CN103349663B - Compound clobetasol propionate lipid composite ointment and preparation method thereof - Google Patents
Compound clobetasol propionate lipid composite ointment and preparation method thereof Download PDFInfo
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- CN103349663B CN103349663B CN201310086596.7A CN201310086596A CN103349663B CN 103349663 B CN103349663 B CN 103349663B CN 201310086596 A CN201310086596 A CN 201310086596A CN 103349663 B CN103349663 B CN 103349663B
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Abstract
The present invention provides a clobetasol propionate and tretinoin ointment agent. According to the present invention, a phospholipid and a positively charged lipid are mainly adopted to wrap drugs to prepare a lipid complex, wherein the positively charged lipid complex can concurrently wrap two drugs, encapsulation efficiency is high, and leakage is not easily generated; with the lipid complex, drug absorption can be promoted, and drug retention in skin can be increased; the multi-component low co-melting system is adopted to prepare the solid dispersion, such that the composite antioxidant component in the formula is uniformly dispersed in the same system; an oil phase matrix and an emulsifying agent are added so as to further prepare into a cream agent or an ointment agent in one step; and the preparation has characteristics of good emulsifying uniformity and high stability, and can be used for treatment of psoriasis, chronic dermatitis and eczema, skin papule type amyloidopathia, lichen planus, and non-atopic dermatitis.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of compound recipe clobetasol propionate and all-trans retinoic acid lipid complex and preparation method thereof, this lipid complex has the feature of high Cutaneous permeation, high dermal drug hold-up, ointment, ointment can be prepared into further, be mainly used in the diseases such as treatment psoriasis vulgaris, dermatitis, eczema.
Background technology
Clobetasol propionate and tretinoin are conventional external dermatological medicine, determined curative effect.Clobetasol propionate (CP) is a kind of potent hormone, and life-time service can cause the side effect such as atrophoderma, and side effect conventional in tretinoin use procedure is skin irritation.In addition, Drug Percutaneous Absorption enters blood circulation and then can produce systematic toxic and side effects.Therefore existing public technology is devoted to utilize compound compatibility technology and nano liposome preparations technology to improve curative effect of medication, reduces toxic and side effects.Particularly utilize the nano-carrier technology packaging medicine comprising liposome, the similar cellularity utilizing liposome and the Biofilm characteristics had and function, by hydration, fusion and penetration, liposome can carry active substance through horny layer, more drug is made to be trapped between epidermis and corium, reach corresponding site of action and maintain certain hour, effect molecular amounts making absorption enter blood system reduces, the curative effect of medicine in local can be improved, effectively avoid systemic adverse reactions.
Patent application CN1234365C discloses the compound preparation of a kind of clobetasol propionate and tretinoin, combined by the compatibility agent of two kinds of medicines, clobetasol propionate can alleviate the skin irritation symptom of tretinoin, and tretinoin can alleviate the atrophoderma that clobetasol propionate causes.Clinical trial results shows, after composition compound recipe, both curative effects strengthen, and untoward reaction alleviates.But according to its product description, still there will be the side effect such as skin irritation that tretinoin causes and the atrophoderma that clobetasol propionate causes.What this compound recipe adopted is common ointment preparation technique, and its supplementary product kind, Proportionality design are mainly used angle to consider based on preparation figuration, conveniently.And systematic study and concern are not done for the Transdermal absorption of medicine, skin delay aspect.
Adopt nanometer formulation bag carrier technology, such as liposome, micelle bag carry drug technique, liposome, micelle can carry active substance through horny layer, more drug is made to be trapped between epidermis and corium, reach corresponding site of action and maintain certain hour, effect molecular amounts making absorption enter blood system reduces, and can improve the curative effect of medicine in local, effectively avoid systemic adverse reactions.Another patent application 201110412475.8 discloses the Liposomal formulation of a kind of compound recipe clobetasol propionate and tretinoin, neutral synthetic phospholipid, positively charged lipid and cholesterol is adopted to prepare compound recipe clobetasol propionate and Tretinoin liposome preparation, this liposome preparatory techniques can wrap up two kinds of medicines simultaneously, entrapment efficiency is high, particle size distribution is little and even, Liposomal formulation about the particle mean size 100nm of preparation.Compared with common compound recipe clobetasol propionate tretinoin ointment, in skin, Liposomal formulation has higher medicine retention amount and lower agent permeates therethrough rate, better skin Targeting Effect can be reached, the Transdermal absorption reducing medicine enters sanguimotor amount, reach increase curative effect of medication, reduce poisonous side effect of medicine object.
Patent application 201210151469.6 provides the micellar solution of a kind of compound recipe clobetasol propionate and tretinoin, mainly utilizes nano-micelle prepared by phospholipid and cholate, packaging medicine, the polypeptide drug-loaded micelle solution that final formation is homogeneous, transparent.This micellar solution preparation technology is simple, does not need special process such as high pressure breast even grade, finished product impurity content can not be caused to increase in preparation process.
But because tretinoin is unstable, be easy to oxidative degradation, although more than invention is prepared further in production process and is added antioxidant composition and delay drug degradation, but when reckoning without use composite oxidant, different composite oxidant dissolubilities is different, is difficult to be dispersed in same preparation system simultaneously.The present invention is on the basis of preparing charge positive charge lipid complex, adopt solid dispersions technique that the antioxidant of different dissolution properties is dispersed in same system, satisfactory solves this problem, after making to prepare medicament lipid complexes, follow-up compound anti-oxidation uniform ingredients is added in system, and the even operation of follow-up emulsifying is carried out smoothly, prepare high osmosis, highly homogeneous lipid complex ointment.
Summary of the invention
The object of the invention provides a kind of compound recipe clobetasol propionate and tretinoin ointment.It is characterized in that clobetasol propionate and dimension A to be prepared into lipid complex, and composite antioxidant composition is prepared into solid dispersion, then add oil phase substrate further, be finally prepared into compound recipe clobetasol propionate and tretinoin ointment.
The object of the invention provides a kind of compound recipe clobetasol propionate and tretinoin lipid complex ointment.Compared with common ointment, this lipid complex can go deep into and be detained in skin by carrying medicaments, has the characteristic of high dermal drug hold-up.
The invention provides a kind of compound recipe clobetasol propionate and tretinoin lipid complex ointment, it is characterized in that lipid complex film strips has positive charge, because under physiological condition, cell surface is electronegative, lipid complex film body positively charged is conducive to encapsulation object and retains in skin.Tretinoin is acidulous material in addition, with negative charge after ionization, therefore contrary with lipid film surface charge.Medicine and film produce electrostatic interaction and combine closely, and reduce seepage.In addition charged lipid will increase the resistance between double-layer of lipoid, so both can obtain larger envelope volume, and can improve stability again.
Clobetasol propionate of the present invention and tretinoin lipid complex ointment, containing two kinds of pharmaceutically-active ingredients, be respectively clobetasol propionate and tretinoin, be all insoluble in water.The present invention adopts neutral synthetic phospholipid, positively charged lipid to be prepared into lipid complex as liposome stock packaging medicine.
The lipid complex of compound recipe clobetasol propionate provided by the invention and tretinoin, is first prepared into medicament lipid complexes by medicine parcel.Containing clobetasol propionate 1mg-50mg, tretinoin 1mg-50mg, neutral synthetic phospholipid 20-100mg, positively charged lipid 50-150mg in every 1000mg lipid composite solution.Neutral synthetic phospholipid by phase transition temperature higher than the synthetic phospholipid of body temperature and phase transition temperature used in combination with certain proportion lower than the phospholipid of body temperature, make final Liposomal formulation namely have certain flexibility, there is again suitable membrane stability, reduce drug leakage.Phase transition temperature is selected from hydrogenated phospholipid (HSPC) or distearoyl phosphatidylcholine or dipalmitoyl phosphatidyl choline higher than the phospholipid of body temperature; Phase transition temperature is selected from dimyristoyl phosphatidyl choline or DLPC lower than the phospholipid of body temperature; Positively charged lipid is selected from stearmide.
Lipid complex provided by the invention wraps up clobetasol propionate and tretinoin simultaneously, and be surprised to find that add the envelop rate that positively charged lipid can significantly improve tretinoin in matrix material, and the proportioning of neutral synthetic phospholipid by different phase transition temperature of more than two kinds, prepare the lipid complex that simultaneously can wrap up clobetasol propionate and tretinoin.
The lipid complex of compound recipe clobetasol propionate provided by the invention and tretinoin, its preparation process is: medicine and lipid materials are dissolved in the dichloromethane of 10 times of weight and the mixture of ethanol, be placed in Rotary Evaporators, under 50 DEG C of conditions, evaporating organic solvent, form medicine immobilized artificial membrane, add the phosphate buffer of the pH value 4.5-5.5 of appropriate volume, vibration aquation, form lipid complex suspension, lipid complex suspension is passed through the even secondary of high pressure breast again, finally by 100nm polycarbonate membrane, obtain medicament lipid complexes.In the lipid complex of gained, clobetasol propionate envelop rate is greater than 85%; The envelop rate of tretinoin is greater than 85%; Particle mean size is less than 200nm.
The invention provides a kind of compound recipe clobetasol propionate and tretinoin lipid complex ointment.It is characterized in that, be prepared into solid dispersion containing composite antioxidant composition in ointment, it is characterized in that, contain:
Multicomponent solid dispersion carrier 950 parts-990 parts
Composite antioxidant 10 parts-100 parts
Compound anti-oxidation dosage form composition of the present invention, it is characterized in that: the composition at least containing the different antioxidation mechanism of more than 3 kinds, comprises free radical absorbent, enzyme antioxidant, oxygen scavenger, metal ion chelation agent, singlet oxygen quencher, antioxidation phenols etc.
Compound anti-oxidation dosage form composition of the present invention, is characterized in that: the composition at least containing the different antioxidation mechanism of more than 3 kinds, comprises free radical absorbent, oxygen scavenger, metal ion chelation agent etc.
Free radical absorbent of the present invention, comprises BHA (Butylated hydroxyanisole), BHT (dibenzylatiooluene), TBHQ (tertiarybutylhydroquinone), epicatechol gallate (comprising its propyl ester, monooctyl ester, ten diester).
Oxygen scavenger of the present invention, comprises ascorbic acid, vitamin E.
Genus ion chelating agent of the present invention, comprises EDTA, citric acid.
Combination antioxidant of the present invention, first adopts multi-component eutectic system, is prepared into solid dispersion, then is added in other substrate of ointment further, the uniform ointment formulation of final formation.
Multicomponent eutectic system of the present invention contains: lanoline, paraffin, Tween 80.
Multicomponent eutectic system of the present invention, what it is characterized in that component ratio selects is lowest total of the melting point ratio of component.
The lowest total of the melting point scope 60 DEG C-70 DEG C of multicomponent eutectic system of the present invention.
After multicomponent eutectic system melt of the present invention, add combination antioxidant composition, form eutectic solid dispersion.
Composite antioxidant solid dispersion of the present invention, its preparation process is: get lanoline, paraffin, Tween 80, heating and melting, add composite antioxidant, is quickly cooled to below lowest total of the melting point temperature, prepares solid dispersion.
The lipid complex ointment of compound recipe clobetasol propionate provided by the invention and tretinoin, contains in 1000 parts of ointment:
Medicament lipid complexes 40-70 part
Compound anti-oxidation dosage form solid dispersion 50-100 part
Oil phase substrate 800-950 part
Emulsifying agent 30-100 part
Oil phase substrate is selected from as one or more in stearic acid, liquid paraffin, vaseline, octadecanol.
Emulsifying agent is selected from one or more in sorbester p18, sodium laurylsulfate, glyceryl monostearate.
Preparation process: get oil phase substrate and oil-soluble ingredients is heated to 80 DEG C of meltings. add compound anti-oxidation dosage form solid dispersion, melting is even; Separately get the lipoplex solution of bag medicine carrying thing; 80 DEG C of conditions, lipid complex aqueous phase is added to oil phase with thread, limit edged stirs, and is condensed to room temperature.Obtain.
The advantage of the present invention and existing technology is: the technology of preparing of lipid complex of the present invention can take into account the envelop rate of clobetasol propionate and tretinoin, and the lipid complex granularity of preparation is little and even, mean diameter is less than 200nm, is conducive to agent permeates therethrough horny layer and is detained and skin part.In vitro study experimental result shows: 1) the clobetasol propionate vitro Drug transdermal cumulative release percentage rate of usual cream agent is apparently higher than lipid complex ointment; 2) the tretinoin vitro Drug transdermal cumulative release percentage rate of usual cream agent is apparently higher than lipid complex ointment; 3) content of dispersion in the skin of usual cream agent is starkly lower than lipid complex ointment.Illustrate that lipid complex ointment has the feature of the relative targeting of better skin.
Following examples are mainly used for further illustrating the present invention, instead of limit the scope of the invention.
Embodiment 1: the preparation of medicament lipid complexes
The prescription table of table 1 medicament lipid complexes
| Title | Consumption |
| Clobetasol propionate | 5mg |
| Tretinoin | 2.5mg |
| HSPC | 50mg |
| Stearmide | 100mg |
| PH5.0 phosphate buffer adds to | 1000mg |
Preparation technology: get clobetasol propionate, tretinoin, HSPC, stearmide be dissolved in 10 times of w ethanol; Under 50 DEG C of conditions, rotate evaporate to dryness organic solvent, obtain drug-phospholipid coprecipitate thin film; Add pH5.0 phosphate buffer, vibration aquation is dissolved completely to medicine-mixed micelle coprecipitate thin film, obtains medicament lipid complexes.
In the lipid complex of gained, clobetasol propionate envelop rate is 94.7%; The envelop rate of tretinoin is 98.7%; Particle mean size is 30.7nm.
Embodiment 2: composite antioxidant solid dispersion
The preparation of table 2 composite antioxidant solid dispersion
| Title | Consumption |
| Propyl gallate | 0.2 |
| Vitamin E (VE) | 0.5 |
| 2,6-ditertbutylparacresol | 0.2 |
| Citric acid | 0.1 |
| Lanoline | 15g |
| Paraffin | 7g |
| Tween 80 | 1g |
Preparation process is: get lanoline, paraffin, Tween 80, and 70 DEG C of heating and meltings, add composite antioxidant, are quickly cooled to below lowest total of the melting point temperature, prepare solid dispersion.
Embodiment 3: the preparation of compound recipe clobetasol propionate tretinoin ointment
The prescription table of table 3 compound recipe clobetasol propionate tretinoin ointment
| Title | Consumption |
| Embodiment 1 medicament lipid complexes | 55 parts |
| Embodiment 2 compound antioxidant solid dispersion | 75 parts |
| Sorbester p18 | 30 parts |
| Sodium laurylsulfate | 40 parts |
| Stearic acid | 100 parts |
| Liquid paraffin | 100 parts |
| Octadecanol | 200 parts |
| Vaseline | 400 parts |
Preparation technology: get stearic acid, liquid paraffin, octadecanol, vaseline, 80 DEG C of heating and meltings, add sorbester p18 and are dissolved in oil phase substrate, another Example 2 compound antioxidant solid dispersion, and dissolve with in oil phase substrate, melting is even; Example 1 medicament lipid complexes, under 80 DEG C of conditions, is added in above-mentioned oil phase substrate with thread, adds sodium laurylsulfate, and emulsifying is even, obtains compound recipe clobetasol propionate tretinoin ointment.
Embodiment 4: dermal drug hold-up is tested
Adopt embodiment 3 compound prescription Biejiarangan, common compound prescription Biejiarangan, carry out isolated skin permeability test.
Isolated skin permeability test, after healthy rat anesthesia is put to death, belly wool is eliminated with shears, take off undamaged skin, removing subcutaneous tissue, be fixed on the supply chamber of Franz diffusion cell after cleaning, add the normal saline of 20%PEG400 in receiving chamber as release medium, keep endodermis and solution close contact.Getting quantitative sample puts in supply chamber, and regulate water-bath to make outer jacket layer temperature constant in (37 ± 1) DEG C, mixing speed is 100r/min, when 24h, take off skin, measures medicament contg in skin.
| Testing index | Lipid complex product | Common ointment product |
| Clobetasol propionate dermal drug hold-up (μ g/g) | 17.2±3.4 | 7.9±2.3 |
| Tretinoin skin hold-up (μ g/g) | 5.9±1.9 | 3.7±1.5 |
| Clobetasol propionate is accumulative through percentage rate (%) | 1.3±0.3 | 2.2±0.4 |
| Tretinoin is accumulative through percentage rate (%) | 0.9±0.2 | 2.5±0.5 |
Result shows: in lipid composite preparation skin, medicine retention amount is apparently higher than common ointment.
Claims (13)
1. an ointment for clobetasol propionate and tretinoin, is characterized in that, contains:
Lipid complex 40-70 part prepared by (l) clobetasol propionate and tretinoin
(2) solid dispersion 50-100 part of being prepared into of composite antioxidant composition
(3) oil phase substrate 800-950 part
(4) emulsifying agent 30-100 part
In final preparation, the concentration of clobetasol propionate is 0. 01%-0.1 (W/W), and the concentration of tretinoin is 0. 005-0. 05% (W/W);
Described composite antioxidant at least contains the composition of the different antioxidation mechanism of more than 3 kinds, is selected from free radical absorbent, enzyme antioxidant, oxygen scavenger, metal ion chelation agent, singlet oxygen quencher, antioxidation phenols;
Described composite antioxidant adopts multi-component eutectic system to unite and is prepared into solid dispersion.
2. ointment according to claim 1, is characterized in that, contains in lipid complex described in every l000mg:
(1) clobetasol propionate 1mg-50mg
(2) tretinoin 1mg-50mg,
(3) neutral synthetic phospholipid 20-100 mg
(4) positively charged lipid 50-150mg
Neutral synthetic phospholipid comprises phase transition temperature higher than the phospholipid of body temperature and the phase transition temperature phospholipid lower than body temperature, and phase transition temperature is selected from hydrogenated phospholipid or distearoyl phosphatidylcholine or dipalmitoyl phosphatidyl choline higher than the phospholipid of body temperature; Phase transition temperature is selected from dimyristoyl phosphatidyl choline or DLPC lower than the phospholipid of body temperature; Positively charged lipid is selected from stearmide.
3. ointment according to claim 2, is characterized in that, described lipid complex is obtained by following preparation process:
Medicine and lipid materials are dissolved in the dichloromethane of 10 times of weight and the mixture of ethanol, be placed in Rotary Evaporators, under 50 DEG C of conditions, evaporating organic solvent, forms medicine immobilized artificial membrane, adds the phosphate buffer of the pH value 4.5-5.5 of appropriate volume, vibration aquation, form lipid complex suspension, then by lipid complex suspension by the even secondary of high pressure breast, finally by 100nm polycarbonate membrane.
4. ointment according to claim 2, is characterized in that, in described lipid complex, the envelop rate of clobetasol propionate and tretinoin is all more than 80%, and mean diameter is less than 200nm.
5. ointment according to claim 2, is characterized in that, the solid dispersion that described composite antioxidant composition is prepared into contains:
Multicomponent solid dispersion carrier 950 parts-990 parts
Composite antioxidant 10 parts-100 parts.
6. ointment according to claim 5, is characterized in that, described multicomponent solid dispersion carrier be selected from lanoline, paraffin, Tween 80 one or more.
7. ointment according to claim 1, is characterized in that, described composite antioxidant at least contains the composition of the different antioxidation mechanism of more than 3 kinds, is free radical absorbent, oxygen scavenger, metal ion chelation agent.
8. ointment according to claim 7, is characterized in that, described free radical absorbent is selected from Butylated hydroxyanisole, dibenzylatiooluene, tertiarybutylhydroquinone, epicatechol gallate; Oxygen scavenger is selected from ascorbic acid, vitamin E; Metal ion chelation agent is selected from EDTA, citric acid.
9. ointment according to claim 8, is characterized in that, described epicatechol gallate is propyl gallate, gallateoctylester, lauryl gallate.
10. ointment according to claim 5, it is characterized in that, described solid dispersion is obtained by following preparation process: multicomponent solid dispersion, in eutectic point melting, adds combination antioxidant composition, rapid cooling, forms eutectic solid dispersion.
11. ointments according to claim 1, is characterized in that, described oil phase substrate, are selected from as one or more in stearic acid, liquid paraffin, vaseline, octadecanol.
12. ointments according to claim 1, is characterized in that, described emulsifying agent is selected from one or more in Tween 80, sodium laurylsulfate, glyceryl monostearate.
The ointment of 13. clobetasol propionate according to claim 1 and tretinoin, is characterized in that, is used for the treatment of psoriasis, chronic dermatitis eczema, skin rashes type amyloid disease, lichen planus, ergotropy dermatitis.
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| CN105651987A (en) * | 2016-01-29 | 2016-06-08 | 苏州联辰生物技术有限公司 | Method for manufacturing novel nano beam concentration material |
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| CN106309353A (en) * | 2015-06-19 | 2017-01-11 | 江苏吉贝尔药业股份有限公司 | Ointment used for treating psoriasis and preparation method thereof |
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| CN102038672B (en) * | 2009-10-10 | 2014-04-16 | 广东东阳光药业有限公司 | Medicinal composition for treating acne |
| CN102429913B (en) * | 2011-12-13 | 2013-04-10 | 江苏圣宝罗药业有限公司 | Compound clobetasol propionate liposome and preparation thereof |
| CN102772385B (en) * | 2012-08-22 | 2013-07-24 | 上海长城药业有限公司 | Stable tretinoin tablets and preparation method thereof |
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| CN105651987A (en) * | 2016-01-29 | 2016-06-08 | 苏州联辰生物技术有限公司 | Method for manufacturing novel nano beam concentration material |
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