CN1125141A - Solid dispersed substance containing cyclosporin A and its applciation of External use dosage form - Google Patents
Solid dispersed substance containing cyclosporin A and its applciation of External use dosage form Download PDFInfo
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- CN1125141A CN1125141A CN 94119148 CN94119148A CN1125141A CN 1125141 A CN1125141 A CN 1125141A CN 94119148 CN94119148 CN 94119148 CN 94119148 A CN94119148 A CN 94119148A CN 1125141 A CN1125141 A CN 1125141A
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- cyclosporin
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Abstract
The present invention relates to a preparation intermediate containing cyclosporin A. Said intermediate contains 10-90% of cyclosporin A and 90-10% of carrier. The above-mentioned two materials are respectively dissolved in absolute ethyl alcohol (or absolute ethyl ether), then uniformly mixed together and steamed for removing organic solvent, cooled and solidified so obtaining the invented intermediate. Said intermediate is mainly used for preparing the medicine preparation for external use for treating dermopathies, such as psoriasis, allergic dermatitis, atopic dermatitis and alopecia areata.
Description
The present invention relates to a kind of preparation intermediate that contains cyclosporin A, be mainly used to especially dermopathic external type medicaments such as psoriasis, allergic dermatitis, atoipc dermatitis, alopecia areata of preparation treatment dermatosis.
Cyclosporin A is a kind of immunosuppressive substance, during oral administration, mainly plays the immunologic rejection inhibitory action in the organ transplantation, and is also effective to dermatosis such as psoriasis, atoipc dermatitis, allergic dermatitises in addition.Because oral administration can produce irreversible kidney, liver toxicity, this is very unreasonable to above-mentioned treating skin disease.Cyclosporin A is water insoluble, very easily dissolving in methanol, ethanol, acetone, EC, and the physicochemical properties of cyclosporin A have limited its percutaneous permeability, make it can not enter skin easily and arrive diseased region.The percutaneous permeation and the clinical efficacy that how to improve cyclosporin A are difficult problems of abroad capturing at present.The Japan holy Mary medical department department of dermatologry Mizoguch.M of that university etc. had once reported (Lancet, 1992,339:1120) the cyclosporin A ointment of treatment psoriasis and atoipc dermatitis, having designed a kind of ointment base uses as cyclosporin A ointment, in the prescription with olive oil, micropowder silica gel 2000, Polyethylene Glycol (5) glyceryl monostearates etc. are as ointment base, cyclosporin A content is respectively 1%, 5%, 10%, but clinical observation result is not fairly obvious to the psoriasis effect.Other has the part of cyclosporin A of U.S. Pat 4997193 report and the method for whole body drug combination.Its content suppresses the immunologic rejection medication at skin transplantation, mention and utilize substrate, the certain proportioning of permeation promoter and cyclosporin A is mixed and made into ointment, plaster, gel, Emulsion, liquid agent, spray, can know for " Powdered " speech from used cyclosporin A simultaneously, its invention does not surpass to molecular weight that 1,000 non-hydrophobic cyclosporin A can penetrate smoothly and skin permeation proposes a theoretical property thinking and the science on the methodology are improved, only make relevant dosage form according to traditional pharmaceutics experience, and above-mentioned two documents, all do not adopt the solid dispersion technology, so the medicament medicine bad dispersibility of being developed is to serious, obstinate dermatosis effects such as psoriasis are undesirable.
The objective of the invention is to overcome the deficiency of above-mentioned technology and provide and utilize the solid dispersion technology to make the solid dispersion that contains cyclosporin A, to increase infiltration and the permeability of cyclosporin A in skin.
The solid dispersion technology is the new technique of modern medicinal agents, in solid dispersion, medicine exists with molecule, colloid or ultra-fine grain state, the dispersion of medicine in medium and the dissolution velocity of medicine have been increased, thereby produce efficient and quick-acting at agents area, in solid dispersion, there is the dissolution velocity that has also increased medicine in medicine with amorphous or metastable state.
According to above-mentioned thinking, made the solid dispersion that contains cyclosporin A, specific embodiment and parameter are as follows: cyclosporin A and carrier pulverize separately are sieved, take by weighing 10-90% and 90-10% above-mentioned two materials respectively, then cyclosporin A is dissolved in the dehydrated alcohol (or absolute ether), adds stirring fused or be dissolved in the carrier of dehydrated alcohol (or absolute ether), continue to stir, steam in the water-bath and remove organic solvent, cooling curing.Finished product is observed under cross-polarized light with polarizing microscope and is colourless amorphous state or the existence of colour superfine microcrystalline state, behind the heating and melting, cooling, under polarizing microscope, have the radial homogeneous body of distinctive birefringence color or be not birefringent phenomenon, obviously be different from the colourless or faint yellow bar-shaped crystallization of raw material cyclosporin A.Finished product is visually homogeneous, white or flaxen waxy solid or semisolid.
Above-mentioned carrier can be poloxamer, polyvinylpyrrolidone, soybean phospholipid, polyethylene glycol 6000, carbamide, methylcellulose, citric acid, acrylic resin etc.
During above-mentioned preparation solid dispersion, for cyclosporin A being uniformly dispersed in carrier and easilier existing with molecule, colloid or ultra-fine grain state, and preparation cyclosporin A content requirement during external preparation, the weight percentage of cyclosporin A and carrier is respectively 10-50% and 90-50%, and carrier is selected poloxamer, soybean phospholipid, polyvinylpyrrolidone, polyethylene glycol 6000, carbamide, methylcellulose, acrylic resin etc. for use.
Because the molecular weight of cyclosporin A is bigger, the angle layer of epiderm skin plays the external medicine of defence and invades intravital barrier action, cause the permeability of medicine relatively poor, make medicine be difficult to absorb with capacity, skin absorption promoter is permeation promoter such as Laurel nitrogen oxadiazon, dimethyl sulfoxide, dimethyl formamide, ethyl sebacate, carbamide, propylene glycol, oleic acid etc. can change the fine and close state of keratodermatitis, reduce cuticular barrier action, improve the percutaneous permeation of cyclosporin A, so when the preparation solid dispersion that contains cyclosporin A of the present invention, can also add the effective dose permeation promoter, described effective dose generally is no more than 5% of exterior-applied formulation that whole cyclosporin A solid dispersion makes, it can add as follows: when above-mentioned preparation solid dispersion, add carrier at cyclosporin A and mix the permeation promoter that adds effective dose when stirring, water-bath is steamed and is removed organic solvent, cooling curing then.
Utilize the above-mentioned cyclosporin A solid dispersion that contains the solid dispersion of cyclosporin A or contain permeation promoter, can make various cyclosporin A external preparation, as gel, ointment, liquid agent, plaster, aerosol, dermatosiss such as treatment psoriasis (psoriasis) atoipc dermatitis, allergic dermatitis, alopecia areata, especially serious, obstinate psoriasis, effect is much better than the preparation and the various therapeutic regimen of cyclosporin A in the past.
By statement on the above-mentioned theory and technologic description, we have provided the methodological improvement of cyclosporin A percutaneous penetration of drugs, how from experimentally be sure oing to disperse to increase behind the cyclosporin A transdermal characteristic of medicine with the solid dispersion technology, we have designed following experiment: skin membrane 2 is placed between two ponds of horizontal Valia-Chien diffusion cell (accompanying drawing 1), stratum corneum side is to donor pond 1, fix with 502 glue, accept to add in the pond 3 the 10ml normal saline, the normal saline supersaturated solution that adds the cyclosporin A solid dispersion in the donor pond, use the alligator clamp solid, place 32.0 ± 0.1 ℃ water bath with thermostatic control, magnetic stirring bar 4 stirs, in 1,2,3,4,5,6,7,8,9, took a sample respectively in 10 hours and the normal saline of additional equal volume, sample filters through microporous filter membrane (0.45um), use high effective liquid chromatography for measuring, the result gets the empirical average value 5-8 time, and experimental result is as follows:
Cyclosporin A transdermal penetration kinetic parameter sees Table 1, and J is for to stablize flow rate in the table, and D is a diffusion coefficient, and Pm is an infiltration coefficient.
Table 1 ciclosporin is through whole bark osmotic engine mathematic(al) parameter
r a b tL(h) J(ug/cm
2.s) Pm(cm/s)
10
3 10
60.9944 -0.067 0.535 0.125 2.093 4.8210.9725 -0.099 0.477 0.207 1.866 4.2980.9893 -0.027 0.281 0.097 1.098 2.5290.9984 -0.129 0.519 0.249 2.031 4.6790.9965 -0.394 0.560 0.704 2.192 5.049
0.276 1.856 4.275
± 0.247 ± 0.440 ± 1.014 skins are handled cyclosporin A transdermal penetration kinetic parameter table 2 skin through permeation promoter and are handled ciclosporin transdermal penetration kinetic parameter through permeation promoter
r a b tL(h) J(ug/cm.s) P(cm/s)
10
3 10
50.9899 -0.319 1.586 0.201 6.206 1.4300.9889 -0.343 1.152 0.298 4.507 1.0380.9747 -0.679 0.989 0.686 3.869 0.8910.9471 -0.266 0.963 0.276 3.768 0.8680.9912 -0.685 0.939 0.729 3.673 0.846
4.405 1.015
± 1.059 ± 0.244 from experimental data as can be known: skin is handled without permeation promoter, cyclosporin A solid dispersion Chinese medicine can see through intact skin, but its regime flow is lower by (2.093 * 10ug/cm.s), when being added with permeation promoter, can increase the longitude infiltration of cyclosporin A, with steady state flow from 2.093 * 10
-3Ug/cm
2.s bring up to 4.405 * 10
-3Ug/cm
2.s with infiltration coefficient from 4.275 * 10
-6Cm/s brings up to 1.015 * 10
-5Cm/s.
Simultaneously, under above-mentioned equal experiment condition, can not detect, the percutaneous permeation extreme difference is described with high performance liquid chromatography to the normal saline suspension of the cyclosporin A of not making solid dispersion.
From above-mentioned experimental data as can be known, be contained in its transdermal better performances of cyclosporin A in the solid dispersion, the solid dispersion that is added with permeation promoter more so illustrates the present invention program's feasibility.
Embodiment:
1, the solid dispersion that contains cyclosporin A 10%.
Cyclosporin A: 10%,
Soybean phospholipid: 90%;
Cyclosporin A and carrier pulverize separately are sieved, take by weighing two materials of aforementioned proportion, then cyclosporin A is dissolved in the dehydrated alcohol (or absolute ether), join stirring fused or be dissolved in the carrier of dehydrated alcohol (or absolute ether), continue to stir, steam to remove organic solvent in the water-bath, cooling curing is made and is contained 10% cyclosporin A solid dispersion.
2, the solid dispersion that contains cyclosporin A 25%.
Cyclosporin A: 25%,
Polyvinylpyrrolidone or soybean phospholipid: 25%;
Make by example 1 technology and to contain 25% cyclosporin A solid dispersion.
3, the solid dispersion that contains cyclosporin A 48%.
Cyclosporin A: 48%,
Poloxamer or soybean phospholipid: 52%;
Make by example 1 technology and to contain 48% cyclosporin A solid dispersion.
4, be added with the solid dispersion that contains 25% cyclosporin A of permeation promoter.
Cyclosporin A: 25%,
Polyvinylpyrrolidone or soybean phospholipid: 71%,
Vitamin E: 0.030%,
Laurel nitrogen ketone or dimethyl sulfoxide: add to 100%;
During above-mentioned preparation solid dispersion, cyclosporin A adds when continuing to stir in the carrier, adds vitamin E, laurocapram (or dimethyl sulfoxide), continue to stir, steam to remove organic solvent in the water-bath, cooling curing, contain the cyclosporin A solid dispersion of permeation promoter.
5, be added with the solid dispersion that contains cyclosporin A 48% of permeation promoter.
Cyclosporin A: 48%,
Soybean phospholipid or poloxamer: 50%;
Vitamin E: 0.015%
Laurel nitrogen ketone or dimethyl sulfoxide: add to 100%;
Make by above-mentioned example 4 technologies.
6, cyclosporin A solid dispersion gel.
Example 2 contains 25% cyclosporin A solid dispersion: 8%,
CBP 941:20%,
Dimethyl sulfoxide: 3%,
Purified Water adds to: 100g;
Earlier that CBP 941 and Purified Water is expanded, adding permeation promoter and cyclosporin A solid dispersion are mixed makes gel, is loaded in the ointment tube, and every gram gel contains cyclosporin A 80mg.
7, cyclosporin solid dispersion ointment.
Example 1 contains 10% cyclosporin A solid dispersion: 50%
Anhydrous lanolin: 10%
Laurel nitrogen ketone or dimethyl sulfoxide: 2%
Vitamin E: 0.015%
Vaseline adds to: 100%
With fusion in the water-bath of cyclosporin A solid dispersion, add permeation promoter and anhydrous lanolin and vaseline mixing and grind and make the cyclosporin A ointment, fill is in ointment tube, and every gram contains cyclosporin A 50mg.
8, cyclosporin A solid dispersion ointment.
10% cyclosporin A solid dispersion in the example 1: 32%
Anhydrous lanolin: 5%
Liquid paraffin: 10%
Laurel nitrogen ketone or dimethyl sulfoxide: 1%
Vitamin E: 0.015%
Vaseline adds to 100%
Make the cyclosporin A solid dispersion ointment that contains cyclosporin A 15mg/g by example 7 technologies.
9, cyclosporin A solid dispersion plaster.
25% cyclosporin A solid dispersion in the example 2: 20%
Vitamin E: 0.1%
Laurel nitrogen ketone: 3%
Adhesive: polymethyl methacrylate, butyl acrylate, the copolymer of Isooctyl acrylate monomer adds to full dose 100%
The cyclosporin A solid dispersion is dissolved in adds vitamin E, Laurel nitrogen ketone in the ethyl acetate, and mix coating, remove ethyl acetate, make it into 500mg cyclosporin/subsides plaster with adhesive.
10, cyclosporin A solid dispersion solution.
10% cyclosporin A solid dispersion in the example 1: 50%
Vitamin E: 0.015%
Dimethyl sulfoxide or Laurel nitrogen ketone: 2%
95% ethanol adds to 100%
Above-mentioned each composition is dissolved in the ethanol, in the close plug bottle of packing.
11, cyclosporin A solid dispersion aerosol: 32%
Propylene glycol: 30%
Vitamin E: 0.1%
Laurel nitrogen ketone or carbamide: 1%
Ethanol adds to 100%
It is an amount of to pour into freon F12
The cyclosporin A solid dispersion is added vitamin E and Laurel nitrogen ketone with dissolve with ethanol, add propylene glycol again, fill propellant freon (F12) is made aerosol, and every gram contains cyclosporin A medicine 80mg.
12, the cyclosporin A Ointment in Treatment psoriasis case observation that utilizes the present invention to make, the cyclosporin A solid dispersion ointment of making according to the foregoing description 7 or 8, carry out preliminary clinical observation on the therapeutic effect having investigated under its in-vitro percutaneous infiltration situation, choose in the whole body the most serious to 10 routine psoriatics, the most obstinate skin lesion position, cyclosporin A solid dispersion preparation is applied to the affected part, one twice-daily was (though these patients used fluocinonide in the past, clobetasol, extract oral and external there is no effect), the skin lesion area obviously reduces after all patient's medications, has no adverse reaction.
Claims (13)
1, a kind of solid dispersion that contains cyclosporin A is characterized in that:
In a, this solid dispersion
Cyclosporin A 10-90%,
Carrier 90-10%;
B, solid dispersion are made by following method: cyclosporin A and carrier pulverize separately are sieved, take by weighing two materials of above-mentioned a ratio respectively, then cyclosporin A is dissolved in the dehydrated alcohol (or absolute ether), add stirring fused or be dissolved in the carrier of dehydrated alcohol (or absolute ether), continue to stir, steam in the water-bath and remove organic solvent, cooling curing.
2, the solid dispersion that contains cyclosporin A as claimed in claim 1 is characterized in that:
Cyclosporin A 10-50%,
Carrier 90-50%.
3, the solid dispersion that contains cyclosporin A as claimed in claim 1 or 2 is characterized in that described carrier can be poloxamer, soybean phospholipid, polyvinylpyrrolidone, polyethylene glycol 6000, carbamide, methylcellulose, acrylic resin etc.
4, the solid dispersion that contains cyclosporin A as claimed in claim 1 or 2 is characterized in that described carrier is poloxamer (or soybean phospholipid)
Cyclosporin A 20%,
Poloxamer (or soybean phospholipid) 80%.
5, the solid dispersion that contains cyclosporin A as claimed in claim 1, it is characterized in that mixing under the stirring state mutually in the carrier when cyclosporin A adds, the permeation promoter that adds effective dose again, as Laurel nitrogen ketone, dimethyl sulfoxide, dimethyl formamide, ethyl sebacate, carbamide, propylene glycol, oleic acid etc., steam then and remove organic solvent, cooling curing.
6, the solid dispersion that contains cyclosporin A as claimed in claim 5 is characterized in that described permeation promoter is a Laurel nitrogen ketone, and content accounts for 5% of solid dispersion weight.
7, a kind of external preparation that contains cyclosporin A comprises ointment, gel, solution, plaster, aerosol, it is characterized in that utilizing the described solid dispersion that contains cyclosporin A of aforesaid right requirement 1 or claim 5 to make.
8, the external preparation that contains cyclosporin A as claimed in claim 7 is characterized in that described ointment prescription is as follows:
The solid dispersion 50% that contains cyclosporin A 10%,
Anhydrous lanolin 10%,
Laurel nitrogen oxadiazon (or dimethyl sulfoxide) 0.015%,
Vaseline adds to 100%.
9, the external preparation that contains cyclosporin A as claimed in claim 7 is characterized in that made gel prescription is as follows:
The solid dispersion 8% that contains cyclosporin A 25%,
CBP 941 20%,
Dimethyl sulfoxide 3%,
Purified Water adds to 100%.
10, the external preparation that contains cyclosporin A as claimed in claim 7 is characterized in that described solution prescription is as follows:
The curing that contains cyclosporin A 10% disperses thing 50%,
Vitamin E 0.015%,
Dimethyl sulfoxide (or Laurel time ketone) 2%,
95% ethanol adds to 100%.
11, the external preparation that contains cyclosporin A as claimed in claim 7 is characterized in that described plaster prescription is as follows:
The curing that contains cyclosporin A 25% disperses thing 20%,
Vitamin E 0.1%,
Laurel nitrogen oxadiazon 3%,
Adhesive: polymethyl methacrylate, butyl acrylate Isooctyl acrylate monomer
Copolymer add to 100%.
12, the external preparation that contains cyclosporin A as claimed in claim 7 is characterized in that described aerosol formulations is as follows:
The curing that contains cyclosporin A 25% disperses thing 32%,
Propylene glycol 30%,
Laurel nitrogen oxadiazon (or carbamide) 1%,
95% ethanol adds to 100%,
Propellant: freon F12 is an amount of.
13, a kind of curing that contains cyclosporin A disperses the application of thing as preparation treatment dermatosis medicine, it is characterized in that making aforesaid right requirement 7 described external preparation, dermatosis such as treatment psoriasis, atoipc dermatitis, allergic dermatitis, alopecia areata.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94119148 CN1125141A (en) | 1994-12-22 | 1994-12-22 | Solid dispersed substance containing cyclosporin A and its applciation of External use dosage form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94119148 CN1125141A (en) | 1994-12-22 | 1994-12-22 | Solid dispersed substance containing cyclosporin A and its applciation of External use dosage form |
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| Publication Number | Publication Date |
|---|---|
| CN1125141A true CN1125141A (en) | 1996-06-26 |
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|---|---|---|---|
| CN 94119148 Pending CN1125141A (en) | 1994-12-22 | 1994-12-22 | Solid dispersed substance containing cyclosporin A and its applciation of External use dosage form |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998052549A2 (en) * | 1997-05-20 | 1998-11-26 | Fumapharm Ag | Use of fumaric acid derivatives |
| US7320999B2 (en) | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
| US8399514B2 (en) | 2007-02-08 | 2013-03-19 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
| US8980832B2 (en) | 2003-09-09 | 2015-03-17 | Biogen Idec International Gmbh | Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
| CN114869895A (en) * | 2022-04-10 | 2022-08-09 | 复旦大学附属中山医院 | Application of 2-Methoxyestradiol in the Preparation of Medicines for Treating Psoriasis |
-
1994
- 1994-12-22 CN CN 94119148 patent/CN1125141A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ299960B6 (en) * | 1997-05-20 | 2009-01-07 | Fumapharm Ag | Use of fumaric acid derivative |
| WO1998052549A3 (en) * | 1997-05-20 | 1999-04-08 | Fumapharm Ag | Use of fumaric acid derivatives |
| WO1998052549A2 (en) * | 1997-05-20 | 1998-11-26 | Fumapharm Ag | Use of fumaric acid derivatives |
| US7803840B2 (en) | 1998-11-19 | 2010-09-28 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
| US7612110B2 (en) | 1998-11-19 | 2009-11-03 | Biogen Idec International Ag | Utilization of dialkylfumarates |
| US7619001B2 (en) | 1998-11-19 | 2009-11-17 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
| US7320999B2 (en) | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
| US7915310B2 (en) | 1998-11-19 | 2011-03-29 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
| US8524773B2 (en) | 1998-11-19 | 2013-09-03 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
| US8759393B2 (en) | 1998-11-19 | 2014-06-24 | Biogen Idec International Gmbh | Utilization of dialkylfumarates |
| US8980832B2 (en) | 2003-09-09 | 2015-03-17 | Biogen Idec International Gmbh | Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
| US8399514B2 (en) | 2007-02-08 | 2013-03-19 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
| CN114869895A (en) * | 2022-04-10 | 2022-08-09 | 复旦大学附属中山医院 | Application of 2-Methoxyestradiol in the Preparation of Medicines for Treating Psoriasis |
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