CN1583175A - Skin targeting medicinal composition and its preparation and use - Google Patents
Skin targeting medicinal composition and its preparation and use Download PDFInfo
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- CN1583175A CN1583175A CNA2004100132825A CN200410013282A CN1583175A CN 1583175 A CN1583175 A CN 1583175A CN A2004100132825 A CNA2004100132825 A CN A2004100132825A CN 200410013282 A CN200410013282 A CN 200410013282A CN 1583175 A CN1583175 A CN 1583175A
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Abstract
A composite medicine with skin target for treating pointed condyloma, viral or fungal infection of skin, and eczema is prepared from oil, surfactant, surfactant assistant, osmotic promoter, active medicine and water through proportional mixing, and adding gel matrix.
Description
Invention field
The present invention relates to a kind of microemulsion with skin targeting, micro emulsion gel pharmaceutical composition and its production and use.
Background of invention
Microemulsion is a kind of system of being made up of oil, surfactant, cosurfactant and aqueous favoring, has appearance transparent, Thermodynamically stable, isotropism, dispersed phase drop mean diameter less than characteristics such as 150nm.Microemulsion as a kind of novel drug delivery system have good stability, solvability is strong, viscosity is low, preparation is simple, easily industrialization, etc. advantage.
Local skin such as podophyllotoxin, imiquimod with active medicine skin is had tangible zest such as scratch where it itches in the part, erythema, burning sensation, excitement, tenderness, ulcer, erosion and pain, after the absorption of medicine percutaneous enters blood, can produce serious general toxic and side effects, limit it and in clinical, used.
The present invention is surprised to find, local skins such as podophyllotoxin, imiquimod are made microemulsion with active medicine after, have tangible skin targeting, can increase its absorption in skin, the general that reduces medicine absorbs, and in addition, has also significantly reduced the zest of medicine to skin.In addition, also be surprised to find that, gel-type vehicle such as carbomer, carrageenin, xanthan gum etc. are joined in the microemulsion, can further make micro emulsion gel, on the basis that keeps the above-mentioned advantage of microemulsion, the viscosity of microemulsion is increased, easy to use.In addition, microemulsion or gel can be made dosage forms such as gel, patch.
Summary of the invention
The present invention creatively provides a kind of pharmaceutical composition with skin targeting and its production and use, local skin is wrapped in microemulsion, the micro emulsion gel with active medicine, can reduce zest to medicine skin, improve the hold-up of medicine in skin simultaneously, reduce medicine and enter intravital dose, reduce whole body and absorb the toxic and side effects of bringing, thereby produce the skin targeting.
Technical scheme provided by the invention is: have the pharmaceutical composition of skin targeting, comprising: the oil of 0.5-70wt%, the surfactant of 10-80wt%, 3-60wt% help the water of the local skin of the penetration enhancer of surface activity, 0-8wt% and 0.05-8wt% with active medicine and 0.5-70wt%.
Aforementioned pharmaceutical compositions also can contain the gel-type vehicle of 0-5wt%.
As better scheme of the present invention, above-mentioned local skin active medicine with pharmaceutical composition of skin targeting by 0.15-6wt%, the oil of 2-30wt%, the surfactant of 15-50wt%, the cosurfactant of 5-30wt%, the penetration enhancer of 0-4wt%, the gel-type vehicle of 0-4wt%, the water of 0.5-70wt% is formed.
Above-mentioned local skin comprises podophyllotoxin, imiquimod etc. with active medicine.
The C that above-mentioned oil is preferably liquid
8-C
16Fatty acid and ester thereof (as fatty glyceride, isopropyl fatty acid ester etc.), vegetable oil and glyceride thereof; Isopropyl myristate more preferably, isopropyl palmitate, the coconut oil monooctyl ester, three sad caprins are (as Myritol 318, the Germany Huls AG product Miglyol of company 812), Semen Maydis oil, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, oleic acid, linoleic acid, ethyl oleate, Ethyl linoleate, glycerol trioleate, and Semen Maydis oil, the glyceride of Oleum Arachidis hypogaeae semen or soybean oil, the ethoxylated vegetable oils such as Labrafil M 2125 CS of the transesterification that the Semen Maydis oil of esterification and Polyethylene Glycol reaction obtain, Labrafil M 1944 CS (Cattefoss é company product, France) etc.
That first-selected is Miglyol 812, isopropyl myristate, isopropyl palmitate, Semen Maydis oil glyceride, oleic acid, ethyl oleate, Labrafil M 2125 CS.
Be used for surfactant of the present invention preferably:
(1) reaction natural or hydrogenant Oleum Ricini and oxirane is produced, and comprises polyoxyethylene (40) castor oil hydrogenated, polyoxyethylene (60) castor oil hydrogenated and polyoxyethylene castor oil.At first be polyoxyethylene (40) castor oil hydrogenated.
(2) Sorbitan ethoxylate, as the product of the commodity of known type tween (Tween) by name as polysorbas20, tween 21, polysorbate40, tween 41, polysorbate60, tween 61, polysorbate65, Tween 80, sorbimacrogol oleate100, polysorbate85 etc.First-selected is Tween 80.
(3) polyoxyethylene fatty acid ester.The polyoxyethylene in this series products or the molecular weight of Polyethylene Glycol are 400-6000, and hydrophile-lipophile balance value is 10-25.Preferably stearic acid polyoxyethylene (8) ester, stearic acid polyoxyethylene (12) ester, stearic acid polyoxyethylene (24) ester, stearic acid polyoxyethylene (40) ester, stearic acid polyoxyethylene (50) ester and stearic acid polyoxyethylene (100) ester, stearic acid polyoxyethylene (110) ester.First-selection is the stearic acid polyoxyethylene fatty acid ester of naming with Myrj 53 on market in this series products.
(4) polyoxyethylene aliphatic alcohol ether.This series products is to be 1 by alcohols with mol ratio: 2-30 and oxirane carry out additive reaction and make.Preferably lauryl alcohol polyethylene glycol oxide (23) ether, stearyl alcohol polyoxyethylene (10) ether, spermol polyoxyethylene (10) ether, stearyl alcohol polyoxyethylene (20) ether, oleic alcohol polyoxyethylene (10) ether etc.First-selected is lauryl alcohol polyethylene glycol oxide (23) ether, stearyl alcohol polyoxyethylene (20) ether.
(5) polyoxyethylene-polyoxypropylene copolymer and block copolymer, commodity Poloxamer by name or Pluronic particularly preferably are Poloxamer 188.
(6) lecithin.Preferably soybean lecithin and Ovum Gallus domesticus Flavus lecithin.
(7) two-(2-ethylhexyl) succinate sodium sulfonates.
Selected single surfactant hydrophile-lipophile balance value is at least 10.The comprehensive hydrophile-lipophile balance value of blended surfactant at least also should be 8.
Be suitable for cosurfactant of the present invention ethanol, propylene glycol, isopropyl alcohol, glycerol, n-butyl alcohol, 1.3-butanediol, 1,2-ethohexadiol, sorbitol, triacetyl glycerine etc. are arranged.Ethanol, 1 is preferably arranged, 2-propylene glycol, glycerol, triacetyl glycerine, first-selected is 1, the 2-propylene glycol.
Be suitable among the present invention there being the gel-type vehicle in the micro emulsion gel: (1) carbomer series comprises carbomer 910,934,934P, 940,941,971,974P, 980,981,2020; (2) cellulose derivative is as carboxymethyl cellulose and sodium salt thereof, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose; (3) other is also just like xanthan gum, arabic gum, carrageenin, sodium alginate etc.
Particularly suitable gel-type vehicle is Acritamer 940,934, xanthan gum, carrageenin, arabic gum, sodium alginate.First-selected is Acritamer 940 and xanthan gum.
Be suitable for penetration enhancer of the present invention and comprise alkene terpenoid, fatty acid and ester thereof, azone, oleic acid, ethyl oleate, Mentholum, Camphora, Borneolum Syntheticum, limonene are preferably arranged.Particularly suitable is water solublity azone, Mentholum, Borneolum Syntheticum, limonene, and first-selected is Mentholum.
Drug regimen pH of the present invention is controlled at 5-8, and when exceeding this scope, available pH regulator agent is regulated, and the pH regulator agent comprises sodium hydroxide, triethanolamine, ammonia etc., preferred triethanolamine.
The present invention also further comprises some additives, as antioxidant (fourth hydroxyanisol, fourth hydroxy-methylbenzene, vitamin E, tea polyphenols etc.), antiseptic (ethyl hydroxybenzoate, chlorobutanol etc.), wetting agent (glycerol and propylene glycol).These additives can account for the 0-0.5wt% of microemulsion gross weight.
Pharmaceutical composition with skin targeting provided by the invention comprises the pharmaceutical composition of microemulsion and micro emulsion gel, and its preparation method is:
(1) has the preparation of drug combination of the microemulsion of skin targeting
Local skin is dissolved in the mixed liquor by oil, surfactant, cosurfactant with active medicine, penetration enhancer, forms oil phase, under stirring, in oil phase, add entry, make microemulsion; Perhaps local skin is dissolved in the mixed liquor of oil, surfactant with active medicine, penetration enhancer, makes oil phase, cosurfactant with after water mixes, is added oil phase under stirring condition, make microemulsion; Perhaps oil, surfactant, cosurfactant are mixed, form oil phase, under stirring condition, add entry, after making the microemulsion of medicine carrying not, add local skin again with active medicine and penetration enhancer, be stirred to the microemulsion that obtains after the dissolving fully and be pharmaceutical composition with skin targeting.
(2) has the preparation of drug combination of the micro emulsion gel of skin targeting
With oil, surfactant, cosurfactant, local skin with active medicine, penetration enhancer, water mixed microemulsion (method of pharmaceutical composition that has the microemulsion of skin targeting by above-mentioned preparation), gel-type vehicle is added in the above-mentioned microemulsion that makes, after stirring swelling, obtain micro emulsion gel; Or local skin is dissolved in the mixed liquor by oil, surfactant, cosurfactant with active medicine, penetration enhancer, form oil phase, again water and gel-type vehicle are mixed and made into water-soluble bloated body, will make micro emulsion gel behind oil phase and the water-soluble bloated body mix homogeneously; Or local skin is dissolved in the mixed liquor by oil, surfactant, cosurfactant with active medicine, penetration enhancer, form oil phase, water is divided into two fens in 1: 0.2～5 ratio, a and oil phase is made microemulsion, another divides and gel-type vehicle is mixed and made into water-soluble bloated body, will make the pharmaceutical composition of the micro emulsion gel with skin targeting behind microemulsion and the water-soluble bloated body mix homogeneously.
The preparation that the present invention can prepare is: the micro emulsion gel with active medicine of skin targeting can directly be used as gel, simultaneously various local skin preparations such as microemulsion and the various external liquid of micro emulsion gel, ointment, patch, cream.Above-mentioned preparation can be used for the treatment of viral infection, the fungal infection of condyloma acuminatum, skin.Treatment especially for condyloma acuminatum.
The present invention is owing to adopted microemulsion and micro emulsion gel, compare with prior art (tincture and emulsifiable paste) and to demonstrate following superiority: the first, active medicine strengthens drug effect in the absorption of epidermis, the general that significantly reduces medicine absorbs the toxic and side effects of bringing, and has tangible skin targeting.Can be used for treating the viral infection of skin, as herpes-ness progenitalis infection; Can treat eczema, cutaneous fungal infection etc. effectively.The second, because the O/W structure of non-irritating adjuvant and microemulsion makes active medicine directly not contact skin in large quantities, avoided the serious zest of active medicine to skin.Can obviously reduce local due to the active medicine slightly to the inflammatory reaction of moderate, as burn, scratch where it itches, pain, erosion etc.The 3rd, micro emulsion gel provides higher stickiness, has also kept skin targeting preferably simultaneously, is convenient to dosed administration and as the basis of various dosage forms.
With by way of example the microemulsion that has the skin targeting among the present invention and the pharmaceutical composition of micro emulsion gel are described below.
Embodiment 1
Pharmaceutical composition with podophyllotoxin microemulsion of skin targeting
With the 3g isopropyl palmitate, 40g polyoxyethylene (40) castor oil hydrogenated, the 20g mixed with propylene glycol behind the formation mixed solution, makes podophyllotoxin 0.5g and Camphora 2g be dissolved in this mixed solution, makes oil phase.Under stirring condition, slowly distilled water is added in the oil phase, make total amount reach 100g, obtain clear microemulsion after stirring and be pharmaceutical composition with skin targeting.Measure its effective grain size during with 25 ℃ of laser particle analyzers (Nano ZS90 type, Britain Ma Erwen company), effective grain size is 70.81nm.
Embodiment 2
Pharmaceutical composition with podophyllotoxin micro emulsion gel of skin targeting
With the 3g isopropyl myristate, the 30g Tween 80, the 30g mixed with propylene glycol behind the formation mixed solution, makes 0.5g podophyllotoxin and 2g Mentholum be dissolved in this mixed solution, makes oil phase.Get the 0.375g Acritamer 940 and mix with water, add the 0.5g triethanolamine after the swelling, mix with oil phase the back that stirs, and is stirred to make complete evenly, obtains having the pharmaceutical composition of the podophyllotoxin micro emulsion gel of skin targeting.With laser particle analyzer measure 1ml water and 0.05mg micro emulsion gel 25 ℃ the time and the diluent deposited in particle grain size distribution, the largest particles is less than 150nm.
Embodiment 3
Pharmaceutical composition with podophyllotoxin microemulsion of skin targeting
With 5g MCT (Miglyol 812), the 30g tween, 5g Poloxamer 188, the 30g propylene glycol, 15g ethanol mixes, and behind the formation mixed solution, adds 0.5g podophyllotoxin and 3g Camphora, after the stirring and dissolving, makes oil phase.Under stirring condition distilled water is slowly added in the oil phase, make total amount reach 100g, after stirring, the microemulsion that obtains transparent homogeneous is the pharmaceutical composition with skin targeting.The particle diameter that laser particle analyzer records this microemulsion is 83.08nm.
Embodiment 4
Pharmaceutical composition with podophyllotoxin micro emulsion gel of skin targeting
With 6g MCT (Miglyol 812), the 35g tween, the 20g propylene glycol, the 10g isopropyl alcohol mixes, and behind the formation mixed solution, adds podophyllotoxin 0.15g and limonene 2g, after the stirring and dissolving, makes oil phase.Get xanthan gum 2.0g, add in the suitable quantity of water, mix with oil phase after forming uniform hydrogel matrix, making total amount after stirring is the podophyllotoxin micro emulsion gel with skin targeting of 100g, is the pharmaceutical composition with skin targeting.Measure the effective grain size of 20 times of water diluents of 0.07g micro emulsion gel, effective grain size is 93.85nm.
Embodiment 5
Pharmaceutical composition with podophyllotoxin microemulsion of skin targeting
Get 10g oleic acid, 30g stearic acid polyoxyethylene (50) ester, 5g two-(2-ethylhexyl) succinate sodium sulfonate, 35g propylene glycol, 5g n-butyl alcohol add 0.15g podophyllotoxin and 5g Borneolum Syntheticum after mixing the formation mixed solvent again, make oil phase after the dissolving.Under stirring condition, distilled water is slowly added in the oil phase, make total amount reach 100g, make the microemulsion of homogeneous transparent after stirring, be pharmaceutical composition with skin targeting.
Embodiment 6
Pharmaceutical composition with podophyllotoxin micro emulsion gel of skin targeting
Get 2g isopropyl myristate, 1g Labrafil M 2125 CS, the 40g Tween 80, the 15g propylene glycol, mixing adds podophyllotoxin 0.15g, Borneolum Syntheticum 2g and 2g Mentholum after forming mixed solvent again, makes oil phase after the dissolving.Under stirring condition, slowly add entry 17.85g, make uniform microemulsion after stirring, add 1.0g carbomer 934 and 1g triethanolamine again, make the podophyllotoxin micro emulsion gel after stirring, be pharmaceutical composition with skin targeting.
Embodiment 7
Pharmaceutical composition with podophyllotoxin microemulsion of skin targeting
Get 6g oleic acid, the 2g glycerol trioleate, the 10g soybean lecithin, the 30g Tween 80, the 15g propylene glycol, 10g ethanol is made mixed solvent behind the mix homogeneously, add podophyllotoxin 1.0g, makes oil phase after the stirring and dissolving.Slowly water adds in the oil phase under stirring condition, makes microemulsion after stirring, and is the pharmaceutical composition with skin targeting.
Embodiment 8
Pharmaceutical composition with podophyllotoxin micro emulsion gel of skin targeting
Get ethyl oleate 10g, the Tween 80 of 30g, propylene glycol 30g, glycerol 15g mixes the back and forms mixed solvent, adds podophyllotoxin 0.5g again, makes oil phase after the dissolving.Under stirring condition, in oil phase, slowly add distilled water 13g.Add carrageenin 1.5g, make the podophyllotoxin micro emulsion gel that total amount is 100g after being stirred to evenly, be pharmaceutical composition with skin targeting.
Embodiment 9
Get Semen Maydis oil glyceride 40g, 30g polyoxyethylene hydrogenated Oleum Ricini 40, propylene glycol 10g, triacetyl glycerine 5g makes mixed solution after the mixing, add imiquimod 8g, make oil phase after the dissolving, add distilled water, make total amount reach 100g in stirring condition, get the microemulsion of transparent and homogeneous after stirring, be pharmaceutical composition with skin targeting.
Embodiment 10
Get the microemulsion 50g of embodiment 9, add arabic gum 1.75g, make the micro emulsion gel of podophyllotoxin after stirring, be pharmaceutical composition with skin targeting.
Embodiment 11
Study on the stability
Adopt the method that keeps sample for a long time to observe.Get tetradecylic acid glyceride 2g, the 35g Tween 80, the 25g propylene glycol is made and is added podophyllotoxin 0.5g and Mentholum behind the mixed solution, and the dissolving back forms oil phase.In oil phase, slowly add distilled water, make total amount reach 100g, promptly get the podophyllotoxin microemulsion after stirring, be pharmaceutical composition with skin targeting.Get an amount of podophyllotoxin microemulsion, be sealed in the test tube, place under the room temperature and to preserve 12 months, the content of routine observation sample, outward appearance, character and phenomenons such as layering, flocculation whether occur.
At room temperature, layering, flocculation phenomenon did not appear in the podophyllotoxin microemulsion in 12 months, and content, particle diameter outward appearance all do not have obvious change.
Embodiment 12
Study on the stability
Adopt the method that keeps sample for a long time to observe.Get isopropyl palmitate 10g, the Tween 80 of 30g, 10g stearyl alcohol polyoxyethylene (20) ether.Propylene glycol 15g, mixing adds podophyllotoxin 0.15g and Borneolum Syntheticum 3g after forming mixed solvent again, makes oil phase after the dissolving.Under stirring condition, slowly add entry 17.85g, make uniform microemulsion after stirring, add 1.0g carbomer 934 and 1g triethanolamine again, make the podophyllotoxin micro emulsion gel after stirring, be pharmaceutical composition with skin targeting.Get an amount of podophyllotoxin micro emulsion gel, be sealed in the test tube, place under the room temperature and to preserve 12 months, the content of routine observation sample, outward appearance, character and phenomenons such as layering, flocculation whether occur.
At room temperature, layering, flocculation phenomenon did not appear in the podophyllotoxin microemulsion in 12 months, and content, particle diameter outward appearance all do not have obvious change.
Podophyllotoxin in the described any compositions of embodiment 1-12 can replace with another kind of medicine imiquimod.Mode with embodiment is illustrated below.
Embodiment 13-18
The imiquimod microemulsion and the micro emulsion gel pharmaceutical composition that all can be had the skin targeting by the preparation method of described microemulsion of embodiment 1-10 and micro emulsion gel uniformly.The maximum particle diameter of 20 times of diluents of embodiment 13 and 17 prepared micro emulsion gels is 150nm, and embodiment 14,15,16,18 prepared microemulsion effective grain sizes are all less than 100nm.
Embodiment 17,18 has been carried out the long-time stability investigation, layering, flocculation phenomenon did not occur in 12 months, content, particle diameter outward appearance all do not have obvious change.
Embodiment 19
Skin is detained experimentation
To embodiment 11,12,15,17 gained have the podophyllotoxin of skin targeting and the microemulsion and the micro emulsion gel pharmaceutical composition of imiquimod carries out the investigation of skin targeting.
With body weight is the depilation of 15 ± 0.5kg children pig abdominal part, and the air tap inserting method takes off skin of abdomen after putting to death, and removes subcutaneous fat, cleans skin with distilled water.The reuse normal saline cleans skin, and is standby after blotting with filter paper.Tried thing and be respectively podophyllotoxin microemulsion medicinal composition (being called for short podophyllotoxin microemulsion group), podophyllotoxin micro emulsion gel pharmaceutical composition (being called for short podophyllotoxin micro emulsion gel group), imiquimod microemulsion medicinal composition (being called for short imiquimod microemulsion group), imiquimod micro emulsion gel pharmaceutical composition (being called for short imiquimod micro emulsion gel group), commercially available podophyllotoxin tincture, commercially available imiquimod cream with skin targeting.Adopt improvement Franz diffusion cell to carry out the transdermal test, diffusion cell is incubated with a constant temperature (37 ℃) cyclic water jacket, and skin is fixed between supply chamber and the reception tank, and skin surface is towards supply chamber, and effectively infiltrating area S is 2.8cm
2, the reception tank volume is 7.0ml, reception liquid is normal saline, and the thing that tried of 1.0g is evenly coated skin surface in the supply chamber, opens magnetic stirrer and stirs with the speed of 300r/min.In 1,2,4,6,8,24 h take out to receive liquid 0.5ml (all adding the normal saline of equivalent after each sampling), the sample of obtaining are carried out centrifugal, get supernatant, measure the content of podophyllotoxin and imiquimod.And unit of account area accumulation releasing medicine through skin penetration amount Q, medicine is as shown in table 1 in the accumulation transdermal amount of each time point.After transdermal experiment finishes, take off skin, behind the residue on flush away skin two sides, from skin, extract medicine, get the skin hold-up of respectively being tried thing, as shown in table 2.
Table 1 shows that the present invention has the accumulation transdermal amount of the podophyllotoxin pharmaceutical composition of skin targeting and imiquimod pharmaceutical composition significantly less than commercially available podophyllotoxin tincture and imiquimod cream (P＜0.001), during pro-8h, microemulsion and micro emulsion gel group be transdermal not all, and only when 24h, there is small amount of drug to see through, and tincture and ointment percutaneous rate are fast, and the transdermal amount is big.Simultaneously as known from Table 2, pharmaceutical composition of the present invention can improve the hold-up of medicine in skin greatly, far above tincture and ointment.This demonstrates microemulsion of the present invention and the micro emulsion gel pharmaceutical composition has the good skin targeting.
Accumulation Transdermal absorption transdermal amount (the μ g/cm of the microemulsion of table 1 podophyllotoxin of the present invention, imiquimod and micro emulsion gel pharmaceutical composition
2)
Group 1h 2h 4h 6h 8h 24h
Podophyllotoxin microemulsion group 00000 0.067
Podophyllotoxin micro emulsion gel group 00000 0.035
Commercially available podophyllotoxin 0 0.2 0.33 0.43 0.625 1.05
Imiquimod microemulsion group 00000 0.05
Imiquimod micro emulsion gel 00000 0.045
Commercially available imiquimod cream 0 0.35 0.62 1.02 1.32 1.86
Table 2 is respectively tried the hold-up of thing in skin when 24h
Tried the hold-up (μ g) of thing medicine in skin
Podophyllotoxin microemulsion group 6.7
Podophyllotoxin micro emulsion gel group 6.8
Podophyllotoxin tincture 1.2
Imiquimod microemulsion group 10.5
Imiquimod micro emulsion gel group 12.3
Imiquimod cream 2.4
Embodiment 20
The microemulsion of podophyllotoxin of the present invention, imiquimod, micro emulsion gel pharmaceutical composition skin irritation Journal of Sex Research.
To embodiment 11,12, the microemulsion of 15,17 gained podophyllotoxins and imiquimod and micro emulsion gel pharmaceutical composition carry out the rabbit skin irritation and investigate.
Family's rabbit back spinal column both sides depilation (the depilation area is about body surface area 10%), divide single administration or multiple dosing (successive administration) all two kinds of methods, every kind of method is divided two groups of intact skin group and damaged skin groups again, every group of 3 rabbit, every rabbit skin of back Fen Si district: clear area, podophyllotoxin microemulsion (pharmaceutical composition of the present invention) district, podophyllotoxin micro emulsion gel (pharmaceutical composition of the present invention) district, imiquimod microemulsion (pharmaceutical composition of the present invention) district, imiquimod micro emulsion gel (pharmaceutical composition of the present invention) district, podophyllotoxin tincture (commercially available prod) district, imiquimod cream (commercially available prod) district.To respectively be tried thing respectively and be applied to respective regions respectively.Remove the residual thing that tried with warm water after 24 hours, observe to remove and tried behind the thing to smear the position in 1,24,48 and 72 hour and have or not situations such as erythema and edema, and the recovery situation of above-mentioned variation and time.Type according to skin irritation reaction mark (erythema: 0: no erythema, 1: reluctantly visible erythema, 2: moderate erythema, 3: serious erythema, 4: the aubergine erythema also has the eschar generation; Edema: 0: nothing is red and swollen, and 1: visible reluctantly red and swollen, 2: slightly as seen, and 3: the about 1cm of cutaneous protuberance, profile is clear, and 4: the above and expanded range of the about 1cm of edema protuberance).Calculate stimulus intensity according to mean scores, if mean scores less than 0.4, is nonirritant; 0.5～1.9 is slight zest; 2.0～5.9 is the moderate zest; 6.0～8.0 is strong and stimulating.
The microemulsion of table 3 podophyllotoxin and imiquimod, micro emulsion gel are to the zest of rabbit skin
Intact skin damaged skin intact skin damaged skin
Group
Single administration single administration multiple dosing multiple dosing
Podophyllotoxin microemulsion group 0.120 ± 0.110
*0.132 ± 0.385
*0.232 ± 0.115
*0.229 ± 0.138
*
Podophyllotoxin micro emulsion gel group 0.126 ± 0.103
*0.111 ± 0.192
*0.556 ± 0.121
*0.285 ± 0.101
*
Imiquimod microemulsion group 0.110 ± 0.099
*0.131 ± 0.112
*0.236 ± 0.105
*0.241 ± 0.128
*
Imiquimod micro emulsion gel group 0.135 ± 0.120
*0.142 ± 0.152
*0.254 ± 0.141
*0.217 ± 0.154
*
Commercially available podophyllotoxin tincture 0.652 ± 0.211 0.854 ± 0.274 0.798 ± 0.185 1.865 ± 0.241
Commercially available imiquimod cream 0.684 ± 0.225 0.955 ± 0.251 0.753 ± 0.208 1.745 ± 0.201
The result is as shown in table 3, and the podophyllotoxin among the present invention and the microemulsion of imiquimod, micro emulsion gel pharmaceutical composition are to the skin nonirritant, and podophyllotoxin tincture and imiquimod cream are obvious to the zest of skin.This shows, microemulsion of the present invention, the safety of micro emulsion gel pharmaceutical composition obviously be better than going on the market preparation (with blank relatively: * P＜0.01).
Embodiment 21
The microemulsion of podophyllotoxin of the present invention, imiquimod, the skin-tolerant research of micro emulsion gel pharmaceutical composition and observe because of general absorbs the toxicity that produces.
To embodiment 11,12, the microemulsion of 15,17 gained podophyllotoxins and imiquimod and micro emulsion gel pharmaceutical composition carry out the investigation of rabbit skin-tolerant and observe because of general absorbs the toxic reaction that produces.
Observe the rabbit intact skin of growing up and contact the microemulsion of commercially available podophyllotoxin tincture, commercially available imiquimod cream agent, podophyllotoxin and imiquimod and the general toxic reaction that the micro emulsion gel pharmaceutical composition is produced in a short time with damaged skin.Each given the test agent is with the dosed administration of 5g sample/kg rabbit.Behind commercially available podophyllotoxin tincture, the commercially available imiquimod cream administration 24h, animal has produced serious skin irritation such as erythema, erosion etc., and systemic toxic reactions such as vomiting, diarrhoea have appearred in animal simultaneously.And behind the microemulsion of podophyllotoxin and imiquimod and the micro emulsion gel pharmaceutical composition administration 24h, rabbit does not have the phenomena of mortality, no significant changes such as the weight of animals, skin, hair, eyes, mucosa, circulation, extremity activity, animal do not have general toxic reactions such as vomiting, diarrhoea, thrombocytopenia, peripheral nervous paralysis.This shows, the safety of the microemulsion of podophyllotoxin of the present invention and imiquimod, micro emulsion gel pharmaceutical composition is better, can tolerate higher drug dose, does not have tangible dermal toxicity, nothing has tangible skin targeting because of systematicness absorbs the toxicity that produces.
Embodiment 22
Microemulsion and its special feature of micro emulsion gel pharmaceutical composition that the present invention has the skin targeting be, can make podophyllotoxin and imiquimod microemulsion, the various external liquid of micro emulsion gel pharmaceutical composition, gel, patch, cream, spray, solution, ointment according to the method for routine.During with the above various preparation for treating condyloma acuminatum of podophyllotoxin, the content of podophyllotoxin is 0.15-0.5%, medication every day 2 times, and 3 days is a course of treatment.During the above various preparation for treating condyloma acuminatum of imiquimod, its medicament contg is 2-5%, once a day, on every Wendesdays time, uses 6-8 week altogether.
Above-mentioned pharmaceutical composition and preparation thereof with skin targeting can replace with the active medicine that other local skin is used, and can obtain similar skin targeting effect.
Claims (10)
1, have the pharmaceutical composition of skin targeting, comprising: the penetration enhancer of the oil of 0.5-70wt%, the surfactant of 10-80wt%, 3-60wt% cosurfactant, 0-8wt% and the local skin of 0.05-8wt% are with the water of active medicine and 0.5-70wt%.
2, the pharmaceutical composition with skin targeting according to claim 1 is characterized in that: the gel-type vehicle that contains 0-5wt%.
3, the pharmaceutical composition with skin targeting according to claim 1 and 2 is characterized in that: oil is liquid C
8-C
16The mixture of one or more of the ethoxylated vegetable oils of the transesterification that the Semen Maydis oil of fatty acid and ester thereof, vegetable oil and glyceride thereof, esterification and Polyethylene Glycol reaction obtain.
4, the pharmaceutical composition with skin targeting according to claim 1 and 2 is characterized in that: surfactant is polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated Oleum Ricini, lecithin, polyoxyethylene aliphatic alcohol ether, polyoxyethylene-polyoxypropylene copolymer and block copolymer, two-(2-ethylhexyl) succinate sodium sulfonate; Cosurfactant is one or more the mixture in ethanol, propylene glycol, isopropyl alcohol, glycerol, n-butyl alcohol, the triacetyl glycerine.
5, the pharmaceutical composition with skin targeting according to claim 1 and 2 is characterized in that: described gel-type vehicle is one or more the mixture in carbomer, cellulose derivative, xanthan gum, arabic gum, carrageenin or the sodium alginate.
6, in the compositions with skin targeting according to claim 1 and 2, it is characterized in that: the local skin active medicine is podophyllotoxin or imiquimod.
7, the compositions with skin targeting according to claim 1 and 2 is characterized in that: penetration enhancer is one or more the mixture in azone, Mentholum, Borneolum Syntheticum, Camphora, the limonene.
8, the described preparation of drug combination method of claim 1 with skin targeting, it is characterized in that: oil, surfactant, cosurfactant are mixed obtaining mixed liquor, then local skin is dissolved in the mixed liquor with active medicine, penetration enhancer, form oil phase, under stirring, in oil phase, add entry, make pharmaceutical composition; Perhaps oil, surfactant are mixed and obtain mixed liquor, then local skin is dissolved in the mixed liquor of oil, surfactant with active medicine, penetration enhancer, makes oil phase, with cosurfactant with after water mixes, under stirring condition, add oil phase, make pharmaceutical composition; Perhaps oil, surfactant, cosurfactant are mixed, form oil phase, under stirring condition, add entry, make the microemulsion of medicine carrying not after, add local skin again with active medicine and penetration enhancer, be stirred to dissolving fully, make pharmaceutical composition; Above-mentioned oil, surfactant, cosurfactant, local skin are determined with the ratio of the water of active medicine and 0.5-70wt% in surfactant, 3-60wt% cosurfactant, the penetration enhancer of 0-8wt%, the local skin of 0.05-8wt% that the pharmaceutical composition that makes contains oil, the 10-80wt% of 0.5-70wt% with the addition of active medicine, penetration enhancer, water.
9, the described preparation of drug combination method of claim 2 with skin targeting, it is characterized in that: with oil, surfactant, cosurfactant, local skin active medicine, penetration enhancer, the mixed microemulsion that gets of water, gel-type vehicle is added in the microemulsion, after stirring swelling, obtain having the pharmaceutical composition of skin targeting; Perhaps oil, surfactant, cosurfactant are mixed and obtain mixed liquor, local skin is dissolved in the mixed liquor with active medicine, penetration enhancer, form oil phase, again water and gel-type vehicle are mixed and made into water-soluble bloated body, will make pharmaceutical composition behind oil phase and the water-soluble bloated body mix homogeneously with skin targeting; Perhaps be dissolved in local skin in the mixed liquor of making by oil, surfactant, cosurfactant with active medicine, penetration enhancer, form oil phase, in addition water is divided into two fens in 1: 0.2～5 ratio, make microemulsion behind a adding oil phase, another divides and gel-type vehicle is mixed and made into water-soluble bloated body, will make the pharmaceutical composition with skin targeting behind microemulsion and the water-soluble bloated body mix homogeneously; Above-mentioned oil, surfactant, cosurfactant, local skin contain the local skin of penetration enhancer, the 0.05-8wt% of surfactant, 3-60wt% cosurfactant, the 0-8wt% of oil, the 10-80wt% of 0.5-70wt% and determine with the ratio of the water of the gel-type vehicle of active medicine, 0-5wt% and 0.5-70wt% in the pharmaceutical composition that makes with the addition of active medicine, penetration enhancer, gel-type vehicle, water.
10, claim 1 or 2 described pharmaceutical compositions with skin targeting, the application in external liquid, gel, patch, cream, spray, solution or the ointment of preparation percutaneous drug delivery.
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| CNB2004100132825A CN1286529C (en) | 2004-06-11 | 2004-06-11 | Skin targeting medicinal composition and its preparation and use |
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| CN100450484C (en) * | 2006-10-11 | 2009-01-14 | 北京科信必成医药科技发展有限公司 | Imiquimod turbid liquor and gelling agent thereof |
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