CN103830179B - A kind of external preparation and preparation technology thereof containing crotamiton - Google Patents
A kind of external preparation and preparation technology thereof containing crotamiton Download PDFInfo
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- CN103830179B CN103830179B CN201410110464.8A CN201410110464A CN103830179B CN 103830179 B CN103830179 B CN 103830179B CN 201410110464 A CN201410110464 A CN 201410110464A CN 103830179 B CN103830179 B CN 103830179B
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- crotamiton
- external preparation
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- decanoyl
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- 229960003338 crotamiton Drugs 0.000 title claims abstract description 49
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 238000005516 engineering process Methods 0.000 title claims abstract description 18
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims abstract description 12
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 11
- 229920001993 poloxamer 188 Polymers 0.000 claims description 11
- 229940044519 poloxamer 188 Drugs 0.000 claims description 11
- 239000002674 ointment Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 12
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 abstract description 3
- 229920001983 poloxamer Polymers 0.000 abstract description 3
- 229960000502 poloxamer Drugs 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 11
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 7
- 230000001804 emulsifying effect Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010063409 Acarodermatitis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000447727 Scabies Species 0.000 description 3
- 230000000895 acaricidal effect Effects 0.000 description 3
- 239000000642 acaricide Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 208000005687 scabies Diseases 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- -1 aminomethyl phenyl Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 0 CCc(cccc1)c1N(C)C(C=C*C)=O Chemical compound CCc(cccc1)c1N(C)C(C=C*C)=O 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000270322 Lepidosauria Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000037067 skin hydration Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of external preparation and the preparation technology thereof that contain crotamiton, this external preparation is mixed by the component of following parts by weight and forms: crotamiton 100 parts, TC 200-400 part, decanoyl/octanoyl glycerides 100-200 part, poloxamer 400-600 part; Concrete preparation technology is: be dissolved in by crotamiton in TC, then adds decanoyl/octanoyl glycerides, poloxamer, is stirred to dissolve.Preparation technology of the present invention is simple, and fundamentally avoids the problem that medicine is separated with substrate, is beneficial to long term storage and transport.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of medicine external preparation, particularly relate to a kind of external preparation and the preparation technology thereof that contain crotamiton.
Background technology
Scabies parasitizes a kind of chronic infection dermatoses caused by human epidermal layer by a red-spotted lizard demodicid mite, and have localized epidemics's trend, number of patients increases year by year in recent years, therefore early finds, early diagnosis, early treatment serve pivotal role for the diagnosis and treatment of this disease.Scabies is apt to occur in skin delicacy, gauffer position, often from finger seam, the place such as upside before can extensively reaching flexion of upper limb side, the fossa cubitalis, axillary fossa in 1-2 week, under breast, in hypogastric region, gluteal fold, external genitalia, thigh, invade other positions once in a while, but do not invade head and face, but infant skin is more delicate, sarcoptic mite is easy to the Head And Face of attacking children's.Acaricide drives the mechanical irritation that tunnel causes in keratodermatitis, and the allergy that the venom of acaricide secretion and Excreta chafe cause and female acaricide are trapped in keratodermatitis and cause foreign body reaction, all can cause the violent pruritus of skin.Crotamiton emulsifiable paste is the common drug for the treatment of scabies, and by outer liniment for treatment, curative effect is better.
Crotamiton is colourless or pale yellow oily liquid body, micro-smelly, can partly or entirely solidify at low temperatures, very easily dissolve in ethanol or ether, slightly soluble in water, record in Chinese Pharmacopoeia (CHP) 2010 editions two, be N-ethyl-N-(2-the aminomethyl phenyl)-cis of 2-butylene amide and the mixture of transisomer, structural formula is as follows:
At present, the crotamiton emulsifiable paste adjuvant used gone on the market is stearic acid, glyceryl monostearate, glycerol, and when outer wiping uses, greasy feeling is too strong, and its technique is comparatively complicated, and needs to adopt emulsifying device, and production cost is high.
Summary of the invention
In view of prior art Problems existing, the object of the invention is to by screening and technical study adjuvant, thus the crotamiton external preparation that a kind of stability is high, be easy to production is provided.
Amido link in crotamiton compound is easily hydrolyzed, and this is the biggest factor causing preparation instability.In addition, when preparing crotamiton ointment, medicine must be prevented to be separated from substrate.Inventor considers, the most key in the preparation of crotamiton emulsifiable paste is emulsifying, if self-emulsifying microemulsion technology can be applied to crotamiton emulsifiable paste, and will significantly Simplified flowsheet operation.Based on above consideration, inventor, by lot of experiments research also persistent exploration, finally obtains the technical scheme realizing the object of the invention as follows:
An external preparation containing crotamiton, this external preparation is mixed by the component of following parts by weight and forms:
Preferably, the external preparation as mentioned above containing crotamiton, wherein this external preparation is mixed by the component of following parts by weight and forms:
In a most preferred embodiment of the present invention, the external preparation containing crotamiton as above, it is mixed by the component of following parts by weight to form:
External preparation containing crotamiton of the present invention, its preferred dosage form is ointment.
Present invention also offers the preparation technology of the above-mentioned external preparation containing crotamiton, the stability of the crotamiton emulsifiable paste adopting this technique to prepare is high, and does not need complicated emulsifying device, is easy to suitability for industrialized production.
Particularly, the preparation technology of the external preparation as mentioned above containing crotamiton, it comprises the steps: crotamiton to be dissolved in TC, then adds decanoyl/octanoyl glycerides, poloxamer188, is stirred to dissolve.
Compared with prior art, the crotamiton ointment that the present invention relates to and preparation technology's tool thereof have the following advantages and marked improvement:
(1) the present invention has successfully prepared the crotamiton ointment of microemulsified, and be dispersed into nanoparticle rapidly after medicament contact skin hydration, drug effect will improve a lot.
(2) poloxamer188 add the hydrolysis that inhibit crotamiton amido link, improve the quality of products.
(3) general external preparation adopts ethanol as the solvent of crude drug, however ethanol not only zest is strong, and ethanol high volatility, can cause medicine to be separated out, cause curative effect to decline.The present invention, not containing any effumability solvent, adds in other adjuvants in the form of a solution after creatively adopting TC to dissolve crotamiton, not only overcomes the defect that medicine is difficult to mix homogeneously, and avoid the problem of medicine precipitation.
(4) preparation technology is simple, does not need complicated emulsifying device, is easy to industrialized great production.
Detailed description of the invention
Now further describe preparation process of the present invention and implementation result by following examples, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
Embodiment 1
Preparation technology:
Crotamiton is dissolved in TC, then adds decanoyl/octanoyl glycerides, poloxamer188, be heated to 40 DEG C, be stirred to dissolve.
Embodiment 2
Preparation technology:
Crotamiton is dissolved in TC, then adds decanoyl/octanoyl glycerides, poloxamer188, be heated to 40 DEG C, be stirred to dissolve.
Embodiment 3
Preparation technology:
Crotamiton is dissolved in TC, then adds decanoyl/octanoyl glycerides, poloxamer188, be heated to 40 DEG C, be stirred to dissolve.
Embodiment 4
Preparation technology:
Crotamiton is dissolved in TC, then adds decanoyl/octanoyl glycerides, poloxamer188, be heated to 40 DEG C, be stirred to dissolve.
Comparative example 1
Preparation technology:
Crotamiton is dissolved in ethanol, then adds decanoyl/octanoyl glycerides, poloxamer188, be heated to 40 DEG C, be stirred to dissolve.
Embodiment 5: the stability study of crotamiton preparation
1. clo rice grain pattern assay
Chromatographic condition and system suitability: be filler with silica gel, with cyclohexane extraction-oxolane (92:8) for mobile phase, determined wavelength 242nm.Get crotamiton reference substance appropriate, sealing, take out after 6 hours in 150 DEG C of heating, put to room temperature, make the solution about containing 0.1mg in every 1mL with mobile phase dilution, get 20 μ L injection liquid chromatographies, record chromatogram, main peak is crotamiton transisomer, and the chromatographic peak doubly located at main peak relative retention time 0.5-0.6 is crotamiton cis-isomer, and doubly locating chromatographic peak at main peak relative retention time 0.7-0.8 is related substance A.
Algoscopy: get this product and be about 50mg, accurately weighed, put in 100mL measuring bottle, dissolve with mobile phase and be diluted to scale, shaking up, precision measures 5mL, puts in 100mL measuring bottle, is diluted to scale with mobile phase, shake up, as need testing solution.Precision measures need testing solution 20 μ L, injection liquid chromatography, record chromatogram; Separately get crotamiton reference substance, be measured in the same method, transisomer peak area sum suitable with crotamiton by external standard method calculates, and to obtain final product.Testing result is see table 1.
2. determination of related substances
Get this product appropriate, accurately weighed, add mobile phase and dissolve and dilute the solution made about containing 0.5mg in every lmL, as need testing solution; Precision measures need testing solution lmL, puts in 100mL measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution.According to the chromatographic condition under assay item, get contrast solution 20 μ 1, note people chromatograph of liquid, regulates detection sensitivity, makes the peak height of crotamiton transisomer chromatographic peak be about 30% of full scale; Precision measures need testing solution and contrast solution respectively notes people's chromatograph of liquid respectively again, and record chromatogram is to 2.5 times of crotamiton transisomer peak retention time.If any impurity peaks in the chromatogram of need testing solution, relative retention time is that the peak area of N-ethyl-N-(2-the tolyl)-3-crotonamide (impurity I) of 0.7 ~ 0.8 must not be greater than suitable in contrast solution, transisomer peak area summation 0.75 times (0.75%).Anyly in need testing solution be less than peak that is suitable in contrast solution, transisomer peak area summation 0.02 times and can ignore.Testing result is see table 1.
The stability indicator of sample prepared by each embodiment before and after table 1 accelerated test
Known by the result of the test of analytical table 1, crotamiton preparation prepared by embodiment of the present invention 1-4 is through accelerating to investigate, and content is substantially constant, and related substance slightly increases; Comparative example 1 replaces TC with ethanol, and because of ethanol high volatility, cause medicine to be separated out, therefore poloxamer is difficult to available protecting medicine, therefore related substance increases obviously.Meanwhile, the product prepared of the embodiment of the present invention before acceleration after appearance character do not change, be uniform solution; And comparative example 1 is because of ethanol volatilization, cause medical separation.
Claims (5)
1. the external preparation containing crotamiton, is characterized in that described external preparation is mixed by the component of following parts by weight and forms:
Crotamiton 100 parts
TC 200-400 part
Decanoyl/octanoyl glycerides 100-200 part
Poloxamer188 400-600 part.
2. the external preparation containing crotamiton according to claim 1, is characterized in that described external preparation is mixed by the component of following parts by weight and forms:
Crotamiton 100 parts
TC 220-300 part
Decanoyl/octanoyl glycerides 130-170 part
Poloxamer188 450-520 part.
3. the external preparation containing crotamiton according to claim 1, is characterized in that described external preparation is mixed by the component of following parts by weight and forms:
Crotamiton 100 parts
TC 250 parts
Decanoyl/octanoyl glycerides 150 parts
Poloxamer188 500 parts.
4. the external preparation containing crotamiton according to any one of claim 1-3, is characterized in that described external preparation is ointment.
5. the preparation technology of the external preparation containing crotamiton according to any one of claim 1-3, it is characterized in that this technique comprises the steps: crotamiton to be dissolved in TC, then add decanoyl/octanoyl glycerides, poloxamer188, be stirred to dissolve.
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| CN201410110464.8A CN103830179B (en) | 2014-03-24 | 2014-03-24 | A kind of external preparation and preparation technology thereof containing crotamiton |
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| CN201410110464.8A CN103830179B (en) | 2014-03-24 | 2014-03-24 | A kind of external preparation and preparation technology thereof containing crotamiton |
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| CN107468637A (en) * | 2016-06-08 | 2017-12-15 | 厦门恩成制药有限公司 | Compound tazarotene urea external preparation and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308537A (en) * | 1998-07-10 | 2001-08-15 | 久光制药株式会社 | Steroid-containing cataplasms and process for producing the same |
| CN102018661A (en) * | 2011-01-18 | 2011-04-20 | 中山大学 | External preparation for resisting funguses and preparation method of external preparation |
-
2014
- 2014-03-24 CN CN201410110464.8A patent/CN103830179B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308537A (en) * | 1998-07-10 | 2001-08-15 | 久光制药株式会社 | Steroid-containing cataplasms and process for producing the same |
| CN102018661A (en) * | 2011-01-18 | 2011-04-20 | 中山大学 | External preparation for resisting funguses and preparation method of external preparation |
Non-Patent Citations (1)
| Title |
|---|
| 克罗米通霜剂的制备;贺曾佑;《药学通报》;19831231;第18卷(第11期);第49页 * |
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Effective date of registration: 20151022 Address after: 266000 Licang, Qingdao, No. nine East water road, No. 320, No. Applicant after: Gu Xiangmao Address before: 721001 Zhongshan West Road Baoji city Shaanxi province Jintai District No. 78 Chen Ji pharmaceutical Applicant before: Duan Yiling |
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Correction item: Patentee|Address|Patent agency|agent Correct: Gu Xiangmao|266000 Licang, Qingdao, No. nine East water road, No. 320, No.|Shenzhen Shenzhou Joint Intellectual Property Agency (general partnership) 44324|Deng Yang False: Duan Yiling|721001 Zhongshan West Road Baoji city Shaanxi province Jintai District No. 78 Chen Ji pharmaceutical|Beijing Jinshi patent agency (general partner) 11470|Qiang Honggang Number: 46 Volume: 31 |
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Correction item: Patentee|Address|Patent agency|agent Correct: Gu Xiangmao|266000 Licang, Qingdao, No. nine East water road, No. 320, No.|Shenzhen Shenzhou Joint Intellectual Property Agency (general partnership) 44324|Deng Yang False: Duan Yiling|721001 Zhongshan West Road Baoji city Shaanxi province Jintai District No. 78 Chen Ji pharmaceutical|Beijing Jinshi patent agency (general partner) 11470|Qiang Honggang Number: 46 Page: The title page Volume: 31 |
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Inventor after: Han Feng Inventor after: Liu Ruiquan Inventor before: Bian Yuping |
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Effective date of registration: 20170105 Address after: 262100 Shandong city of Weifang province Anqiu Qingyun Road No. 315, building 30, unit 2, No. 503 Patentee after: Han Feng Address before: 266000 Licang, Qingdao, No. nine East water road, No. 320, No. Patentee before: Gu Xiangmao |
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Granted publication date: 20151118 Termination date: 20170324 |