CN1292751C - Imiquimod or its derivative liposome for local skin and its preparing method and use - Google Patents
Imiquimod or its derivative liposome for local skin and its preparing method and use Download PDFInfo
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- CN1292751C CN1292751C CNB021136475A CN02113647A CN1292751C CN 1292751 C CN1292751 C CN 1292751C CN B021136475 A CNB021136475 A CN B021136475A CN 02113647 A CN02113647 A CN 02113647A CN 1292751 C CN1292751 C CN 1292751C
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- imiquimod
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- local skin
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Abstract
The present invention relates to liposome for local skin and preparation thereof. Imiquimod or a derivative thereof, a fat phase, acid and alkali solution and a rack agent are prepared into liposome of imiquimod or a derivative thereof. The liposome for local skin can be used for treating virus infection, wart, eczema, etc. of the skin. The liposome for local skin can mainly be used for treating melanoma, basal cell carcinoma and other dermatoma diseases. The liposome for local skin can also be used for treating many other diseases. Imiquimod liposome and cream are applied to the par. Aff of animals which have the melanoma; after 4 weeks, the death rate/the death time is used as the assessment index; a preliminary result shows that after 29 days, the death rate of a control group is 74%, the death rate of a cream group is 70%, and the death rate of a liposome group is 38%.
Description
The present invention relates to the local skin drug-supplying system, particularly local skin drug-supplying system liposome and preparation thereof, and be applied to treat viral infection, cutaneous fungal infection and the wart etc. of skin carcinoma, skin.
Imiquimod (imiquimod), chemistry 1-isobutyl group by name-1H-imidazoles [4,5-C] quinoline-4-amine, it is an immunomodulator, also is interferon inducers (Interferon Inducer).RikerLabs by the U.S. develops at first.3M company and Japanese first drugmaker are transferred the possession of in the back.The new drug application of 3M company proposition in 1997 is by drugs approved by FDA, and go on the market in the U.S. October.Traded commodity is called Aldara, is 5% imiquimod cream of 250mg unit dose package, is used for the treatment of viral infection such as I type and II type herpes-ness progenitalis infection and genital wart.Modal side effect was that erythema takes place during this medicine used, and toxigenicity when high dose is mainly the symptom and nausea and vomiting and the lymphopenia that are similar to the miazines anticarcinogen.At U.S.Pat No4,689,338 have reported imiquimod as antiviral agent and interferon inducers, and have introduced the multiple dosage form of this chemical compound topical.In EP.0 376 534 A1, mainly introduced imiquimod and directly made, comprised ointment, ointment, patch etc. through the skin drug-supplying system.The weak point of above-mentioned various dosage forms is that the storage dose in local skin affected part is few, and Transdermal absorption amount height causes whole body to absorb the side effect that brings.Purposes also only is percutaneous drug delivery treatment viral infection, herpes infection.
Purpose of the present invention is just for overcoming above-mentioned weak point of the prior art, and provide a kind of imiquimod or derivatives thereof liposome local skin drug-supplying system, comprise that preparation and preparation method thereof and expansion comprise the scope for the treatment of purposes such as skin carcinoma, to increase the local skin dose, reduce transdermal amount and whole body and absorb the side effect that brings.
The present invention is a kind of local skin imiquimod or derivatives thereof liposome, gets in 1000mg: 1 imiquimod or derivatives thereof 0.1mg-400mg; 2. fat contains phospholipid or derivatives thereof or their mixture 1mg-400mg, cholesterol or derivatives thereof or their mixture 0mg-100mg mutually; 3. any that can dissolve imiquimod or derivatives thereof, phospholipid or derivatives thereof or their mixture, cholesterol or derivatives thereof or their mixture can and be given birth to salifiable acid solution 10mg-500mg with alkali generation neutralization reaction; 4. neutralization reaction can take place and give birth to salifiable alkaline solution 10mg-500mg in any with acid; Above-mentioned component is added water to 1000mg be prepared, forming pH is the emulsion of 4-12, removes the salt of generation, adds caffolding agent 1-50mg, and lyophilization makes the dried frozen aquatic products of imiquimod or derivatives thereof liposome.
Wherein the derivant in the imiquimod or derivatives thereof is 1-butyl-1H-imidazoles [4,5-C] quinoline-4-amine; Phospholipid is lecithin, fabaceous lecithin, kephalin; The derivant of phosphide class is distearoyl phosphatidyl choline or two palmityl phosphatidyl glycerols; Derivant in the cholesterol or derivatives thereof is the cholesterol acetonyl ester.
The preparation that the present invention can prepare is: the various local skin preparations such as various external liquid, ointment, cream, gel, patch or liniment that contain imiquimod or derivatives thereof liposome.Above-mentioned preparation can be applied to treat viral infection, cutaneous fungal infection and the wart etc. of skin carcinoma, skin.
The present invention compared with prior art has following advantage: the imiquimod or derivatives thereof lipid physical ability that makes increases the local skin dose, reduces transdermal amount and whole body and absorbs the side effect that brings.Remove the viral infection that can be used for treating skin, as I type and II type herpes-ness progenitalis infection; Wart such as genital wart etc.; Eczema, cutaneous fungal infection outside the multiple sclerosis etc., mainly can be treated skin carcinoma, as melanoma, basal cell carcinoma and other cutaneous tumor diseases.Because it is an interferon inducers, can also treat many other diseases.
Pharmacodynamic experiment research: malignant melanoma (maliganant melanoma) be a kind of pernicious big, development is fast, shift the tumor of wide and poor prognosis.Late case can have regional lymph nodes and visceral metastases.Malignant melanoma is sent out in skin well, and mirror is performance down: oncocyte often starts from corium, epidermis intersection, sends out and soaks into to skin corium to epidermal area simultaneously.With B
16The subcutaneous vaccination of-F melanoma cell is in kunming mice (20 ± 2g, male and female half and half, Sichuan Industrial Institute of Antibiotics provides), and be divided into matched group, emulsifiable paste group, liposome group at random, local skin is smeared imiquimod or derivatives thereof liposome and emulsifiable paste after one week, with mortality rate/death time be evaluation index, PRELIMINARY RESULTS is as follows: 29 days mortality rates: matched group is 74%; The emulsifiable paste group is 70%; The liposome group is 38%.This shows that the melanomatous drug effect utmost point of imiquimod or derivatives thereof liposome therapeutic is better than imiquimod cream (P＜0.001) significantly.
The experiment in vitro result of study shows: 1. see Figure of description 1, imiquimod cream transdermal test in vitro cumulative release percentage rate is higher than imiquimod or derivatives thereof liposome.2. see Figure of description 2, show through the t check: imiquimod cream group and imiquimod liposome group are relatively, its after 30 hours imiquimod percentage composition difference in cortex statistical significance (P＜0.001) is arranged, the lipid physical ability increases the amount of cortex imiquimod greatly.
Below be the drawing explanation of Figure of description of the present invention:
Fig. 1 is a transdermal test in vitro cumulative release percentage rate of the present invention.
Fig. 2 is the percentage composition of the present invention in cortex.
1. 1 kinds of local skins of embodiment imiquimod or derivatives thereof liposome, the special feature of its composition is to get 1. imiquimod or derivatives thereof 100mg in 1000mg, 2. fat contains mutually: (1) phospholipid or derivatives thereof or their mixture 100mg, (2) cholesterol or derivatives thereof or their mixture 0.05mg, 3. can dissolve the imiquimod or derivatives thereof, phospholipid or derivatives thereof or their mixture, cholesterol or derivatives thereof or their mixture can with the acetic acid 210mg of alkali generation neutralization reaction, 4. under agitation add and neutralization reaction to take place and give birth to salifiable alkali with acid: sodium carbonate 250mg, above-mentioned prescription is added water to 1000mg to be prepared, formation pH is 4 emulsion, remove the acetate of generation, be imiquimod or derivatives thereof liposome, add caffolding agent mannitol 10mg again, obtain the lipidosome freeze-dried product of imiquimod or derivatives thereof.
2. 1 kinds of local skin imiquimod liposomees of embodiment, the special feature of its composition is to get 1. imiquimod 5mg in 1000mg, and 2. fat contains mutually: (1) lecithin 130mg, (2) cholesterol 1mg, 3. acetic acid 210mg, 4. under agitation add sodium bicarbonate 239mg, above-mentioned prescription is added water to 1000mg be prepared, formation pH is 6 emulsion, remove the acetate of generation, be the imiquimod liposome, add caffolding agent glucose 20mg again, obtain the lipidosome freeze-dried product of imiquimod.
3. 1 kinds of local skin imiquimod liposomees of embodiment, the special feature of its composition is to get 1. imiquimod 0.5mg in 1000mg, and 2. fat contains mutually: (1) fabaceous lecithin 10mg, (2) cholesterol 5mg, 3. acetic acid 105mg, 4. under agitation add strong aqua ammonia 500mg, above-mentioned prescription is added water to 1000mg be prepared, formation pH is 12 emulsion, remove the acetate of generation, be the imiquimod liposome, add caffolding agent mannitol 10mg again, obtain the lipidosome freeze-dried product of imiquimod.
4. 1 kinds of local skin imiquimod liposomees of embodiment, the special feature of its composition is to get 1. imiquimod 1mg in 1000mg, 2. kephalin 10mg, 3. propanoic acid 210mg 4. under agitation adds sodium phosphate 272mg, above-mentioned prescription is added water to 1000mg to be prepared, formation pH is 8 emulsion, removes the salt of generation, is the imiquimod liposome, add caffolding agent mannitol 20mg again, obtain the lipidosome freeze-dried product of imiquimod.
5. 1 kinds of local skin imiquimod derivative liposomes of embodiment, the special feature of its composition is to get 1. imiquimod derivant 1-butyl-1H-imidazoles [4 in 1000mg, 5-C] quinoline-4-amine 400mg, 2. fat contains mutually: (1) distearoyl phosphatidyl choline 10mg, (2) cholesterol acetonyl ester 0.05mg, 3. formic acid 10mg, 4. under agitation add sodium hydrogen phosphate 10mg, above-mentioned prescription is added water to 1000mg to be prepared, formation pH is 5 emulsion, removes the salt of generation, is the imiquimod derivative liposome, add caffolding agent alginic acid 10mg again, obtain imiquimod derivative liposome dried frozen aquatic products.
6. 1 kinds of local skin imiquimod liposomees of embodiment, the special feature of its composition is to get 1. imiquimod 100mg in 1000mg, 2. fat contains mutually: (1) two palmityl phosphatidyl glycerol 400mg, (2) cholesterol acetonyl ester 0.05mg, 3. propanoic acid 10mg, 4. under agitation add sodium phosphate 50mg, above-mentioned prescription is added water to 1000mg to be prepared, formation pH is 7 emulsion, remove the salt of generation, be the imiquimod liposome, add caffolding agent alginic acid 50mg again, obtain the lipidosome freeze-dried product of imiquimod.
7. 1 kinds of local skin imiquimod derivative liposomes of embodiment, the special feature of its composition is to get 1. imiquimod derivant 1-butyl-1H-imidazoles [4 in 1000mg, 5-C] quinoline-4-amine 10mg, 2. fat contains mutually: (1) kephalin 1mg, (2) cholesterol 100mg, 3. formic acid 400mg, 4. under agitation add sodium hydrogen phosphate 400mg, above-mentioned prescription is added water to 1000mg to be prepared, formation pH is 4 emulsion, removes the salt of generation, is the imiquimod derivative liposome, add caffolding agent glucose 20mg again, obtain imiquimod derivative liposome dried frozen aquatic products.
8. 1 kinds of local skins of embodiment preparation of imiquimod or derivatives thereof liposome, its special feature is: method is routinely prepared the various local skin preparations such as various external liquid, ointment, cream, gel, patch or liniment that contain imiquimod or derivatives thereof liposome.
9. 1 kinds of local skins of embodiment purposes of imiquimod or derivatives thereof liposome and preparation, the patch that will contain imiquimod or derivatives thereof liposome is used for the treatment of viral infection, cutaneous fungal infection and the wart etc. of skin carcinoma, skin.Use contains imiquimod concentration more than 5%, and paste every day one, or follow the doctor's advice, and is affixed on the affected part, pasted altogether 7-28 days.
10. 1 kinds of local skins of embodiment purposes of imiquimod or derivatives thereof liposome and preparation, ointment, cream, the gel that will contain imiquimod or derivatives thereof liposome, remove the viral infection that can be used for treating skin, as I type and II type herpes-ness progenitalis infection; Wart such as genital wart etc.; Eczema, cutaneous fungal infection outside the multiple sclerosis etc., mainly can be treated skin carcinoma, as melanoma, basal cell carcinoma and other cutaneous tumor diseases.Because it is an interferon inducers, can also treat many other diseases.Use contains imiquimod concentration more than 5%, and ointment, cream, gel are applied to the affected part, every day 3 times, or follow the doctor's advice shared 7-28 days.
11. 1 kinds of local skins of embodiment purposes of imiquimod or derivatives thereof liposome and preparation, the disease of using the external liquid, ointment or the cream treatment that contain imiquimod or derivatives thereof liposome is with embodiment 10.Use contains imiquimod concentration at 2.5%-5%, and external liquid faces with before adding water 0.5ml-1ml or using liniment, is applied to the affected part, every day 3 times, or follow the doctor's advice shared 7-28 days.
Claims (7)
1. a local skin is characterized in that getting in 1000mg with imiquimod or derivatives thereof Liposomal formulation:
(1) imiquimod or derivatives thereof 0.1mg-400mg;
(2) fat contains phospholipid or derivatives thereof or their mixture 1mg-400mg, cholesterol or derivatives thereof or their mixture 0mg-100mg mutually;
(3) any that can dissolve imiquimod or derivatives thereof, phospholipid or derivatives thereof or their mixture, cholesterol or derivatives thereof or their mixture can and be given birth to salifiable acid solution 10mg-500mg with alkali generation neutralization reaction;
(4) neutralization reaction can take place and give birth to salifiable alkaline solution 10mg-500mg in any with acid;
Above-mentioned component is added water to 1000mg be prepared, forming pH is the emulsion of 4-12, removes the salt of generation, adds caffolding agent 1-50mg, and lyophilization makes the dried frozen aquatic products of imiquimod or derivatives thereof liposome;
Wherein the derivant in the imiquimod or derivatives thereof is 1-butyl-1H-imidazoles [4,5-C] quinoline-4-amine; Phospholipid is lecithin, fabaceous lecithin, kephalin; The derivant of phosphide class is distearoyl phosphatidyl choline or two palmityl phosphatidyl glycerols; Derivant in the cholesterol or derivatives thereof is the cholesterol acetonyl ester.
2. a kind of local skin according to claim 1 is characterized in that with imiquimod or derivatives thereof Liposomal formulation: described any can with alkali generation neutralization reaction and to give birth to salifiable acid solution be formic acid, acetic acid or propanoic acid.
3. a kind of local skin according to claim 1 imiquimod or derivatives thereof Liposomal formulation is characterized in that: described any can neutralization reaction take place and give birth to salifiable alkaline solution with acid is ammonia, sodium bicarbonate, sodium hydrogen phosphate or sodium phosphate alkaline solution.
4. a kind of local skin according to claim 1 imiquimod or derivatives thereof Liposomal formulation, it is characterized in that: described caffolding agent is mannitol, glucose, alginic acid.
5. a kind of local skin according to claim 1 is characterized in that: be external liquid, ointment, cream, gel, patch or liniment with imiquimod or derivatives thereof Liposomal formulation.
6. a kind of local skin according to claim 1 application of imiquimod or derivatives thereof Liposomal formulation in the medicine of viral infection, cutaneous fungal infection and the wart of preparation treatment skin carcinoma, skin.
7. a kind of local skin according to claim 5 application of imiquimod or derivatives thereof Liposomal formulation in external liquid, ointment, cream, gel, patch and the liniment of viral infection, cutaneous fungal infection and the wart of preparation treatment skin carcinoma, skin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021136475A CN1292751C (en) | 2002-04-23 | 2002-04-23 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB021136475A CN1292751C (en) | 2002-04-23 | 2002-04-23 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
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| CN1377648A CN1377648A (en) | 2002-11-06 |
| CN1292751C true CN1292751C (en) | 2007-01-03 |
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| CNB021136475A Expired - Fee Related CN1292751C (en) | 2002-04-23 | 2002-04-23 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007514644A (en) * | 2003-04-10 | 2007-06-07 | スリーエム イノベイティブ プロパティズ カンパニー | Methods and compositions for improving immune response |
| US20040265351A1 (en) | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
| WO2006122716A1 (en) * | 2005-05-18 | 2006-11-23 | Heidelberg Pharma Gmbh | Use of ether-linked lysophosphatidylcholines and alkylphosphocholines for the treatment of papilloma virus induced warts and sarcoids |
| CN103202803B (en) * | 2012-12-18 | 2015-05-13 | 苏州大学 | Imiquimod vesicle gel and preparation method for same |
| CN107137345A (en) * | 2017-05-25 | 2017-09-08 | 广东药科大学 | A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0376534A1 (en) * | 1988-12-15 | 1990-07-04 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine |
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2002
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0376534A1 (en) * | 1988-12-15 | 1990-07-04 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine |
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