clinical consumption of these article is big, determined curative effect, and market prospect is good.At present, the meropenem preparation of list marketing is a powder ampoule agent for injection, but because meropenem less stable in aqueous solution, so the injection problem that attenuating, related substance increase that in storing process, usually occurs tiring.
Summary of the invention
The object of the invention is exactly the meropenem lyophilizing fat micro sphere preparation that a kind of steady quality, quality better will be provided, and a kind of method for preparing said preparation is provided simultaneously.
The objective of the invention is to realize like this:
Meropenem lyophilizing fat micro sphere preparation provided by the present invention is the component that includes following weight in every 1000ml water for injection:
Meropenem 2-15g, oil for injection 20-100g, stabilizing agent 0-20g, emulsifying agent 10-80, glycerol 10-30g, freeze drying protectant 50-200g.
Oil for injection wherein is pharmaceutically useful vegetable oil, and like soybean oil, Oleum Arachidis hypogaeae semen, Oleum Brassicae campestris, Petiolus Trachycarpi oil, oleum lini, olive oil, wherein soybean oil, olive oil are because its potency ratio is higher, so be preferred.
Freeze drying protectant of the present invention can be selected from glucide, like glucose, lactose, galactose, mannitol, sorbitol, xylitol, sucrose, trehalose or the like.But in order further to improve the quality of preparation, freeze drying protectant preferably is made up of glucide and cyclodextrin material, and wherein the consumption of glucide is 49.9-195g, and the consumption of cyclodextrin material is 0.1-5g.Wherein glucide is selected from any one or the two or more mixture in glucose, lactose, galactose, mannitol, sorbitol, the xylitol; Described cyclodextrin material is selected from any one or the two or more mixture in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, the HP-.
Stabilizing agent of the present invention can be selected one or more the mixture in oleic acid, dibenzylatiooluene, the alpha-tocopherol for use.
Emulsifying agent of the present invention can be selected from phospholipid, like lecithin, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine or the like.
The method for preparing of meropenem lyophilizing fat micro sphere preparation provided by the present invention, carry out according to following steps:
A, in preparing tank, put into oil for injection in proportion, emulsifying agent is scattered in the oil for injection;
B, adding meropenem, abundant stirring and evenly mixing form oil phase;
C, glycerol add water for injection, and stirring and evenly mixing forms water;
E, oil phase and water are carried out emulsifying, transfer that pH value is the 4.5-8.0 scope in the emulsion;
Regulate homogenization pressure through the high pressure homogenize appearance in f, the emulsion, obtain uniform emulsion;
Add freeze drying protectant in g, the emulsion, form the meropenem freeze-dried emulsion through lyophilization.Wherein cryodesiccated process and technological parameter can be adjusted with reference to prior art.
When transferring the emulsion pH value, can select one or more mixture in hydrochloric acid, citric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, boric acid, Borax, the Tris for use.
Optimizing technology parameters in the inventive method is: 50-60 ℃ of insulation behind the b step operation adding meropenem, fully stir 10min, mixing formation oil phase with 3000 rev/mins; At 50-60 ℃, colostrum is processed in 200 rev/mins of stirrings to water with oily in the e step preface.
In order to improve the emulsifying effectiveness of this preparation, preferably adopt the two-stage homogenizing, promptly the one-level homogenization pressure is 450-650kg/cm
2, double-stage homogenization pressure 100-140kg/cm
2, homogenizing 5-7 time.It is little to obtain mean diameter thus, the emulsion of narrow particle size distribution.
A step valve pressure 600kg/cm preferably
2, secondary valve pressure 120kg/cm
2, 7 gained preparations of homogenizing, mean diameter is minimum, particle size distribution is the narrowest.When a step valve pressure at 600kg/cm
2The time, along with the increase of the even number of times of high pressure breast, the particle diameter of emulsion droplet reduces gradually; When cycle-index surpasses 7 times; Particle diameter reduces not obvious, even when continuing to increase cycle-index, particle diameter has the trend of increase; This possibly be because the increase of cycle-index also can make the temperature of system raise, and has increased the accumulative tendency of small-particle.Therefore, cycle-index is decided to be 7 times.
In above-mentioned c step operation, preferably the water temperature with water for injection is controlled at 50-60 ℃, and then glycerol is added water for injection, and stirring and evenly mixing forms water, can further improve the emulsifying effectiveness of emulsion thus.
Meropenem fat micro sphere preparation provided by the invention can significantly reduce the hydrolysis and the oxidation of effective ingredient, can keep the integrity of lipoid microsphere structure simultaneously, has significantly improved the stability that medicine is stored thus.
The freeze drying protectant that the inventive method brings Selection In in the emulsion of homogenization pressure; And obtain exsiccant meropenem lyophilizing fat micro sphere preparation through lyophilization; Not only guaranteed its breakdown of emulsion not in the process of low-temperature freeze drying thus; And each item index of lyophilizing emulsion also all meets the requirement of microemulsion ejection preparation, and the suitable suitability for industrialized production of carrying out.
The inventive method technological process is simple, and the microgranule roundness in the emulsion is good, and envelop rate is high; Steady quality; Emulsion particle can be controlled in 100-500nm, and medicine is arrived around the target area thereupon, and reaches required drug level very soon; Therefore can reduce dosage, reduce the toxic and side effects of medicine human normal tissue.
Medicine of the present invention after the hydration vibration, is recovered to meropenem Emulsion using and can meropenem lyophilizing fat micro sphere preparation being measured adding water for injection on demand, promptly can be used for intravenous drip.
Meropenem lyophilizing fat micro sphere preparation of the present invention all meets the regulation of Chinese Pharmacopoeia through acute toxicity test, chronic toxicity test, abnormal toxicity test and thermal source check.
The specific embodiment
Embodiment 1
Pharmaceutical formulation: meropenem 12g, soybean oil 80g, refine yolk lecithin 60g, glycerol 20g, cyclodextrin 1g, glucose 100g, water for injection 1000ml.
Concrete preparation technology: in preparing tank, refine yolk lecithin 60g, meropenem 12g are scattered in the 80g soybean oil, 50 ℃ of insulations are fully stirred 10min, mixing formation oil phase with 2500 rev/mins; 20g glycerol is scattered in water for injection and forms water; Water and oil phase are mixed, 50-60 ℃ of insulation, 150 rev/mins are stirred 10min, process thick breast; And use 0.2mol/L sodium hydrogen phosphate phosphate sodium dihydrogen buffer solution adjusting pH value is 7.5; Carry out homogenizing repeatedly through high pressure homogenizer, obtain uniform emulsion.To the beta-schardinger dextrin-that wherein adds 1g, make its dissolving then, obtain solution I.The 100g glucose with after the suitable quantity of water dissolving, is obtained solution II.Solution I and solution II are mixed, solution is settled to 1000ml, the 0.22 μ m filter membrane of going forward side by side carries out aseptic filtration, removes moisture through lyophilization again, obtains the meropenem freeze-dried emulsion.
Embodiment 2
Pharmaceutical formulation: meropenem 6.7g, soybean oil 30g, refine yolk lecithin 25g, glycerol 15g, enuatrol 2g, cyclodextrin 335mg, glucose 125g, water for injection 1000ml.
Concrete preparation technology: in preparing tank, refine yolk lecithin 25g, meropenem 6.7g are scattered in the 30g soybean oil, 60 ℃ of insulations are fully stirred 10min, mixing formation oil phase with 3000 rev/mins; 15g glycerol and 2g enuatrol are scattered in water for injection and form water; Water and oil phase are mixed, 60 ℃ of insulations, 200 rev/mins are stirred 15min, process thick breast; And use citric acid solution adjusting pH value is 6.5; Carry out homogenizing repeatedly through high pressure homogenizer, obtain uniform emulsion.When carrying out homogenizing, adopt the two-stage homogenizing, a step valve pressure 600kg/cm
2, secondary valve pressure 120kg/cm
2, homogenizing 7 times.To the beta-schardinger dextrin-that wherein adds 335mg, make its dissolving then, obtain solution I.The 125g glucose with after the suitable quantity of water dissolving, is obtained solution II.Solution I and solution II are mixed, solution is settled to 1000ml, the 0.22 μ m filter membrane of going forward side by side carries out aseptic filtration, removes moisture through lyophilization again.The condition of vacuum lyophilization is: under the 10Pa-20Pa vacuum pressure, quick freezing to temperature-50 ℃ is warming up to-40 ℃ again, keeps 2 hours, so repeats twice; Sublimation drying temperature-25---35 ℃, 20 hours drying times; 20 ℃ of parsing-desiccation temperature, 5 hours drying times.Obtain the meropenem freeze-dried emulsion thus.
Embodiment 3
Pharmaceutical formulation: meropenem 25g, olive oil 175g, PHOSPHATIDYL ETHANOLAMINE 137.5g, glycerol 50g, enuatrol 8g, alpha-cyclodextrin 3g, mannitol 300g, water for injection 2500ml.
Concrete preparation technology: in preparing tank, refined phosphatide acyl ethanolamine 137.5g, meropenem 25g are scattered in the 175g olive oil, 50-60 ℃ of insulation fully stirred 10min, mixing formation oil phase with 3000 rev/mins; 50g glycerol and 8g enuatrol are scattered in water for injection and form water; Water and oil phase are mixed, 50-60 ℃ of insulation, 200 rev/mins are stirred 15min, process thick breast; And use 0.2mol/L sodium hydrogen phosphate phosphate sodium dihydrogen buffer solution adjusting pH value is 7.5; Carry out homogenizing repeatedly through high pressure homogenizer, obtain uniform emulsion.To wherein adding the 3g alpha-cyclodextrin, make its dissolving then, obtain solution I.300g mannitol with after the suitable quantity of water dissolving, is obtained solution II.Solution I and solution II are mixed, solution is settled to 2500ml, aseptic filtration, lyophilization obtains the meropenem freeze-dried emulsion.The meropenem freeze-dried emulsion that makes measured on demand add water, after the hydration vibration, be recovered to meropenem Emulsion.
Embodiment 4
Pharmaceutical formulation: meropenem 20g, Oleum Arachidis hypogaeae semen 87.5g, Phosphatidylserine 75g, glycerol 45g, alpha-tocopherol 35g, gamma-cyclodextrin 3g, lactose 250g, water for injection 2500ml.
Concrete preparation technology: in preparing tank, refine yolk lecithin 75g, meropenem 20g are scattered in the 87.5g soybean oil, 50-60 ℃ of insulation fully stirred 10min, mixing formation oil phase with 3000 rev/mins; 45g glycerol and 35g alpha-tocopherol are scattered in water for injection and form water; Water and oil phase are mixed, 50-60 ℃ of insulation, 200 rev/mins are stirred 15min, process thick breast; And use 0.05mol/L Tris hydrochloride buffer adjusting pH value is 7.5; Carry out homogenizing repeatedly through high pressure homogenizer, obtain uniform emulsion.To wherein adding the 3g beta-schardinger dextrin-, make its dissolving then, obtain solution I.The 250g lactose with after the suitable quantity of water dissolving, is obtained solution II.Solution I and solution II are mixed, solution is settled to 2500ml, aseptic filtration, lyophilization obtains the meropenem freeze-dried emulsion.The meropenem freeze-dried emulsion that makes measured on demand add water, after the hydration vibration, be recovered to meropenem Emulsion.
Embodiment 5
Pharmaceutical formulation: meropenem 20g, olive oil 75g, refine yolk ovum phosphorus 80g, glycerol 45g, alpha-tocopherol 35g, γ β--cyclodextrin 2.5g, lactose 300g, water for injection 2500ml.
Concrete preparation technology: in preparing tank, refine yolk lecithin 80g, meropenem 20g are scattered in the 75g olive oil, 50-60 ℃ of insulation fully stirred 10min, mixing formation oil phase with 3000 rev/mins; 40g glycerol and 40g alpha-tocopherol are scattered in water for injection and form water; Water and oil phase are mixed, 50-60 ℃ of insulation, 200 rev/mins are stirred 15min, process thick breast; And use 0.05mol/L Tris hydrochloride buffer adjusting pH value is 7.5; Carry out homogenizing repeatedly through high pressure homogenizer, obtain uniform emulsion.To wherein adding the 2.5g beta-schardinger dextrin-, make its dissolving then, obtain solution I.The 300g lactose with after the suitable quantity of water dissolving, is obtained solution II.Solution I and solution II are mixed, solution is settled to 2500ml, aseptic filtration, lyophilization obtains the meropenem freeze-dried emulsion.The meropenem freeze-dried emulsion that makes measured on demand add water, after the hydration vibration, be recovered to meropenem Emulsion.
Embodiment 6 particle diameters are investigated
Change of size situation before and after the Emulsion lyophilizing, lyophilized formulations are tested particle diameter after with the water for injection emulsion, and be as follows:
Change of size situation before and after table 1 lyophilizing
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| Particle diameter (nm) before the lyophilizing | ?340 | ?202 | ?218 | ?272 | ?315 |
| Particle diameter after the lyophilizing (nm) | ?349 | ?210 | ?252 | ?291 | ?336 |
Can know that according to table 1 particle diameter does not have significant change before and after this Emulsion lyophilizing, meets the requirement of NF standard.
Embodiment 7 stability studies are investigated
Sample to making among above five embodiment carries out quality testing; And carried out under 40 ℃ of high temperature, relative humidity 75% ± 5% condition under accelerated test 6 months and 25 ℃ of temperature, relative humidity 60% ± 10% condition long term test simultaneously 18 months, test result (sees table 2, table 3, table 4 for details) as follows:
Table 2: initial mass testing result
Table 3: accelerated test result
Table 4: long-term test results
Annotate: listing powder pin is the meropenem lyophilized injectable powder of buying on the market.
Can find out by above test data; The meropenem lyophilizing fat micro sphere preparation constant product quality of the present invention's preparation; Each item quality index does not have significant change after quickening June and long-term 18 months; Especially active constituent content is constant, and relevant thing with the prolongation of waiting time significant change does not take place yet, and then there is tangible weak point in existing meropenem lyophilized injectable powder on the market.
Claims (5)
1. injection meropenem fat micro sphere preparation; It is characterized in that including in every 1000ml water for injection the component of following weight: meropenem 2-15g; Oil for injection 20-100g, stabilizing agent 1-20g, emulsifying agent 10-80g, glycerol 10-30g, freeze drying protectant 50-200g; Wherein said freeze drying protectant is made up of glucide and cyclodextrin material, and wherein the consumption of glucide is 49.9-195g, and the consumption of cyclodextrin material is 0.1-5g; Described glucide is selected from any one or the two or more mixture in glucose, lactose, galactose, mannitol, sorbitol, the xylitol; Described cyclodextrin material is selected from any one or the two or more mixture in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, the HP-; Described oil for injection is a kind of in soybean oil, the olive oil or the mixture of the two; Described stabilizing agent is one or more the mixture in oleic acid, dibenzylatiooluene, the alpha-tocopherol; Emulsifying agent is a phospholipid.
2. the method for preparing of the described meropenem fat micro sphere preparation of claim 1 is characterized in that it carries out according to following steps:
A, in preparing tank, put into oil for injection in proportion, emulsifying agent is scattered in the oil for injection;
B, adding meropenem, abundant stirring and evenly mixing form oil phase;
C, glycerol add water for injection, and stirring and evenly mixing forms water;
E, oil phase and water are carried out emulsifying, transfer that pH value is the 4.5-8.0 scope in the emulsion;
Regulate homogenization pressure through the high pressure homogenize appearance in f, the emulsion, obtain uniform emulsion;
Add freeze drying protectant in g, the emulsion, form the meropenem freeze-dried emulsion through lyophilization.
3. the method for preparing of meropenem fat micro sphere preparation according to claim 2 is characterized in that described homogenization pressure, one of which step valve pressure 600kg/cm
2, secondary valve pressure 120kg/cm
2, homogenizing 7 times.
4. the method for preparing of meropenem fat micro sphere preparation according to claim 2 is characterized in that the water temperature of water for injection is controlled at 50-60 ℃ in the said c step operation.
5. the method for preparing of meropenem fat micro sphere preparation according to claim 2 is characterized in that described b step operation adds 50-60 ℃ of insulation behind the meropenem, fully stirs 10-15min with 2000-3000 rev/min, and mixing forms oil phase; Water and oil phase are at 50-60 ℃ in the e step preface, and thick breast is processed in 150-200 rev/min of stirring; The mode of adding freeze drying protectant to wherein adding beta-schardinger dextrin-, makes its dissolving for earlier in g step operation, obtains solution I; After again glucose being dissolved with suitable quantity of water, obtain solution II, solution I and solution II are mixed.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102258487B (en) * | 2011-07-14 | 2012-09-26 | 海南美兰史克制药有限公司 | Meropenem liposome injection |
| CN102335137B (en) * | 2011-08-02 | 2013-06-12 | 天津市嵩锐医药科技有限公司 | Medicinal composition containing meropenem |
| CN102335136B (en) * | 2011-08-02 | 2013-06-12 | 天津市嵩锐医药科技有限公司 | Meropenem medicinal composition for injection and preparation method thereof |
| CN102525961B (en) * | 2012-01-17 | 2013-02-13 | 山东罗欣药业股份有限公司 | Powder injection of meropenem composition for injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101536979A (en) * | 2009-04-08 | 2009-09-23 | 邓菊娟 | Edaravone lipid microsphere formulation and preparation method |
| CN101716147A (en) * | 2010-01-18 | 2010-06-02 | 北京泰德制药有限公司 | Alprostadil liposome microsphere preparation |
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101536979A (en) * | 2009-04-08 | 2009-09-23 | 邓菊娟 | Edaravone lipid microsphere formulation and preparation method |
| CN101716147A (en) * | 2010-01-18 | 2010-06-02 | 北京泰德制药有限公司 | Alprostadil liposome microsphere preparation |
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
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Effective date of registration: 20130703 Address after: 050091 No. 6 Huaxing Road, Zhonghua South Street, Hebei, Shijiazhuang Patentee after: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group Patentee after: Shijiazhuang Pharmaceutical Group Ouyi Pharma Co., Ltd. Address before: 050091 No. 6 Huaxing Road, Zhonghua South Street, Hebei, Shijiazhuang Patentee before: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group |