CN106265524A - Hydrochloric acid sarafloxacin solid dispersed formulation and preparation method thereof - Google Patents
Hydrochloric acid sarafloxacin solid dispersed formulation and preparation method thereof Download PDFInfo
- Publication number
- CN106265524A CN106265524A CN201610772286.4A CN201610772286A CN106265524A CN 106265524 A CN106265524 A CN 106265524A CN 201610772286 A CN201610772286 A CN 201610772286A CN 106265524 A CN106265524 A CN 106265524A
- Authority
- CN
- China
- Prior art keywords
- hydrochloric acid
- polyvidone
- acid sarafloxacin
- ethanol
- sarafloxacin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 142
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229950007734 sarafloxacin Drugs 0.000 title claims abstract description 73
- 239000007787 solid Substances 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000009472 formulation Methods 0.000 title claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 92
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 61
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 61
- 238000003756 stirring Methods 0.000 claims abstract description 25
- 238000001291 vacuum drying Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 3
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- -1 carbostyril compound Chemical class 0.000 description 2
- 229960000740 enrofloxacin Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- XZSWHQCDTYJZJA-UHFFFAOYSA-N 5-(methylamino)pyridine-3-carboxylic acid Chemical compound CNC1=CN=CC(C(O)=O)=C1 XZSWHQCDTYJZJA-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000255789 Bombyx mori Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 240000008415 Lactuca sativa Species 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 235000012045 salad Nutrition 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to hydrochloric acid sarafloxacin solid dispersed formulation and preparation method thereof.Concrete technical scheme is: first adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and make hydrochloric acid sarafloxacin be completely dissolved;After volatilizing ethanol in water-bath, gained solid is vacuum dried, pulverizes and sieve, gets product.Prescription of the present invention is extremely simple, by the simple preparation method of specialized designs and step, can obtain the dissolubility hydrochloric acid sarafloxacin solid dispersed formulation up to 1g/L in water, with low cost, is beneficial to promote.
Description
Technical field
The present invention relates to a kind of hydrochloric acid sarafloxacin solid dispersed formulation and preparation method thereof, it is adaptable to field of veterinary.
Background technology
According to the inventors knowledge, sarafloxacin (Sarafloxacin) be first by U.S.'s approval for the of food animal
Three generations's quinolones, it is FDA approval after enrofloxacin (Enrofloxacin), single promise sand star (Danafloxacin)
The special quinolones of another veterinary.Succeeded in developing by Abbott of the U.S. the earliest, common with hydrochlorate clinically, i.e.
Hydrochloric acid sarafloxacin (Sarafloxacin Hydrochloride).
Hydrochloric acid sarafloxacin has a broad antifungal spectrum, antibacterial activity are strong, to gram positive bacteria, negative bacterium, anaerobe, mycoplasma,
Chlamydia all has good killing action, can be used for preventing and treat various bacterial disease, as pig, the colibacillosis of chicken,
Salmonellosis, mycoplasma and staphylococcic infection are it can also be used to aquatic animal, silkworm sensitive organism infectious disease.But
Hydrochloric acid sarafloxacin poorly water-soluble, which greatly limits its application, needs to find one in higher concentrations in clinical practice
The preparation being easy to dissolve is to be greatly improved the Clinical practice of this product.
Finding through retrieval, Patent No. CN201010248879.3, Authorization Notice No. are CN101919804B, entitled
" solid dispersion veterinary drug prepare in application " Chinese invention patent, its solid dispersion include carbostyril compound and
Water-solubility carrier, carbostyril compound includes that sarafloxacin, water-solubility carrier include polyvidone;Its preparation method includes grinding
Method, fusion method, solvent-spray drying method.
Summary of the invention
The technical problem to be solved is: overcome the problem that prior art exists, it is provided that a kind of hydrochloric acid salad is husky
Star solid dispersed formulation, dissolubility is high;Thering is provided its preparation method, step is simple simultaneously.
The technical scheme that the present invention solves its technical problem is as follows:
A kind of hydrochloric acid sarafloxacin solid dispersed formulation, is characterized in that, by hydrochloric acid sarafloxacin and polyvidone by weight
0.5~1:2~10 are made by procedure below:
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone is 1 with the w/v of ethanol
~20g:20~100ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and make hydrochloric acid sarafloxacin be completely dissolved;Yu Shui
After bath volatilizes ethanol, gained solid is vacuum dried, pulverizes and sieve, gets product.
Preferably, the weight ratio of described hydrochloric acid sarafloxacin and polyvidone is 1:2~6, or described hydrochloric acid sarafloxacin
It is 1:4 with the weight ratio of polyvidone.
Preferably, the w/v of described polyvidone and ethanol is 5~15g:25~80ml, or described polyvidone with
The w/v of ethanol is 6~10g:40~60ml.
Preferably, described polyvidone uses PVPK15.
Present invention also provide that
A kind of hydrochloric acid sarafloxacin solid dispersed formulation preparation method, is characterized in that, comprise the following steps:
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone is 1 with the w/v of ethanol
~20g:20~100ml;Be added thereto to again the weight ratio of hydrochloric acid sarafloxacin, hydrochloric acid sarafloxacin and polyvidone be 0.5~
1:2~10, continues stirring and makes hydrochloric acid sarafloxacin be completely dissolved;After volatilizing ethanol in water-bath, gained solid is vacuum dried,
Pulverize and sieve, getting product.
Preferably, at least 1.5 hours are stirred after adding hydrochloric acid sarafloxacin.
Preferably, bath temperature is 80 DEG C, and vacuum drying temperature is 60 DEG C.
Compared with prior art, prescription of the present invention is extremely simple, by the simple preparation method of specialized designs and step, i.e.
The dissolubility hydrochloric acid sarafloxacin solid dispersed formulation up to 1g/L in water can be obtained, with low cost, it is beneficial to promote.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail.But the invention is not restricted to given example.
Embodiment 1
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 0.5g, polyvidone (PVPK15) 2g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
1g:20ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;In
After 80 DEG C of water-baths volatilize ethanol, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 2
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15) 20g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
20g:100ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;
After volatilizing ethanol in 80 DEG C of water-baths, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 3
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15) 8g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
8g:50ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;In
After 80 DEG C of water-baths volatilize ethanol, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 4
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 1g, polyvidone (PVPK15) 6g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
6g:40ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;In
After 80 DEG C of water-baths volatilize ethanol, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 5
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 1g, polyvidone (PVPK15) 5g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
5g:25ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;In
After 80 DEG C of water-baths volatilize ethanol, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 6
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15) 15g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
15g:80ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;
After volatilizing ethanol in 80 DEG C of water-baths, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 7
The hydrochloric acid sarafloxacin solid dispersed formulation of the present embodiment, its prescription composition and preparation technology are as follows:
Hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15) 10g
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, and polyvidone with the w/v of ethanol is
10g:60ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and within least 1.5 hours, make hydrochloric acid sarafloxacin be completely dissolved;
After volatilizing ethanol in 80 DEG C of water-baths, by gained solid 60 DEG C vacuum drying, pulverize and sieve, getting product.
Embodiment 8 contrast experiment
For verifying the dissolubility advantage that hydrochloric acid sarafloxacin solid dispersed formulation of the present invention has, choose following sample and carry out
Sample dissolubility contrast test under room temperature, including: the sample of embodiment 1~3 preparation, hydrochloric acid sarafloxacin raw material, comparative sample
1, comparative sample 2, comparative sample 3, comparative sample 4.
Above-mentioned comparative sample 1, its prescription forms and preparation process is: by hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15)
After 8g, ethanol 50ml three directly mix, it is spray-dried to obtain solids, solids 60 DEG C is vacuum dried and i.e. obtains comparative sample 1.
Above-mentioned comparative sample 2, its prescription forms and preparation process is: by hydrochloric acid sarafloxacin 2g, polyvidone (PVPK15)
After 8g, ethanol 50ml three directly mix, volatilizing ethanol in 80 DEG C of water-baths, 60 DEG C are vacuum dried and i.e. obtain comparative sample 2.
Above-mentioned comparative sample 3, its prescription forms and preparation process is: first mixed with ethanol 50ml by hydrochloric acid sarafloxacin 2g
Even, add polyvidone (PVPK15) 8g mixing, in 80 DEG C of water-baths, volatilize ethanol, 60 DEG C are vacuum dried and i.e. obtain comparative sample 3.
Above-mentioned comparative sample 4, its prescription forms and preparation process is: first mixed by polyvidone (PVPK15) 8g and ethanol 50ml
Even, add hydrochloric acid sarafloxacin 2g mixing, then rotatory vacuum evaporation, remove ethanol, 60 DEG C of vacuum drying.
Experimental technique and condition: weigh a certain amount of test sample powder, be placed in 100ml, temperature is the water of 25 DEG C ± 2 DEG C
In, shook 30 seconds every 5 minutes, observe dissolving situation after 15 minutes, and calculate the apparent solubility of each sample with this.Result is such as
Shown in table 1.
Table 1 solubility experiment result
As can be seen from Table 1, compared to raw material and each comparative sample, the embodiment 1 to 3 dissolubility in water has and significantly carries
High.This illustrates that the combination of prescription of the present invention and preparation process can play the technique effect being substantially better than prior art.
Additionally, the preparation process of comparative sample 1 relates to being spray-dried, and the spray drying of organic solvent, need explosion-proof
The safety operation aspects such as measure increase cost.The rotatory vacuum evaporation step of comparative sample 4 preparation process is only suitable at laboratory
Use, it is difficult to implement industrialization.
Claims (7)
1. a hydrochloric acid sarafloxacin solid dispersed formulation, is characterized in that, by hydrochloric acid sarafloxacin and polyvidone by weight 0.5
~1:2~10 is made by procedure below:
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, the w/v of polyvidone and ethanol be 1~
20g:20~100ml;It is added thereto to hydrochloric acid sarafloxacin again, continues stirring and make hydrochloric acid sarafloxacin be completely dissolved;In water-bath
In volatilize ethanol after, by gained solid be vacuum dried, pulverize and sieve, get product.
2. the hydrochloric acid sarafloxacin solid dispersed formulation addressed according to claim 1, is characterized in that, described hydrochloric acid sarafloxacin and
The weight ratio of polyvidone is 1:2~6, or the weight ratio of described hydrochloric acid sarafloxacin and polyvidone is 1:4.
3. the hydrochloric acid sarafloxacin solid dispersed formulation addressed according to claim 1, is characterized in that, described polyvidone and ethanol
W/v is 5~15g:25~80ml, or the w/v of described polyvidone and ethanol be 6~10g:40~
60ml。
4. the hydrochloric acid sarafloxacin solid dispersed formulation addressed according to claim 1, is characterized in that, described polyvidone uses
PVPK15。
5. a hydrochloric acid sarafloxacin solid dispersed formulation preparation method, is characterized in that, comprises the following steps:
First adding in ethanol by polyvidone, stirring makes polyvidone be completely dissolved, the w/v of polyvidone and ethanol be 1~
20g:20~100ml;The weight ratio being added thereto to hydrochloric acid sarafloxacin, hydrochloric acid sarafloxacin and polyvidone again is 0.5~1:2
~10, continue stirring and make hydrochloric acid sarafloxacin be completely dissolved;After volatilizing ethanol in water-bath, by the vacuum drying of gained solid, powder
Broken and sieve, get product.
6. the preparation method addressed according to claim 5, is characterized in that, stirs at least 1.5 hours after adding hydrochloric acid sarafloxacin.
7. the preparation method addressed according to claim 5, is characterized in that, bath temperature is 80 DEG C, and vacuum drying temperature is 60 DEG C.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110575438A (en) * | 2018-06-07 | 2019-12-17 | 湖南省湘中制药有限公司 | preparation and application of blonanserin solid dispersion |
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CN103735512A (en) * | 2013-12-06 | 2014-04-23 | 鼎正动物药业(天津)有限公司 | Enrofloxacin solid dispersion and preparation method thereof |
CN105362230A (en) * | 2015-11-27 | 2016-03-02 | 中牧南京动物药业有限公司 | Technological method for preparing sarafloxzcin hydrochloride soluble powder based on solid dispersion technology |
-
2016
- 2016-08-31 CN CN201610772286.4A patent/CN106265524B/en active Active
Patent Citations (3)
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CN101919804A (en) * | 2010-08-05 | 2010-12-22 | 洛阳惠中兽药有限公司 | Application of solid dispersion to preparation of veterinary drugs |
CN103735512A (en) * | 2013-12-06 | 2014-04-23 | 鼎正动物药业(天津)有限公司 | Enrofloxacin solid dispersion and preparation method thereof |
CN105362230A (en) * | 2015-11-27 | 2016-03-02 | 中牧南京动物药业有限公司 | Technological method for preparing sarafloxzcin hydrochloride soluble powder based on solid dispersion technology |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110575438A (en) * | 2018-06-07 | 2019-12-17 | 湖南省湘中制药有限公司 | preparation and application of blonanserin solid dispersion |
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