The invention relates to a transdermal medication preparation of artemether, which comprises artemether as the main drug, transdermal absorption enhancer or percutaneous absorption carrier and other pharmaceutical adjuvants. Antimalarial artemether can be used as a new immunomodulator and can be used for treating certain skin disease as studies show. The artemether of the transdermal medication preparation can directly act on skin surface of patients and enter dermis layer and subcutaneous tissue through penetrating through epidermis. The transdermal medication preparation of artemether can greatly increase dosage of artemether in skin of patients to increase therapeutic effect at lower dosage compared with other administration mode of artemether. The transdermal medication preparation of artemether has the advantages of convenient administration, strong targeting, no skin irritation and simple preparation. The transdermal medication preparation of artemether can be used for treating skin diseases such as polymorphous light eruption, vegetable-solar dermatitis, atopic dermatitis and eczema.
Treat dermopathic artemether percutaneous drug administration preparation
Technical field
The present invention relates to field of pharmaceutical technology, specifically treat the artemether percutaneous drug administration preparation of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
Background technology
Arteannuin be China pharmacy worker 1971 from feverfew Hemerocallis citrina Baroni mugwort extraction separation to a kind of sesquiterpene lactones compounds with peroxide bridge.On this basis, the independent research of China the world of medicine arteannuin series derivatives medicine such as dihydroarteannuin, Artemether and artesunate.That arteannuin medicine has is efficient, quick-acting, the antimalarial active of low toxicity, and particularly the curative effect to cerebral malaria and anti-chloroquine subtertian malaria is particularly outstanding, is called " maximum of treatment malaria is wished " by World Health Organization (WHO).
In recent years, pharmacological research finds that arteannuin medicine also has immunoregulation effect, can exert an influence to langerhans' cells.Skin and subcutaneous langerhans' cells have picked-up, process, handle antigenic effect, startup person as specific immunity, it is playing the part of very important role in immunologic process, and arteannuin medicine can suppress the activity of langerhans' cells, reaches the excessive immunoreactive effect of blocking-up skin.In addition, arteannuin medicine also can suppress fibroblasts proliferation, and reduces extracellular collagen synthetic quantity, makes cicatrix obviously soften, flatten, thereby brings into play anti-cicatrix effect.Therefore, artemisinin-based drug is expected to increase new indication, promptly is applied to some skin class treatment of diseases.
The existing report of relevant clinical research, Deng Danqi etc. are by oral Artemether capsule for treating polymorphous light eruption (32 examples, effective percentage 84.4%) and farmersskin (63 examples, effective percentage 85.7%), compare with positive control drug hydroxychloroquine sulfate sheet, the curative effect there was no significant difference, and do not find side effect.Further experimentation also confirms, Artemether to ultraviolet radiation after impaired immortalization keratinocyte strain-HaCaT cell have the certain protection effect.
Summary of the invention
The purpose of this invention is to provide a kind of illing skin surface that directly acts on, and can see through the dermopathic artemether percutaneous drug administration preparation of treatment that epidermis enters skin corium and subcutaneous tissue, raising curative effect.
The present invention selects fat-soluble strong (easily transdermal) in the artemisinin derivative and has the Artemether on certain clinical practice basis, is made into percutaneous drug administration preparation.
Artemether percutaneous drug administration preparation of the present invention is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1~20%.
The percentage by weight preferable range of Artemether is 0.2~10% in the preparation.
Artemether percutaneous drug administration preparation of the present invention comprises can be for the various exterior-applied formulations of clinical use, as: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment etc.
Used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the artemether percutaneous drug administration preparation of the present invention, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more.
Used Transdermal absorption carrier comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle in the artemether percutaneous drug administration preparation of the present invention.
Artemether percutaneous drug administration preparation of the present invention can add other pharmaceutic adjuvants according to the needs of preparation, as: excipient, antiseptic etc.
Artemether percutaneous drug administration preparation of the present invention can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
Artemether percutaneous drug administration preparation related experiment of the present invention and result are as follows:
1, different Percutaneous absorption enhancers are to the influence of artemether percutaneous infiltration
Adopt improvement Franz diffusion cell method to carry out the transdermal test in vitro test.The rat abdomen skin of handling well is fixed in the seam of diffusion cell, and effectively diffusion area is 2.8cm 2, accept pool volume 7.0mL, 30% ethanol is acceptable solution, the magnetic agitation rotating speed of transdermal diffusion test instrument is 200rmin -1, bath temperature is 32 ± 0.2 ℃.In supply pool, add Artemether SDS (1% sodium lauryl sulphate) saturated solution that 2.0mL contains different penetration enhancer (0.5%).Respectively at 1,2,4,6,8,10,12 and the 24h 0.2mL that from accept the pond, takes a sample, add the isothermal equal-volume simultaneously and accept medium.Sample is measured content with the HPLC method, calculates accumulative total transit dose (Q), with Q to time of penetration (t) map accompanying drawing 1, the two carries out linear regression gained slope and is infiltration rate constant (Js), 24h accumulative total transit dose is Qr.During 24h, take off skin, dip in cotton swab and get 30% ethanol and wipe skin surfaces externally and internally left drug, shred, the reuse dehydrated alcohol extraction is measured wherein medicament contg, 24h skin hold-up (Qs).With Artemether SDS saturated solution (former medicine) is contrast, different Percutaneous absorption enhancers the results are shown in Table 1 to the influence of artemether percutaneous infiltration, show that these several penetration enhancer commonly used can increase transdermal penetration speed, transit dose and the skin hold-up of Artemether to some extent.
The transdermal penetration characteristic (n=5) of the different Percutaneous absorption enhancer groups of table 1
2, different Transdermal absorption carriers are to the influence of artemether percutaneous infiltration
The transdermal test in vitro test method is the same, the various Transdermal absorption carriers that add Artemether in the supply pool respectively, Artemether SDS saturated solution (former medicine) is contrast, the results are shown in accompanying drawing 2 and table 2, show that Transdermal absorption carriers such as microemulsion, ethosome also can make transdermal penetration speed, transit dose and the skin hold-up of Artemether significantly improve.
The transdermal penetration characteristic (n=5) of the different Transdermal absorption vehicle group of table 2
3, rabbit skin irritation test
Get 12 of healthy male rabbits, body weight 2.0~2.5kg is divided into 6 groups at random, is respectively Artemether SDS solution group, Artemether liposome group, Artemether carrier group, Artemether ethosome group, Artemether microemulsion group and Artemether solid lipid nanoparticle group.24h before the test cuts short the back with tame rabbit back spinal column diamond wool and sloughs with 10% sodium sulfide, and every side depilation area is about 50cm 2Be coated with pastille substrate not respectively at left side skin and make blank, the right side is coated with the equivalent pastille for test preparation, covers with two-layer gauze then, and overlaps with the self-control rabbit and to fix.Behind the administration 24h, dismantle and remove on the skin behind the residue, observe medicine-feeding part and erythema and edema situation occur, press table 3, the standard in 4 is estimated administration every day 1 time, continuous 7
D the results are shown in Table 5, and showing for the examination artemether percutaneous drug administration preparation does not have tangible skin irritation.
Table 3 skin irritation reaction standards of grading
Table 4 skin irritation strength grading
Table 5 rabbit skin irritation test
Artemether can directly act on the illing skin surface after the artemether percutaneous drug administration preparation administration of the present invention, and can enter skin corium and subcutaneous tissue through epidermis, compare with the existing route of administration of Artemether (oral with inject), can increase the dose of Artemether in illing skin (target site) greatly, to improve curative effect, reduce dosage.
Description of drawings
Fig. 1 is the transdermal penetration curve of different Percutaneous absorption enhancer groups of the present invention.
Fig. 2 is the transdermal penetration curve of different Transdermal absorption vehicle group of the present invention.
The specific embodiment
Embodiment 1
Prescription:
Artemether 10g 75% ethanol adds to 100mL
Method for making: get Artemether with 75% dissolve with ethanol and standardize solution, promptly get the Artemether liniment that is used for percutaneous dosing, wherein alcoholic solution be solvent also be that disinfectant also has transdermal enhancing effect simultaneously.
Embodiment 2
Prescription:
Artemether 20g zinc oxide 20g
Borneolum Syntheticum 2g Pulvis Talci adds to 100g
Method for making: get Artemether, zinc oxide, Mentholum and Pulvis Talci fine powder (crossing 100 mesh sieves), adopt the equivalent incremental method fully to mix, promptly get the Artemether powder that is used for percutaneous dosing.
Embodiment 3
Prescription:
Artemether 1g polyvinyl alcohol-124 30g
Mentholum 10g ethanol 500mL
Glycerol 100mL purified water adds to 1000mL
Method for making: get polyvinyl alcohol-124 add fully expand in the G ﹠ W after, heating makes dissolving fully; Other gets Artemether and Mentholum dissolve with ethanol, and under agitation slowly adds in polyvinyl alcohol-124 solution, adds water to full dose again, stirs evenly back packing rapidly, and is airtight, promptly gets the Artemether liniment that is used for percutaneous dosing.
Embodiment 4
Prescription:
Artemether 50g tristerin 70g
Stearic acid 100g white vaseline 120g
Liquid Paraffin 100g glycerol 120g
Sodium lauryl sulphate 10g ethyl hydroxybenzoate 1g
Purified water 480mL
Method for making: getting tristerin, stearic acid, white vaseline and liquid Paraffin heat fused is oil phase; In addition glycerol and water are heated to 90 ℃, add sodium lauryl sulphate again and ethyl hydroxybenzoate is dissolved as water; Then water is slowly poured in the oil phase, the limit edged stirs, until condensation; At last Artemether fine powder (crossing 100 mesh sieves) is added in the above-mentioned substrate, stir, promptly get the Artemether ointment that is used for percutaneous dosing.
Embodiment 5
Prescription:
Artemether 2g polyacrylic resin Eudragit E 10030g
Succinic acid 2g dibutyl sebacate 10g
Isopropyl myristate 6g
Method for making: get medicine and adjuvant in the prescription,, evenly coat mixed liquor on the back lining materials with proper amount of acetone-ethanol (2: 1) dissolving, naturally volatilize solvent, in 60 ℃ of baking ovens, solidify 10min, adhesive on the cooling bonnet, section promptly gets the Artemether paster that is used for percutaneous dosing.
Prescription:
Artemether 5g lecithin 20g
Cholesterol 5g purified water 500mL
Method for making: get Artemether, lecithin, an amount of ether dissolution of cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether add entry again, and 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether liposome that is used for percutaneous dosing.
Embodiment 7
Prescription:
Artemether 5g lecithin 14g
Sodium deoxycholate 4g purified water 500mL
Method for making: get Artemether, lecithin, an amount of ether dissolution of sodium deoxycholate, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether carrier that is used for percutaneous dosing.
Embodiment 8
Prescription:
Artemether 5g lecithin 15g
Ethanol 200mL purified water 300mL
Method for making: get Artemether, lecithin is dissolved in the ethanol, and this ethanol liquid is under agitation slowly splashed in the water, drip off the back and continue to stir 10min, the ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether ethosome that is used for percutaneous dosing.
Embodiment 9
Prescription:
Artemether 16g oleic acid 25g
Tween 80 90g ethanol 135g
Purified water 250mL
Method for making: get Artemether, oleic acid, tween 80 and ethanol, fully mixing splashes into water under stirring, and promptly gets the Artemether microemulsion that is used for percutaneous dosing.
Embodiment 10
Prescription:
Artemether 5g stearic acid 10g
Soybean phospholipid 11g purified water 500mL
Method for making: get Artemether, stearic acid, soybean phospholipid, in 70 ℃ of water-baths, get organic facies with an amount of anhydrous alcohol solution; Water intaking is heated to uniform temp as water in addition, and organic facies is injected aqueous phase, and 80 ℃ are stirred 2h, form colostrum; The ultrasonic 300s that then the colostrum ice bath popped one's head in promptly gets the Artemether solid lipid nanoparticle that is used for percutaneous dosing.
Embodiment 11
Prescription:
Artemether 5g HP-30g
Method for making: get HP-and dissolve with the 60mL purified water, Artemether under agitation splashes in the HP-solution after with an amount of anhydrous alcohol solution, the enclose temperature is 45 ℃, constant temperature stops heating after stirring 5h, the continuation stirring is cooled to room temperature and gets inclusion complex in solution, porphyrize after the lyophilization is crossed 80 mesh sieves, promptly gets the Artemether hydroxypropyl-beta-cyclodextrin inclusion that is used for percutaneous dosing.
Prescription:
Artemether 1g Arlacel-80 20g
Cholesterol 10g purified water 500mL
Method for making: with an amount of ether dissolution of Artemether, Arlacel-80, cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether nonionic surfactant vesicle that is used for percutaneous dosing.
The invention effect
In view of the difficulty of setting up animal model, and Artemether is injected, the safety of oral formulations clinical practice decades, adopts the volunteer that product of the present invention is tested, and the result is as follows:
The invention is not restricted to above embodiment.
1, the dermopathic artemether percutaneous drug administration preparation of a kind of treatment is characterized in that described preparation is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1~20%.
2, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1, the percentage by weight that it is characterized in that Artemether in the described preparation is 0.2~10%.
3, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1 and 2, it is characterized in that said preparation comprises can be for the various exterior-applied formulation of clinical use: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment.
4, artemether percutaneous drug administration preparation according to claim 1 and 2, it is characterized in that used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the said preparation, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more.
5, artemether percutaneous drug administration preparation according to claim 1 and 2 is characterized in that used Transdermal absorption carrier in the said preparation comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle.
6, claim 1 or 2 described artemether percutaneous drug administration preparations is characterized in that can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
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