CN1129573A - Skin absorptive antiviral drug - Google Patents

Abstract

Various skin penetrating experiments and concentration-in-blood meaurements have proved that such extra ingredients of Chinese medicine as oleanolic acid, 18-beta-glycyrrh-etinic acid, beta-myrccne, cineole, ursolic acid, glycyrrhizin and (+)-alpha-pinene are applied along with common used local drugs such as ointment, suspension, gel, solution, picking or spray to get optimal sucking effect.

Description

Skin absorptive antiviral drug

Virus causes harm to cause greatly and shakes within this century, no matter wherein herpes simplex (HSV-1), hepatitis, or acquired immunodeficiency virus (HIV, AIDS) all exists the phenomenon that is difficult to cure.And present known antiviral drugs can be divided into pyrimidine antagonist, purine antagonist, natural alkaloid, antibiotic, and class such as enzyme.Comprising acyclovir (Acyc-lovir, ACV, D1), Dan Xike and (Danciclovir, D3), I is Ah (Ara-A, 9-β-D-arabinofuranosyl adenin-9H-purine-6-amine, D4), enlightening enemy according to (2 ', 3 '-the dideoxy inosine, DDI, D7), enlightening enemy and (2 ', 3 '-DIDEOXYADENOSINE, DDA, 2 ', 3 '-dideoxy-9-β-ribose furan-9H-purine-6-amine, D6), ganciclovir (Ganciclovir, DHPG, 9-(1,3-dihydroxy-2-propoxyl group-methyl) guanine, D2), card is protected and (Car-bovir, D5), precious (the Cordycepin of card enemy, D8), deoxyguanosine (Deoxyguanosi-ne, D9), cytosine arabinoside (Cytarabine, D11), enlightening enemy uncommon (2 ', 3 '-the dideoxy cytidine, DDC, D12), enlightening like the ladder (2 ', 3 '-two dehydrogenations-2 ', 3 '-the deoxythymidine deoxynucleoside, DHH, D14), good and (9-(3-hydroxyl-2-phosphono methoxycarbonyl propyl) adenosine of phosphorus, HPMPA, D10), zidovudine (Zidovudine, ZDV, D13), deoxyribosylthymine (Deoxythymidine, D15), the fluorine iodocytosine (2 '-fluoro-5-idoaracytosine, HIAC, D17), I. D. C (5-iodo-2 '-deoxycytidine, IDC, D18), bromovinyl deoxyuridine (Bromovinyldeoxy uridine, BVDU, D16), BrdU (2 '-Deo-xyuridine, EDU, D19), trifluridine (5-trifluoromethyl-2 '-deoxidation urea glycosides, F3T, D20), thymine arabinoside (1-β-D-arabinofuranosyl adenin thymidine, Ara-T, D21), ribavirin (Ribaviriv, D23), phosphorus good uncommon (9-(3-hydroxyl-2-phosphono methoxycarbonyl propyl) thymidine, HPMPC D22), Lei Baomai (Riboxamide, D24), fixed (the Amantidine of Oman, D25), take turns graceful fixed (Rimantidine, D26), tromantadine (Tromantadine, D27), I (Aritdone, D28); in winter Moroxydine (moroxydine, D29), enviroxime (Enviroxime, D30), foscarnet sodium (Foscamet sodium, D31), the antiviral drugs that is similar structures as shown in table 1.Outer oral, the injection of these drug administration approach, local coating have the central nervous system of inhibition, renal function phenomenon even and existing toxicity is high.

Table 1 antiviral drugs

Table 1 (continuing)

The chemical structural formula of acyclovir (ACV) is for containing just like purine ring shown in Figure 1A (purine) and deoxyguanosine (2 '-deoxyguanosine) the 9-[(2-hydroxy ethoxy of framework) methyl] guanine compound.(HSV 1 for the herpes simplex virus of first type and second type for acyclovir (ACV), 2), chickenpox type varicella zoster virus (Varicella Zostervirus, VZV), Chinese mugwort crust virus (Epstein Barr virus, EBV) and cytomegalic virus (Cytomegalovirus, CMC) inhibitory action is all arranged, and its drug effect is stronger for the first type herpes simplex virus (HSV 1), next is the second type herpes simplex virus (HSV2), chickenpox type varicella zoster virus (VZV), Chinese mugwort crust virus (EBV) and cytomegalic virus (CMV), however inhibitory action is successively decreased in regular turn.The effect of experiment confirm acyclovir (ACV) treatment herpes simplex virus is good than fluorine iodocytosine (HIAC) or ganciclovir (DHPG) in body.And can resist herpes simplex virus second type and first type simultaneously, have more excellent effect than bromovinyl deoxyuridine.As for the effect of utilization acyclovir (ACV) inhibition chickenpox type varicella zoster virus (VZV), the result of very big diversity just appears having in different experiments.Usually the curative effect of acyclovir (ACV) antagonism cytomegalic virus (CMV) is poor than idoxuridine (Idoxuridine), trifluridine (Trifluridine), vidarabine (Vidarabine) or ganciclovir (DHPG) under in vitro tests.Acyclovir (ACV) also can suppress to end and cling to the production ring (productive cycle) of virus, then can't present effect when still being in incubation period for this virus.Acyclovir (ACV) and other ucleosides antiviral agents or interferon also comprise that in order to antagonism some herpesvirus of cytomegalic virus (CMV) has collaborative effect.

The general base that uses of at present commercially available acyclovir (ACV) ointment have Polyethylene Glycol (PEG), aqueous cold cream base (modification aqueous cream) and dimethyl sulfoxide (dimethyl sulfoxide, DMSO).People such as Corey L. contain the polyethylene glycol ointment of 5% acyclovir after 4～6 times continuous 5～7 days in the 326th～334 page of report employing of nineteen eighty-two America-n J.of Medicine the 73rd volume local coating every day, though it can be subjected to the skin absorbs of herpes infection, yet absorbtivity is few and its plasma concentration less than 0.023mg/L, almost can't measure its amount.In addition people such as Poirror R.H. in this year the 393rd page in identical publication report is proposed, 25 eyes have the patient of binding film fornix to apply once (every day 4～6 times) every 5 hours with the polyethylene glycol ointment that contains 3% acyclovir, carry out cataract excising operation (cataract extration) in 5 minutes after the last administration, after measured water acyclovir (ACV) mean concentration of rippling in the liquid (aqueoushumour) is 1.7mg/L, demonstration can obtain the high amount of penetrating.People such as Freeman D.J. in 1986 the 64th～70 page of research of J.of Infectious Diseases the 153rd volume excipient for unit are on the amount of penetrating (Flux) of acyclovir (ACV) topical formulations in the unit interval, the aqueous cold cream base or Polyethylene Glycol (PEG) preparation that relatively contain 5% acyclovir (ACV), and the dimethyl sulfoxide 3 kinds of dosage forms such as (DMSO) that contain 6% acyclovir (ACV), the amount of penetrating of finding the unit interval on the unit are of Polyethylene Glycol (PEG) minimum and in addition two kinds of dosage forms be respectively 8 times and 10 times of its unit interval amount of penetrating.Be published in the research of the 856th～863 page of on the J.Invest.Dermatol. 1992 the 98th volume according to people such as Greg E., it is better than local coating with the effect of oral acyclovir (ACV) to find to treat the first type herpes simplex virus (HSV 1) clinically, and the drug level of affected part epidermis lowers 2 to 3 times than oral medicine.And confirm that through 18 pieces of papers that assessment has been delivered the local coating mode is used acyclovir (ACV) preparation, acyclovir (ACV) can not act on the corium place, and this report confirms that at present commercially available acyclovir (ACV) ointment is invalid.As seen develop acyclovir (ACV) transdermal formulation, so that the tissue generation curative effect that medicine can enter than deep layer has the exploitation meaning.The present invention is a kind of transdermal formulation, and it adds transdermal absorption accelerator to improve the percutaneous absorption effect in containing the topical administration dosage form commonly used of antiviral drugs.

Percutaneous loading system is a kind of controlled delivery system that produces, and will can disengage medicine constantly, lentamente behind its local coating and reaches epidermis, and make medicine penetrate that epidermal area enters blood capillary and arrive the therapeutic purposes district through blood circulation and present curative effect.Such dosage form great advantage is easy to use, safe, is attached to usually on the skin or local the use, can tear off at any time in case of necessity to be unlikely medicine takes place to disengage the danger that exceeds threshold dose suddenly in a large number.General adult's skin gross area is about 2m ², and microvascular blood flow accounts for whole body 1/3rd, so percutaneous loading system has become a kind of route of administration with suitable potentiality in recent years.The design of percutaneous loading system simultaneously also has improvement or removes the advantage of general conventional dosage forms side effect, and can disengage medicine timely and appropriately with the performance greatest treatment efficacy, so obtain splendid evaluation clinically.

Yet percutaneous loading system also is subjected to the medicine physicochemical properties, as partition coefficient, molecular weight size, concentration, molecular polarity; Or the physicochemical property of percutaneous loading system itself, as base polarity, the dissolubility of medicine in base, constituent in the system, base viscosity; Bear skin physiology and pathological condition even, as cuticular storage effect, the skin surface lipid film, level of skin hydration, skin temperature, the coating paste section potential difference opposite sex, skin injury, pathology injury and medicine are in the influence of factors such as skin intracellular metabolite effect.Percutaneous absorbs the transdermal absorption accelerator that the most general difficult problem of loading system is to lack brute force and safety at present.

People obviously improve for the evaluation of oriental medicine under the pure development of medical science in recent years, and for example Japanese health ministry in 1975 is agreed 210 kinds of Chinese medicine compound are applied to national health insurance.Chinese medicine cure the disease the mode that is adopted antiperspirant is arranged, tell, let out, descend, hold in the palm, mend and, class compound recipe prescription such as separate, investigating in the prescription that shows these compound recipes has 150 kinds to contain Radix Glycyrrhizae, its frequency of occurrences accounts for 71.4% for the highest, thereafter in regular turn for Rhizoma Zingiberis Recens accounts for 42.9%, Poria accounts for 35.2%, Radix Paeoniae accounts for 32.9%, Fructus Jujubae accounts for 31.9%, and Ramulus Cinnamomi account for 29.5% etc.And the frequency of occurrences Radix Glycyrrhizae of 93 kinds of compound formulas that other Japanese national pharmaceuticals collection second revised edition is recorded in explaining is still the highest, second is Rhizoma Zingiberis Recens, the crude drug and the above-mentioned situation of six orders in front are identical, and below six order also similar to the frequency that applies to the national health insurance Chinese medicine compound.

The medical material licorice (Glycyrrhizae Radix) that the Chinese medicine compound frequency of utilization is higher, contained main constituent are glycyrrhizic acid (glycyrrhizin), enoxolone triterpene saponin structures (triterpene saponin) such as (glycyrrhetin-ic acid).The Rhizoma Zingiberis Recens of next (Zing-iberis Rhizoma), (α-Pinene), (β-Myrcene), Folium eucalypti globueli (Eucalyptus globulus Labill.) acid (Cineole) and so on quintessence oil (essential oil) is main to beta-myrcene with pinene in the contained main constituent.And the contained main constituent of Fructus Jujubae (Zizyphi Fructus) commonly used is oleanolic acid (Oleanol-ic acid), ursolic acid triterpenes glycoside bodies (triterpenoid) such as (ursolic acid).Contained main constituent is Glcditsia Sinensis glycoside (Gledinin), Glcditsia Sinensis Saponin triterpenes saponin and tannic acids (Tannins) such as (Gleditschia Saponin) in the Fructus Gleditsia (Gleditsia sinensis Lam).Contained main constituent is eburicoic acid (Eburicoic acid), acetyl dehydrogenation pachymic acid (3 β-O-acetyldehydrotumulosic acid), acetyl pachymic acid (3 β-O-acetyltumulosic acid), dehydrogenation eburicoic acid (Dehydroeburicoic acid), ergosterol (Ergosterol) and so on a triterpenes saponin in the Poria (Hoelen).Contained main constituent is peoniflorin (Paeoniflorin) in the Radix Paeoniae root (paeoniae radix), AB (Albiflorin), contain oxygen peoniflorin (Oxypaeoniflorin), paeoniflorigenone (Paeoniflorigenone), benzoic acid peoniflorin (Benzoyl-paeoniflorin), 4-hendecane Galla Turcica (Galla Helepensis) acyl heteroside (Tetraundeca galloylglucose), and cachou extract ((+)-Catechin), procyanidin (Procyanidin B-1), monoterpenes glycoside body class tannic acids such as (monoterpene glycoside).The contained main constituent of Cortex cinnamomi japonici (Ramulus Cinnamomi) (Cinnamoni Cortex et caulis) is Cortex cinnamomi japonici (Ramulus Cinnamomi) ethyl ester (Cinnamyl acetate), cinnamic aldehyde (Cinnamaldehyde) and so on quintessence oil composition and Cortex Cinnamomi terpene (Cinncassiol A), hydrogenation Cortex cinnamomi japonici (Ramulus Cinnamomi) ketenes (Anhydrocinnzeylanol), dehydrogenation phenylethene peaceful (Anhydrocinnzeylanine), phenylethene peaceful (Cinnzeylanine), Cortex cinnamomi japonici (Ramulus Cinnamomi) ketenes class tannic acids such as (Cinnzeylanol).

Conclude the not outer monoterpenes glycoside of main constituent body, triterpenes glycoside body, triterpenes saponin, tannic acid, the quintessence oil of above-mentioned these medical materials, and the triterpenes saponin itself has the character of surfactant, can reduce skin surface tension force, assist medicine to arrive than deep tissues, increase penetrating and therapeutic effect of medicine via skin.Compositions such as quintessence oil, glycyrrhizic acid and enoxolone confirm all to have antiinflammation, glycyrrhizic acid wherein and enoxolone that the sole of inhibition swelling ability is more arranged in vitro tests.

People such as Segal R. in 1987 with treatment herpes simplex (HSV), obtain the 4th, 678, No. 772 patents of the U.S. with gel (Gel) the preparation Orally-administrable of 0.2% idoxuridine (IDU) and 2% glycyrrhizic acid, 0.1% benzoic acid (bonzoic acid).The same year, people such as Segal R. was at the gel of J.Clinic Pharm. the 12nd volume the 1st～7 page of report 2% idoxuridine (IDU) with glycyrrhizic acid, relatively treat the result of herpes simplex on lip or the nose with the treatment latitude that contains 5% idoxuridine as pine (Viruson) commercially available ointment, find that the former not only can shorten healing time, more can reduce pain perception.And people such as Touitou E. in the 267th～272 page of the Drug of next year Design and Delive-ry the 3rd volume point out with complete nude mice skin in 34 ℃ with 25 ℃ under carry out external diffusion experiment, the amount of penetrating (Flux) of finding 2% idoxuridine (IDU) and gel unit interval on unit are of glycyrrhizic acid with 6 times of the different latter of being respectively of ambient temperature with 20 times.

The present invention seeks effective transdermal absorption accelerator through considering safety in Chinese medicine " extra conductant ingredient " composition commonly used.Transdermal absorption accelerator of the present invention is that antiviral drugs, Chinese medicine " extra conductant ingredient " are made an addition to spray, ointment (Ointment), gel (Gel), solution (Solution), topical administration preparations such as suspending agent (Suspension), patch.Above-mentioned Chinese medicine " extra conductant ingredient " removes and to comprise Radix Glycyrrhizae, Rhizoma Zingiberis Recens, Poria, Radix Paeoniae, Fructus Jujubae, and outside the single composition of 6 kinds of Chinese medicines such as Ramulus Cinnamomi, also can comprise monoterpenes glycoside body, triterpenes glycoside body, triterpenes saponin, tannic acid, quintessence oil.Owing to contain the Saponin plant 50 not equal 400 kind of plant arranged, select for use after in screening Chinese medicine compound prescription to comprise as table 2, be usually used in plant Saponin, tannic acid, quintessence oil or terpenoid Chinese medicine " extra conductant ingredient " in the Chinese medicine compound prescription shown in 3.

Table 2 is as the Chinese medicine medical material of transdermal absorption accelerator

Herba Artemisiae Scopariae	(Artemisiae?Capillaris?Herba)：
		Quintessence oil (essential oil); Capillin, capillene, capillone, capillarin, Norcapillene, capillanol
	Flos Matricariae chamomillae		(Chrysanthemum)：
Quintessence oil (essential oil); (-)-α-Bisabolol, α-Farnesene, Matricin, Matricarin, Chamazulene,
		Ascarid lettuce flower	(Cinae?Flos)：o、S
Quintessence oil (essential oil); (-)-α-Pinene, Terpinene, Terpineol, Carvacrol, α-Thuione, (-)-Camphor,
	The Radix Aucklandiae		(Saussureae?Radix)：
Quintessence oil (essential oil); Aplotaxene, Costic acid, Costunolide, Costus lactone, Dehydrocostus lactone, Dihydrocostus lactone, Phellandrene, α-Ionone, β-Ionone, α-Costol, Camphene,
		Pick grass roots	(Valerianae?Radix)：
Quintessence oil (essential oil); (+) Bornylisovalerate, Bornylacetate, Kessane, (-)-Campehne, (+-)-Limonene, α-Terpineol, α-Kessylalcohol, α-Kessylalcohol acetate, Kessanol, Kessoglycol, Valeranone, Fauronyl acetate, Cryptofauronol, Kanokonyl acetate, Linalool, β-Pinene, Kanokonol, α-Pinene
	Herba Menthae		(Menthae?Herba)：
Quintessence oil (essential oil); (-)-Menthol, Acetyllmenthol, (-)-Menthone, (-)-Limoene, (+)-Menthol Pulegone, Piperitone, Isomenthone, Camphene, 3-Octanol, γ-Hexenyl, Penylacetate, α-Pinene, Menthenone
		Folium Perillae	(Perillae?Herba)：
Quintessence oil (essential oil); (-)-Perillaldehyde, (+)-Limonene, α-Pinene, Perillaketone, naginataketone, egomaketone
	Herba Schizonepetae		(Schizonepetae?Herba)：
Quintessence oil (essential oil); (+)-Menthone, (±)-Menthonel, (+)-Limonene, (-)-Pulegone
		Fructus Evodiae	(Evodiae?Fructus)：
Quintessence oil (essential oil); Evodene

Table 2 (continuing)

Fructus Foeniculi	(Foeniculi?Fructus)：
		Quintessence oil (essential oil); Anethole, Estragole, (+)-α-Pinene, (+)-Fenchone, (±)-Limonene, Anisaldehyde
	Flos Caryophylli		(Caryophylli?Flos)：
Quintessence oil (essential oil); Eugenol, Eugenol acetate, Eugenol salicylate, Methyl salicylate, Vanillin, β-Caryophyllene, Humulene, Methyl amylketone, Chavicol, α-Ylangene
		Folium eucalypti globueli (Eucalyptus globulus Labill.)	(Eucalypti?Folium)：
Quintessence oil (essential oil); 1.8-Cineole, P-Cymene, Terpineol, Cuminal, Phellandral, Pinene
	Senea		(Sengae?Radix)：
Quintessence oil (essential oil); Methyl salicylate
		Saponin (saponin); Senegin-I, Senegin-II, Senegin-III, Senegin-IV
Pericarpium Zanthoxyli			(Zanthoxyli?Fructus)：
	Quintessence oil (essential oil); Geraniol, Limoene, Cumic alcohol
		Herba Asari	(Asari?Herba?cum?Radice)：
Quintessence oil (essential oil); Eucarvone, Safrole, Metgyleugenol, Elemicin, Asaricin, β-pinene, (+)-borneol, Croweacin
	Fructus Piperis		(Piperis?Fructus)：
Quintessence oil (essential oil); (-)-α-Phellandrene, β-pinene, Linalool
		Herba Houttuyniae	(Houttuyniae?Herba)：
Quintessence oil (essential oil); Decanoylacetaldehyde, Methylnonyl ketone, Laurinaldehyde
	Fructus Schisandrae Chinensis		(Schizandrae?Fructus)：
Quintessence oil (essential oil); Citral, α-Chamigrene, β-Chamigrene, Chamigrene, Sesquicarene, β-Chamigrenal
		Flos Magnoliae	(Magnoliae?Flos)：
Quintessence oil (essential oil); Methylchavicol, Camphor, 1,8-cineole, ρ-cymene

Table 2 (continuing)

Cloth hurriedly	(Lupuli?Strobilus)：
		Quintessence oil (essential oil); α-humulene, β-humulene, Humuladienone, α-coroaIene, Meta-camphorene, Paracamphorene, Myrcene
	Fructus Alpiniae Oxyphyllae		(Alpiniae?Fructus)：
Quintessence oil (essential oil); Nootkatone, Zingiberene, Zingiberol, α-humulene
		Sand contracts	(Amomi?Semen)：
Quintessence oil (essential oil); (+)-borneol, Bornylacetate, N-eroldiol
	Radix Curcumae		(Curcumae?Tuber)：
Quintessence oil (essential oil); Turmerone, (+)-arturmerone, Zingiberne, (+)-α-phellandrene
		Rhizoma Curcumae	(Zedoariae?Rhizoma)：
Sesquiterpenoids (Sesquiterpenoid); Curzerenone, Curdione, Curcolone, Furanodienone, Furanogermenone, 1,4-cineole, Zederone, Curcumol
	Rhizoma Cyperi		(Cyperi?Rhizoma)：
Quintessence oil (essential oil); Cyperol, α-Cyperone, Cyperene, Cyperotundone, Cypxerolone, Sugenolacetate, Kobusone
		Kind rainbow flower	(Croci?Stigma)：
Quintessence oil (essential oil); Safranal
	Radix Polygalae		(Polygalae?Radix)：
Saponin (saponin); Oniisaponin A-G (A=senegin IV), (B=senegin III), Prosenegeni, Tenuifolin, Senegenin,
		Huang person	(Astragali?Radix)：
Saponin (saponin); Astragaloside I-VIII, Soyasaponin I
	Radix Achyranthis Bidentatae		(Achyranthis?Radix)：
Saponin (saponin); Oleanolic acid glycoside
		The Rhizoma Anemarrhenae	(Anemarrhenae?Rhizoma)：
Saponin (saponin); Timosaponin A-I, Timosaponig A-III, Markogenin, Neogitogenin glycosides

Table 2 (continuing)

Cortex Moutan	(Moutan?Radicis?Cortex)：
		Monoterpenes (Monoterpenoid); Oxypaeoniflorin Benzoylpaeoniflorin, Benzoyloxypaeoiflorin, Paeoniflorin
	Radix Kansui		(Euphorbiae?Kansui?Radix)：
Diterpenes (diterpene); Kansuinin A, B, 20-Deoxyingeol-3-benzoate, Ingenol-3-(2,4-decadienoate)-20-acetate, 20-Deoxyingenol-5-benzoate
		Triterpenes (triterpene); α-Luphol, Tirucallol, Fuphorbadienol, β-Euphorbol
Radix Aconiti Lateralis Preparata			(Aconiti?Tuber)：
	Diterpenes (diterpene); Mseaconitine, Hypaonitine, Jesaconitine, Neopelline, Kobusine, Pseudokobusine, Telatisine, Songorine, Atidine, Napelline, Heteratisine, Lignanine, Hypognavine, Atisine, Aconitine
		Calculus Bovis from Northwest of China person glue	(Tragacantha)：
Triterpenes (triterpene); Tragoside I, Tragoside II
	Radix Ophiopogonis		(Ophiopogonis?Tuber)：
Saponin (seponin); Ophiopoqonin A, ophiopoqonin B, ophiopoqonin C, ophiopoqonin B ｀, ophiopoqonin C ｀, ophiopoqonin D ｀, ophiopoqonin D
		Semen Persicae	(Persicae?Semen)：
Triterpenes (triterpene); 24-methylenecycloartanol
	Rhizoma Cimicifugae		(Cimicifugae?Rhizoma)：
Triterpenes (triterpene); Cimigenol xyloside, 12-hydroxycimigenol, 12-hydroxycimigenol xyloside, Dahurinol, Isodahurinol, 24-o-acetylisodahurinol, Cimigenol
		Cortex Mori	(Mori?Radicis?Cortex)：
Triterpenes (triterpene); α-amyrinacetate, Betulinic acid
	Rhizoma Imperatae		(Imperatae?Rhizoma)：
Triterpenes (triterpene); Cylindrin, Arundoin, Fernenol, Simiarenol, Isoarborinol

Table 3 is as the Chinese medicine medical material of transdermal absorption accelerator

Radix Glycyrrhizae	(Glycyrrhizae?Radix)：
		Triterpenes saponin (triterpene saponin); Glycyrrhizin, glycyrrhetinic acid, 18-β-glycyrrhetinic acid
	Rhizoma Zingiberis Recens		(Zingiberis?Rhizoma)：
Quintessence oil (essential oil); α-Pinene, β-Myrcene, Cineole
		Fructus Jujubae	(Zizyphi?Fructus)：
Triterpenes (triterpenoid); Oleanolic acid, Ursolic acid
	Saponin (saponin); Zizyphus saponin I, Zizyphus saponin II, Zizyphus saponin III, Jujuboside B, maslinic acid, Betulonic acid
Fructus Gleditsia			(Gleditsia?sinensis?Lam.)：
	Triterpenes saponin (triterpene saponin); Gledinin, Gleditschia Saponin
		Tannic acid (Tannins); Cetylalcohol, Nonacosane, Stigmasterol, Sitosterol
	Poria		(Hoelen)：
Triterpenes glycosides (triterpene saponin); Eburicoic acid, Dehydroeburicoic acid, 3 β-O-acetyldehydro tumulosic acid, Ergosterol, 3 β-O-acetyltumulosic acid
		Radix Paeoniae	(paeoniae?radix)：
Monoterpenes glycocide (monoterpene glycoside); Albiflorin, Paeoniflorin Oxypaeoniflorin, Paeoniflorigenone, Benzoylpaeoniflorin
	Tannic acid (Tannins): Tetraundeca, galloylglucose, (+)-Catechin, Procyanidin B-1
Cortex cinnamomi japonici (Ramulus Cinnamomi)			(Cinnamoni?Cortex?et?caulis)：
	Quintessence oil (essential oil): Cinnamaldehyde, Cinnamyl acetate, Phenylpropyl acetate
		Tannic acid (Tannins); Cinnzeylanol, Cinnzeylanine, Anhvdrocinnzeylanine, Cinncassiol A, Cinncassiol B, Cinncassiol C1, Procyanidin C-1, Cinncassiol A 19-monoacetate, Cinncassiol C3, Cinncassiol D1, Cinncassiol A 19-O-glucoside, Cinncassiol D1 19-O-glucoside, Cinncassiol B 19-O-glucoside, Cinncassiol D2 19-O-glucoside, Cinncassiol C1 19-O-glucoside, Anhydrocinnzeylanol, Gallic acid Cinncassiol D4, Cinncassiol E, Cinncassiol C2, Cinncassiol D2, Cinncassiol D3, Procyanidin B-2, Procyanidin B-5, Apigenin 3,7-dirhamnoside, Protocatechuic acid, (-)-Epicatechin

Table 3 (continuing)

Elettaria cardamomum (L.) Maton	(Cardamomi?Fructus)：
		Quintessence oil (essential oil); (+)-α-Terpinyl acetate, 1,8-Cineole, Sabinene Limonene, (+)-α-Terpineol
	The Rhizoma Atractylodis Macrocephalae		(Atractylodis?Rhizoma)：
Quintessence oil (essential oil): Atractylon, Eudesma-4 (14), Atractylenolide I, Hinesol, Atractylenolide II, Atractylenolide III, Elemol, 3 β-acetoxyatractylon, 3 β-hydroxyatractylon, β-eudesmol, Atractylodine, Atractylodinol, acetylatractylodinol, 7 (11)-Dien-8-one
		Radix Angelicae Sinensis	(Angelicae?Sinensis?radix)：
Quintessence oil (essential oil); Butylidenephthalide, Δ 2,4-dihydrophthalic anhydride, n-Valerophenone-U-carboxylic acid
	Radix Ginseng		(Ginseng?Radix)：
Saponins (saponin); Heptaedeca-1-en-4,6-Dihn-3,9-diol panaxydol, 20-glucoginsenoside-Rf, Choline, β-Sitosterol glucoside, Ginsenoside-Rx (x=o, a1, a2, b1, b2, b3, c, d, e, f, g1, g2, h1), Nicotinic acid, β-Sitosterol, β-Elemene, Panaxynol;
		Pericarpium Citri Reticulatae	(Citri?Exocarpium)：
Quintessence oil (essential oil); D-limonene, Linalool, Citral, Hesperidin, Neohesperidin, Naringin, Poncirin, Umbelliferone, Auraptene, Citroptene, Imperatorin, Isoimperatorin, Isoponcimarine, (-)-Synephrine, Citric acid
	Radix Scutellariae		(Scutellariae?Radix)：
Flavonoid (flavonoid); Raicalin, Stigmasterol, Wogoin glucuronide, Wogonin, Baicalein, Uroxylin A, Uroxylin A glucuronide, 5,8-Dihyrdroxy-6,7-dimethoxy-flavone, Skullcap-Flavon I, 5,7,4 '-Trihyroxy-8-methoxy flavone, Skullcap-Flavon II, 5,7,2 ', 6 '-Tetrahydroxy flavone, Campesterol, β-Sitoserol, Koganebananin
		Radix Bupleuri	(Bupleuri?Radix)：
Saponins (saponin); Saikosaponin a, c, d, Oleic acid, α-Spinasterol, Δ 7-Stigmasterol, Linolenic acid, Lignoceric acid, Adonitol Saikogenin F, E, G, Longispinogenin lignoceric acid, Palmitic acid, Angelicin, Stearic acid
	Rhizoma Chuanxiong		(Ligustici?Rhizoma)：
Quintessence oil (essential oil): Cnidium lactone, Ferulic acid, Cnidilide, Neocnidilide

Table 3 (continuing)

Radix Rehmanniae	(Rehmanniae?Radix?et?rhizoma)：
		Flavonoid (flavonoid); Rehmannoside A, B, Aucubin, Nelittoside, Rehmannioside, LenuorideCatalpol
	The Rhizoma Pinelliae		(Pinelliae?Tuber)：
Homogentisic?acid?glucoside、3，4-Dihydroxybenzaldehyde、 Homogentisic?acid、3，4-Dihydroxybenzaldehyde?diglucoside、 β-Sitosterolglucoside、Ephedrine、Choline、β-Sitosterol
		Radix Et Rhizoma Rhei	(Rhei?Rhizoma)：
Anthraquinone class (anthraquinone); Chrysophanol, Aloe-emodin, Physcion, Emodin, Chrysophanol 1-glucoside, Chrysophanoll 8-glucoside, Rhein, Aloe-emodin-8-glucoside, Citreorosein, Physcion-8-glucoside, Fmodin-1-glucoside, Emodin-8-glucoside, Rhein-8-glucoside, Rhein-8-(the glucoside of 6 ｀-oxal-yl), Sennoside A, B, C, D, E, F
	Tannic acid (Tannins); (-)-Fpicatehin, (-)-Epicatechin-3-O-gallate, Procyanidin B-1 3-O-gallate, (+)-Catechin
Cortex Magnoliae Officinalis			(Magnoliae?Cortex)：
	Quintessence oil (esssential oil); β-Fudesmol, α-Pinene, β-Pinene, Camphene, Bornylacetate, Caryophylleneepoxide, Cryptomeridiol, Limonene, Magnolol, Honokiol, Magnocurarine, Magnoflorine, Anonaine, Liriodenine, Salicifoline, α-Eudesmol, Michelarbine
		Fructus Aurantii Immaturus	(Citri?Fructus)：
Quintessence oil (essential oil); D-Limonene, Linalool, Citral, (other are with the Chan skin)
	Radix Platycodonis		(Platycodi?Radix)：
Saponins (saponin); Platycodin A, C, D, D2, Polygalacin D, D2, Inulin, α-Spinasterol, α-Spinasterol glucoside, Stigmast-7-enol, Betulin
		Rhizoma Alismatis	(Alismatis?Rhizoma)：
Triterpenes (triterpene); Alisol A, B, Lecithin, Alisol B monoacetate, Alisol C monoacetate, Alisol A monoacetate, Choline,
	Semen Myristicae		(Myristicae?Semen)：
Quintessence oil (essential oil); (+)-Camhene, (+) Linalool, Safrole, Eugenol, Myristicin, (+)-α-Pinene, (+)-β-Pinene, (+)-Limonene, Xylan, (+)-Borneol, Geraniol, α-Terpineol, Myristin olein, Pentosan, Furfural, Pectin, Lipase, Saponin
		Fructus Amomi Rotundus	(Amomi?Cardamomi?Fructus)：
Quintessence oil (essential oil): (+)-Camphor (+)-Borneol, Humulene epoxide, 1,8-Cineole, α-Pinene, β-Pinene, Caryophyllene, Myrcene, Babinene, Humulene, Carvone,

The antiviral drugs that can be used as transdermic absorbent of the present invention comprises acyclovir (ACV), the medicine that is nucleoside (nucleoside) with other analog shown in Figure 1B-F, acyclovir (D1), ganciclovir (D2), Dan Xike and (D3), I is Ah (D4), card is protected and (D5), enlightening enemy and (D6), the enlightening enemy is according to (D7), card enemy precious (D8), deoxidation guanosine (D9), phosphorus is good and (D10), cytosine arabinoside (D11), enlightening enemy uncommon (D12), zidovudine (D13), enlightening is like ladder (D14), deoxyribosylthymine (D15), bromovinyl deoxyuridine (D16), fluorine iodocytosine (D17), I. D. C (D18), BrdU (D19), trifluorothymidine (D20), thymine arabinoside (D21), phosphorus good uncommon (D22), ribavirin (D23), Lei Baomai (D24), Oman fixed (D25), take turns graceful fixed (D26), tromantadine (D27), I is winter (D28), Moroxydine (D29) enviroxime (D30), foscarnet sodium (D31).Wherein optimum make the medicine of transdermic absorbent be acyclovir (ACV, D1), ganciclovir (DHPG, D2), my Ah (Ara-A, D4), trifluorothymidine (F3T, D20), the fluorine iodocytosine (HIAC, D17), bromovinyl deoxyuridine (BVDU, D16).

Transdermal absorption accelerator of the present invention is in local application's dosage form commonly used, is main composition as being added into 0.1～30% antiviral agents in ointment, suspending agent, gel, solution, patch, the spray.Wherein the content of acyclovir (ACV), bromovinyl deoxyuridine (bromovi-nyldeoxyuridine), ganciclovir (DHPG), vidarabine (Vidarabine), trifluridine (Trifluridine), trifluorothymidine (F3T), fluorine iodocytosine (HIAC) is optimum with 0.1～10%.No matter the excipient that any dosage form is added is advisable with 2%～99.95%; Contain 5% ethylene glycol (EG), 42.5～45% Polyethylene Glycol (PEG 400) and 42.5～45% Polyethylene Glycol (PEG 4000) and can be made into ointment.Gel is selected from sodium carboxymethyl cellulose (CMC Na), Polyethylene Glycol (PEG), glycerol, ethylene glycol (EG) with the excipient that uses can be rendered as three types; All types of except that moisture content should keep in right amount, the first kind is to contain 2～6% sodium carboxymethyl cellulose (CMC Na) and to cooperate 50% glycerol; Second type cooperates 2% sodium carboxymethyl cellulose (CMC Na) to contain 20% ethylene glycol (EG); The 3rd type is only to contain 20% ethylene glycol (EG).And suspending agent is formed to contain 50～98% ethylene glycol (EG) and an amount of moisture content, and solution makes it dissolve mixing fully with enough moisture content with ultrasonic oscillator in addition.The content of promoter is scope with 0.05% to 20% in each dosage form, and optimum content is 0.1% to 8%.

The in-vitro percutaneous penetration test device that the present invention adopts is that the vertical type of improveing voluntarily permeates bottle (Franz Cell) as shown in Figure 2, and its structure is one group of vertical type and separable up and down double glazing container.Its lower floor's container filling contains antibiotic quantitative 0.15N sodium-chloride water solution, and Magnetitum is placed to produce the mixing effect of 600rpm in the bottom.Interlayer between inside and outside wall is kept steady temperature with circulating water flow.Place the inspection product of 0.25g or 0.5g different dosage form in the container of upper strata, upper end open is sentenced preservative film and is covered.Upper and lower two interlayers sandwich respectively tests required animal or human's class skin as the infiltration barrier, and utilizes metal clip to be fixed.Extract the sodium chloride solution sample of 200 μ L at the appointed time by sample tap (sampling port), and the sodium chloride solution that adds 200 μ L immediately is in container, to keep the fixed solution amount.Each sample that is extracted adds the acetaminophenol (Acetaminophen) of 200 μ L, 5 μ g/ml again as the inherent standard product, analyze the content of inspection product with high pressure liquid chromatography (HPLC) method (HPLC), converse the amount of penetrating of medicine according to calibration trace, disengage state for main constituent in the assessment preparation.

After judging that antiviral drugs was through 72 hours in-vitro percutaneous penetration test in the preparation, whether the part medicine is by the ferment metabolism of skin, or experimentation exists the defective that is enough to cause drug loss, calculates with following formula: $R\%=\frac{A^{\′}\mathrm{total}}{\mathrm{Atotal}}\×100\%$

A′total＝A′donor＋A′skin＋A′receptor

A?total＝A?donor

R: the medicine response rate

A total: total dose before the experiment

A donor: the dose of supplying with phase before the experiment

A ' total: the total dose in experiment back

A ' donor: residual dose in the experiment back is supplied with mutually

A ' skin: the dose that experiment back skin part is contained

A ' receptor: the dose of accepting phase after the experiment

The amniotic membrane that the present invention takes off when selecting pregnant woman childbirth respectively, or the skin of abdomen of big ICR of Serpentis whole bark, 25 days, the skin of 80 age in days guinea pigs (guinea pig) and female 7 to 9 weeks or Balb/C kind nude mice (Nude Mice) is as test skin (film) material, the percutaneous of making transdermic absorbent with research antiviral drugs and Chinese medicine " extra conductant ingredient " absorbs situation, and analyzes the amount of penetrating of quantitative antiviral drugs with high pressure liquid chromatography (HPLC) method (HPLC).In addition, carry out testing in the body, medicine is covered in the rabbit ear after 72 hours, measures the acyclovir of this each layer of ear cortex and organize Chinese medicine concentration with rabbit.Preparation of the present invention finds that through experiment in vitro Chinese medicine " extra conductant ingredient " has the percutaneous of promotion assimilation effect, for example contain 0.01% acyclovir (ACV) aqueous solution prescription (#1) preparation that 0.01% glycyrrhizic acid (Glyc-yrrhizin) makes through the external penetration test of 28.75 hours Periostracum Serpentis, its area penetrates cumulant 4.8 μ g/cm as shown in Figure 3 ²For not containing 2 times of glycyrrhizic acid control group prescription (#2).If be 2% acyclovir (ACV) gel of base in containing 2% sodium carboxymethyl cellulose (CMC Na), use 80 ages in days, 25 ages in days Holland Corii Sus domestica respectively, and big female nude mice skins of 7 to 9 weeks percutaneous assimilation effects relatively, after 72 hours as shown in Figure 4 the nude mice skin to penetrate effect better; And the Corii Sus domestica of amniotic membrane or 80 ages in days, 25 ages in days is all very poor for acyclovir (ACV) percutaneous absorption effect.

The at present commercially available normal base that uses of ointment that contains acyclovir (ACV) has Polyethylene Glycol (PEG), aqueous cold cream base and dimethyl sulfoxide (DMSO).The present invention uses 2% sodium carboxymethyl cellulose (CMC Na) instead and makes gel for base, is that base is caused the not good phenomenon of percutaneous assimilation effect to improve Polyethylene Glycol (PEG).As shown in Figure 5, relatively these two kinds of preparations were through 72 hours test, and the cumulant that penetrates of its unit are is followed successively by 34.9 μ g/cm ²With 5.3 μ g/cm ², be that the gel that base is made can reach 7 times percutaneous absorption result than the ointment that is base with Polyethylene Glycol (PEG) with 2% sodium carboxymethyl cellulose (CMC Na).Even in the ointment of Polyethylene Glycol (PEG) base, add the glycyrrhizic acid of different content, through also presenting significant difference on statistics behind the external penetration test, glycyrrhizic acid glycyrrhizic acid in polyethylene glycol ointment is added in demonstration still can't bring into play the effect that promotes that percutaneous absorbs.Yet be to add glycyrrhizic acid in the gel of base with 2% sodium carboxymethyl cellulose (CMC Na), as shown in Figure 6, its unit are penetrates cumulant has obvious significant difference on statistics, however in this gellike glycyrrhizic acid add ratio be higher than at 2% o'clock on the contrary again with the control group not statistics go up significant difference.The accelerating effect mechanism of action that penetrates that shows glycyrrhizic acid has dosage to rely on the phenomenon of (Dosedependent).

(CMC Na) is the gel of base with 2% sodium carboxymethyl cellulose, the Chinese medicine " extra conductant ingredient " of selecting the variety classes different proportion respectively as transdermal absorption accelerator such as ascarid lettuce flower, pick (1S)-pinene contained in grass roots, Herba Menthae, Folium Perillae, Fructus Jujubae, Fructus Piperis, Cortex Magnoliae Officinalis, Flos Magnoliae, Semen Vignae Cylindricae bandit, Rhizoma Curcumae, Rhizoma Zingiberis Recens, Rhizoma Cyperi, the Stigma Croci [(1s)-(-)-α-Pinene]; Contained ursolic acid (Ursolic acid) in uva ursi, Fructus Corni, the Fructus Jujubae; Contained 18-enoxolone (18-β-glycyrrhetinic acid), glycyrrhizic acid in the Radix Glycyrrhizae; Contained oleanolic acid in Fructus Forsythiae, Fructus Corni, Flos Caryophylli, the Fructus Jujubae; The cineole (Cineole) that Flos Magnoliae, Radix Curcumae and Stigma Croci are contained; Fructus Foeniculi, contained (+)-pinene (α-(+)-Pine-ne) of Semen Myristicae; Cortex cinnamomi japonici (Ramulus Cinnamomi), the Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis, Pericarpium Citri Reticulatae, Rhizoma Chuanxiong, senea, Herba Artemisiae Scopariae, Flos Matricariae chamomillae, the Radix Aucklandiae, Herba Schizonepetae, Fructus Foeniculi, Flos Caryophylli, Folium eucalypti globueli (Eucalyptus globulus Labill.), Fructus Aurantii Immaturus, Fructus Evodiae, Pericarpium Zanthoxyli, Herba Asari, Herba Houttuyniae, Fructus Schisandrae Chinensis, Fructus Alpiniae Oxyphyllae, the contained quintessence oil of the sand that contracts; Rhizoma Alismatis, Radix Kansui, tragcanth, Semen Persicae, Rhizoma Cimicifugae, the contained triterpenes saponin (triterpene saponin) of Cortex Mori; The myrcene of cloth, Fructus Amomi Rotundus and Jiang Suohan (β-myrcene) hurriedly; The tannic acid (Tannins) of compositions such as Fructus Gleditsia, Radix Paeoniae, Fructus Corni, Cortex cinnamomi japonici (Ramulus Cinnamomi) and Radix Et Rhizoma Rhei; Through experiment in 72 hours each preparations of unit are penetrate cumulant as shown in Figure 7, prescription (#1) is 605.3 μ g/cm successively ², the prescription (#2) be 206.4 μ g/cm ², the prescription (#3) be 186.0 μ g/cm ², the prescription (#4) be 173.1 μ g/cm ², the prescription (#5) be 125.5 μ g/cm ², the prescription (#6) be 72.5 μ g/cm ², the prescription (#7) be 61.0 μ g/cm ², the prescription (#8) be 54.5 μ g/cm ², the prescription (#9) be 53.4 μ g/cm ²Penetrate cumulant 5.3 μ g/cm with Polyethylene Glycol among Fig. 5 (PEG) for 72 hours unit ares of base ointment ²Can find that relatively the cumulant recruitment that penetrates of each preparation of Fig. 7 is 114 times, 38.9 times, 35 times, 32.6 times, 23.6 times, 13.7 times, 11.5 times, 10.3 times, 10.8 times in regular turn.Wherein the prescription (#2) with the prescription (#1) that contains 2% glycyrrhizic acid and 2% oleanolic acid can produce maximum penetration effect.If in the preparation of 2% acyclovir (ACV) gel, be that the basis is added other promoter respectively and added 1% oleanolic acid, prescription (#5) as prescription (#1) and add that 1% ursolic acid, prescription (#6) add 5% pinene, prescription (#3) adds 20% dimethyl sulfoxide (DMSO) with the prescription (#4) that contains 2% glycyrrhizic acid promoter, and with 2% acyclovir (ACV) suspending agent that contains 2% glycyrrhizic acid write out a prescription (#2) compare; The result as shown in Figure 8, the unit are of respectively writing out a prescription after 72 hours penetrates cumulant and is followed successively by 2687.7 μ g/cm ², 594.4 μ g/cm ², 449.5 μ g/cm ², 221.5 μ g/cm ², 118.6 μ g/cm ², 241.0 μ g/cm ²Penetrate cumulant 5.3 μ g/cm with Polyethylene Glycol among Fig. 5 (PEG) for 72 hours unit ares of base ointment ²Can find that relatively the cumulant recruitment that penetrates of each preparation of Fig. 8 is 507 times, 112 times, 85 times, 41.8 times, 22.4 times, 45.5 times in regular turn, wherein can produce maximum penetration effect with the prescription (#1) that contains 1% oleanolic acid.

In addition, in containing 2% acyclovir (ACV) gel of 2% glycyrrhizic acid, add Fructus Gleditsia (the Gleditsia sinensis Lam.) extract of 1% (#1) and 2% (#2) respectively, with do not contain Fructus Gleditsia control group prescription (#3) external penetration test of 72 hours relatively, the result as shown in Figure 9, the unit are of prescription (#1,2) penetrates cumulant and is followed successively by 2523.9 μ g/cm ², 1158.9 μ g/cm ², 221.5 μ g/cm ²Mode is through penetrating cumulant and increase to 476.2 times, 218.6 times, 41.8 times in regular turn with Polyethylene Glycol (PEG) the ointment unit are of respectively writing out a prescription as previously mentioned.Obviously Fructus Gleditsia can promote the acyclovir percutaneous to absorb and wherein the most effective with 1% Fructus Gleditsia extract.Even and as shown in figure 10 above-mentioned prescription (#2) is used instead 1% oleanolic acid and is replaced, the prescription (#1) that relatively contains 1% oleanolic acid finds that with the prescription that contains 1% Fructus Gleditsia extract (#2) the percutaneous assimilation effect of the two is the same good, confirms that the Fructus Gleditsia extract is splendid transdermal absorption accelerator.As shown in figure 11, medicine is covered in the zoopery that the rabbit ear is carried out, measure acyclovir (ACV) concentration of this each layer of ear cortex after 72 hours, shown in Fig. 1 l, impel medicine to penetrate cuticular degree to contain the effect maximum of 2% glycyrrhizic acid prescription (#1), it is 389.8 μ g/cm that unit are penetrates cumulant ²And best with the prescription (#2) that adds 1% oleanolic acid and 2% glycyrrhizic acid for epidermal area, skin corium, it is 389.8 μ g/cm that unit are penetrates cumulant ²Respectively organize the concentration of Chinese medicine as shown in figure 12, no matter contain 2% acyclovir (ACV) the gel prescription (#1) of 2% glycyrrhizic acid, or both the preparation blood levels of prescription (#2) that add 1% oleanolic acid therein more all have remarkable increase phenomenon, the former is 0.53 ± 0.02 μ g/ml in 72 hours cumulants, be 1.5 times of no promoter prescription (#4) matched group cumulant 0.35 ± 0.03 μ g/ml effect, and the latter 0.48 ± 0.03 μ g/ml it is 1.4 times of matched group.In addition, the blood level of acyclovir (ACV) in the various internal organs of rabbit after measured, 2% sodium carboxymethyl cellulose (CMC Na) prescription (#1) content in liver that discovery contains 2% glycyrrhizic acid be various internal organs, reach 6.89 ± 0.38 μ g/g, only content 3.60 ± 0.36 μ g/g than matched group prescription (#4) increase by 2.2～1.64 times; And for the content of prescription (#2) in heart that Polyethylene Glycol (PEG) adds 2% glycyrrhizic acid, 1% oleanolic acid for base be various internal organs, reach 8.22 ± 1.38 μ g/g, only content 3.90 ± 1.00 μ g/g than matched group prescription (#3) increase by 3.31～1.39 times; Even content is 6.42 ± 0.51 μ g/g in liver, only content 2.49 ± 0.85 μ g/g than matched group increase by 4.22～1.10 times, and do not worry causing murder by poisoning.As shown in figure 13, contain 2% acyclovir (ACV) gel of 2% glycyrrhizic acid in human body skin, through 72 hours, acyclovir concentration ratio matched group significantly increased by 6 times in the skin.

Percutaneous absorbs or the bigger promoter of preparation Semi-polarity may assist medicine to produce bigger percutaneous absorption effect via the polarity passage because medicine can carry out through the sebum road.The fat-soluble index that the present invention utilizes high pressure liquid chromatography (HPLC) method (HPLC) method to try to achieve medicine promoter, its value is listed in Figure 14, table 4.By this table Chinese medicine and solubility parameter of promoter, fat-soluble index as can be known, with 2% acyclovir (ACV), be that base adds 2% glycyrrhizic acid, the formed prescription of 1% oleanolic acid has best percutaneous absorption effect, being based on glycyrrhizic acid polarity helps acyclovir to pass through via polarity passage (Polar pathway) greatly, and oleanolic acid polarity is lower, can help acyclovir to pass through via nonpolar passage (Norpolar pathway), the two complements each other and makes the acyclovir gel produce maximum percutaneous absorption effect.

The solubility parameter of table 4 promoter and lipotropy index promoter solubility parameter lipotropy index

(cal/cm ³) ^1/2aMyrcene 7.91 3.06 cineole 8.36 _ b pinenes 8.83 2.95 oleanolic acid 9.95 _ b enoxolone 10.5 2.86 ursolic acid 10.9 _ b glycyrrhizic acids 12.9 1.32

Because the percutaneous penetration effect of acyclovir (ACV) itself is very poor, and general ill afterwards main therapentic part is at the skin corium of skin.All there is the phenomenon of unsatisfactory curative effect in commercially available product acyclovir (ACV) no matter ointment uses Polyethylene Glycol (PEG), aqueous cold cream base or dimethyl sulfoxide (DMSO) base at present.The present invention adds the terpenoid (terpene), tannic acid (Tannins), quintessence oil (essential oil), terpenoid glycoside body (terpene glyco-side) of Chinese medicine or the like " extra conductant ingredient " as transdermal absorption accelerator.Carry out penetration test and confirm that by blood level the unit are that such preparation produced penetrates cumulant can increase by 500 times approximately than traditional acyclovir ointment through various skins.Utilize the antiviral drugs of local application to also have vidarabine (Vidarabine), trifluridine (Trifluridine), idoxuridine (IDU) at present, the low utmost point of the toxicity of these medicines is applicable to local application of the present invention mode.The present invention can apply to comprise local application's preparations such as ointment, suspending agent, gel, solution, patch, spray, and " extra conductant ingredient " transdermal absorption accelerator that adds can use a kind of Chinese medicine " extra conductant ingredient ", or collocation plurality of Chinese " extra conductant ingredient " absorbs accelerating effect with the percutaneous that increases various antiviral drugs.The present invention is described with different bases with specific embodiment below, adds variable concentrations and different types of Chinese medicine " extra conductant ingredient " and make effective transdermal formulation.

Description of drawings

Figure 1A is the chemical structural formula of acyclovir (ACV).

Figure 1B-F is an antiviral drugs.

Fig. 2 is improvement vertical type infiltration bottle 1. air 2. inspection product 3. Transdermal absorption districts 4. skin membranes, 5. sample taps, 6. receiving slits, 7. outlets, 8. circulating water flows, 9. water inlets, 10. Magnetitums

Fig. 3 is the external penetration test of acyclovir (ACV) aqueous pharmaceutical to Periostracum Serpentis

1 ... 0.01% acyclovir aqueous pharmaceutical+0.01% glycyrrhizic acid (Glycyrr-

hizin)

2 ... 0.01% acyclovir aqueous pharmaceutical

Fig. 4 is that acyclovir (ACV) gel dosage form is to the outer penetration test of variety classes skin volume

1 ... the nude mice skin

2 ... 80 age in days Corii Sus domesticas

3 ... 25 age in days Corii Sus domesticas

The gel dosage form is 2% acyclovir gel (Gel) of base with 2% sodium carboxymethyl cellulose (CMC Na)

Fig. 5 is the external penetration test of acyclovir (ACV) ointment dosage form and gel dosage form

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% Ah former times Lip river of base

Wei gel (Gel)

2 ... with Polyethylene Glycol (PEG) is 5% acyclovir ointment agent (Oin-of base

tment)

Fig. 6 is that the percutaneous of glycyrrhizic acid (Glycyrrhizin) content influence acyclovir (ACV) gel dosage form absorbs

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% glycyrrhizic acid

(Glycyrrhizin) 2% acyclovir gel (Gel)

2 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+5% glycyrrhizic acid

(Glycyrrhizin) 2% acyclovir gel (Gel)

3 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% Ah former times Lip river of base

Wei gel (Gel)

Fig. 7 absorbs for the percutaneous that the promoter kind influences acyclovir (ACV) gel dosage form

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% glycyrrhizic acid

(Glycyrrhizin) 2% acyclovir gel (Gel)

2 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% olive

2% acyclovir gel (Gel) of acid (Oleanolic acid)

3 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% ursolic acid

The 2% acyclovir gel (Gel) of (Ursolic acid)

4 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% acyclovir gel (Gel) of base+5% cineole (Cineole)

5 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+5% myrcene

(the 2% acyclovir gel (Gel) of β-myrcene)

6 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+5% pinene ((+)

The 2% acyclovir gel (Gel) of-α-Pinene)

7 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+5% pinene ((-)

-α-Pinene)

8 ... with 2% sodium carboxymethyl cellulose (CMC Na) is that base+2% Radix Glycyrrhizae is inferior

2% acyclovir of acid (18-β-Glycyrrhetinic acid) coagulates

Colloid (Gel)

9 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% acyclovir

Gel (Gel)

Fig. 8 absorbs for the percutaneous that adds variety classes or different content promoter in acyclovir (ACV) gel that contains glycyrrhizic acid (Glycyrrhizin)

1 ... 2% glycyrrhizic acid (Glycyrrhizin)+1% oleanolic acid (Oleanol-

Ic acid) 2% acyclovir gel (Gel)

2 ... the ethylene glycol of 2% glycyrrhizic acid (Glycyrrhizin)+2% acyclovir

(EG) suspending agent

3 ... 2% glycyrrhizic acid (Glycyrrhizin)+20% dimethyl sulfoxide (DMSO)

2% acyclovir gel (Gel)

4 ... 2% acyclovir gel (Gel) of 2% glycyrrhizic acid (Glycyrrhizin)

5 ... 2% glycyrrhizic acid (Glycyrrhizin)+1% ursolic acid (Ursolic

Acid) 2% acyclovir gel (Gel)

6 ... 2% glycyrrhizic acid (Glycyrrhizin)+5% pinene ((+)-α-Pinene)

2% acyclovir gel (Gel)

Fig. 9 absorbs for the percutaneous that adds different content Fructus Gleditsia (Gleditsia sinensis Lam.) promoter in acyclovir (ACV) gel that contains glycyrrhizic acid (Glycyrrhizin)

1 ... 1% Fructus Gleditsia (Gleditsia sinensis Lam.)+2% glycyrrhizic acid

(Glycyrrhizin) 2% acyclovir gel (Gel)

2 ... 2% Fructus Gleditsia (Gleditsia sinensis Lam.)+2% glycyrrhizic acid

(Glycyrrhizin) 2% acyclovir gel (Gel)

3 ... 2% acyclovir gel (Gel)

Figure 10 absorbs Fructus Gleditsia (Gleditsia sinensis Lam.) extraction for the percutaneous that promoter influences acyclovir (ACV) gel

1 ... 1% oleanolic acid (Oleanolic acid)+2% glycyrrhizic acid (Glyc-

Yrrhizin) 2% acyclovir gel (Gel)

2 ... extraction+2% of 1% Fructus Gleditsia (Gleditsia sinensis Lam.)

2% acyclovir gel (Gel) of glycyrrhizic acid (Glycyrrhizin)

3 ... 2% glycyrrhizic acid (Glycyrrhizin)+0.332% acyclovir gel

Agent (Gel)

4 ... 2% acyclovir gel of 2% glycyrrhizic acid (Glycyrrhizin)

(Gel)

Figure 11 be patch in each cortex of rabbit ear dose distribution scenario behind paster 72hr, the prescription of the numeral in the bracket and its comparison

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% acyclovir gel (n=16) of base+2% glycyrrhizic acid (Glycyrrhizin)

2 ... with 2% sodium carboxymethyl cellulose (CMC Na) is the neat pier of base+2%

2% acyclovir gel (n=of fruit acid (Oleanolic acid)

6)

3 ... 2% acyclovir gel of 2% glycyrrhizic acid (Glycyrrhizin)

(n＝6)

4 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% Ah former times of base

Lip river Wei gel (n=13)

Figure 12 be patch in each cortex of rabbit ear concentration in paster 72hr bleeding from anus, the prescription of the numeral in the bracket and its comparison

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% acyclovir gel (n=6) of base+2% glycyrrhizic acid (Glycyrrhizin)

2 ... 2% glycyrrhizic acid (Glycyrrhizin)+1% oleanolic acid (Oleano-

Lic acid) 2% acyclovir gel (n=3)

3 ... 2% acyclovir gel (n of 2% glycyrrhizic acid (Glycyrrhizin)

＝3)

4 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% Ah former times Lip river of base

Wei gel (n=6)

Figure 13 be patch in each cortex of the rabbit ear each internal organs, tissue concentration behind paster 72hr, the prescription of the numeral in the bracket and its comparison

1 ... with 2% sodium carboxymethyl cellulose (CMC Na) is base+2% Radix Glycyrrhizae

2% acyclovir gel (n=6) of acid (Glycyrrhizin)

2 ... 2% glycyrrhizic acid (Glycyrrhizin)+1% oleanolic acid (Olean-

Olic acid) 2% acyclovir gel (n=3)

3 ... 2% acyclovir gel of 2% glycyrrhizic acid (Glycyrrhizin)

(n＝3)

4 ... with 2% sodium carboxymethyl cellulose (CMC Na) is 2% Ah former times of base

Lip river Wei gel (n=6)

The fat-soluble index of Figure 14 promoter

1 ... glycyrrhizic acid 2 ... enoxolone 3 ... pinene

4 ... beta-myrcene

The modulation of embodiment 1 ointment (Ointment) dosage form

The acyclovir (ACV) of 5% weight percent is dissolved in ethylene glycol (EG) solution of 5% weight percent that is heated to 75 ℃, in another container, the Polyethylene Glycol (PEG) 400 of 45% weight percent and the Macrogol 4000 of 45% weight percent are mixed and heated to 75 ℃, uniform mixing adds the acyclovir mixed solution that has prepared again, and cool quickly stirs and forms in 25 ℃.

Embodiment 2～5 contains the modulation of promoter ointment dosage form

The Fructus Gleditsia (Gled-itsia sinensis Lam.) that adds 1% weight percent according to the preparation method of embodiment 1 respectively extracts liquid, or the glycyrrhizic acid of 1%, 2%, 5% weight percent (Glycyrrhizin), in 75 ℃ of ethylene glycol (EG) solution.

Embodiment 6～8 modulation glycerinated first kind gel (Gel) dosage forms

The acyclovir (ACV) that takes by weighing 2% weight percent is soluble in water with the sodium carboxymethyl cellulose (CMC Na) of 2%, 4%, 6% weight percent, in another container, take by weighing the glycerol (Glycerin) of 50% weight percent, evenly sneak into the acyclovir mixed liquor that has prepared again, add amount of water to 20ml.

Embodiment 9～10 modulation contain the modulation of glycyrrhizic acid first kind gel (Gel) dosage form

Preparation method according to embodiment 6, the sodium carboxymethyl cellulose (CMC Na) that takes by weighing 2% weight percent is soluble in water with the glycyrrhizic acid (Glycyrrhizin) of 2%, 5% weight percent respectively, makes first kind gel (Gel) agent that contains glycyrrhizic acid.

Embodiment 11 modulation contain second type gel (Gel) dosage form of ethylene glycol

The acyclovir (ACV) that takes by weighing 2% weight percent is dissolved in the ethylene glycol (EG) of 20% weight percent, the sodium carboxymethyl cellulose (CMC Na) that takes by weighing 2% weight percent in another container is soluble in water, evenly sneak into the acyclovir mixed liquor that has prepared again, add amount of water to 20ml.

Embodiment 12～19 contains the modulation of second type gel (Gel) dosage form of promoter

According to the preparation method of embodiment 11, take by weighing the pinene [(1s)-(-)-α-Pinene] that 5% weight percent is contained in Wormseed flower, picks grass roots, Herba Menthae, Folium Perillae, Fructus Jujubae, Fructus Piperis, Cortex Magnoliae Officinalis, Flos Magnoliae, Fructus Amomi Rotundus, Rhizoma Curcumae, Rhizoma Zingiberis Recens, Rhizoma Cyperi, Stigma Croci respectively; 2% weight percent is contained in the ursolic acid (Ursolic acid) of uva ursi, Fructus Corni, Fructus Jujubae; 2% weight percent is contained in the enoxolone (18-β-Glycyrrhetinic acid) of Radix Glycyrrhizae or the glycyrrhizic acid (Glycyrrhizin) of 2% weight percent; 2% weight percent is contained in the oleanolic acid (Oleanolic acid) of Fructus Forsythiae, Fructus Corni, Flos Caryophylli, Fructus Jujubae; 5% weight percent is contained in hurriedly the myrcene of cloth, Fructus Amomi Rotundus and Rhizoma Zingiberis Recens (β-myrcene); 5% weight percent is contained in Fructus Foeniculi, myristic pinene [(+)-α-Pinene]; The cineole (Cineole) that 5% weight percent is contained in Flos Magnoliae, Radix Curcumae and Stigma Croci is dissolved in ethylene glycol (EG).

Embodiment 20 modulation only contain ethylene glycol (EG) and are gel (the Gel dosage form of base the 3rd type

The acyclovir (ACV) that takes by weighing 0.247% weight percent is dissolved in 5% weight percent ethylene glycol (EG), the glycyrrhizic acid (Glycyrrhizin) of evenly sneaking into 2% weight percent again is with an amount of moisture content mixing in mortar, in 3, got supernatant under the 000rpm in centrifugal 30 minutes.

Gel (Gel) dosage form of different main composition the 3rd types of embodiment 21 modulation

According to the preparation method of embodiment 20, the acyclovir (ACV) that takes by weighing 0.683% weight percent is dissolved in ethylene glycol (EG), evenly sneaks into glycyrrhizic acid (Glycyrrhizin) mixing of 1% weight percent again, in 3, gets supernatant under the 000rpm in centrifugal 30 minutes.

Gel (Gel) dosage form of different main composition the 3rd types of embodiment 22 modulation

According to the preparation method of embodiment 20, the acyclovir (ACV) that takes by weighing 0.852% weight percent is dissolved in ethylene glycol (EG), sneaks into glycyrrhizic acid (Glycyr-rhizin) mixing of 3% weight percent again, in 3, gets supernatant under the 000rpm in centrifugal 30 minutes.

Embodiment 23 modulation contain the 3rd type gel (Gel) dosage form of two kinds of promoter

Preparation method according to embodiment 20, take by weighing oleic acid (Oleic acid) mixing in mortar in the Semen Hydnocarpi of glycyrrhizic acid, 5% weight percent of acyclovir (ACV), 2% weight percent of 0.305% weight percent respectively, with 3, got supernatant under the 000rpm in centrifugal 30 minutes.

Embodiment 24 modulation contain the 3rd type gel (Gel) dosage form of two kinds of promoter

Preparation method according to embodiment 20, take by weighing the acyclovir (ACV) of 0.648% weight percent, the glycyrrhizic acid of 2% weight percent, enoxolone (18-β-Glycyrrhetinic acid) mixing in mortar of 2% weight percent respectively, with 3, got supernatant under the 000rpm in centrifugal 30 minutes.

Embodiment 25 modulation only contain ethylene glycol (EG) and are gel (Gel) dosage form of base the 3rd type

The acyclovir (ACV) that takes by weighing 1% weight percent is dissolved in 5% weight percent ethylene glycol (EG), the glycyrrhizic acid (Glycyrrhizin) of evenly sneaking into 2% weight percent again is with an amount of moisture content mixing in mortar, in 3, got supernatant under the 000rpm in centrifugal 30 minutes.

Embodiment 26～32 modulation contain gel (Gel) dosage form that different promoter are base with ethylene glycol

According to the preparation method of embodiment 25, take by weighing acyclovir (ACV) and be dissolved in ethylene glycol (EG), in glycyrrhizic acid (Glycyrrhizin), add the oleanolic acid (Oleanolic acid) of 1%, 2% weight percent more respectively; The pinene of 5% weight percent [(+)-α-Pinene]; 1%, the Fructus Gleditsia of 2% weight percent (Gleditsia sinensis Lam.); The dimethyl sulfoxide of 2% weight percent (Dimethylsulfoxid); The ursolic acid of 1% weight percent (Ursoic acid) is dissolved in the ethylene glycol (EG), adds an amount of moisture content mix homogeneously in mortar at last.

The modulation of embodiment 33 suspending agents (Suspension) dosage form

The acyclovir (ACV) that takes by weighing 2% weight percent is dissolved in the ethylene glycol (EG) of 98% weight percent mix homogeneously in mortar.

Embodiment 34 modulation contain suspending agent (Suspension) dosage form of different promoter

According to the preparation method of embodiment 33, in 50% weight percent ethylene glycol (EG), evenly sneak into the glycyrrhizic acid (Glycyrrhizin) in the Radix Glycyrrhizae of 2% weight percent.

Embodiment 35 modulation contain suspending agent (Suspension) dosage form of different promoter

According to the preparation method of embodiment 33, in 96% weight percent ethylene glycol (EG), evenly sneak into enoxolone in the Radix Glycyrrhizae of 2% weight percent (18-β-Glycyrrhetinicacid).

Embodiment 36 modulation contain suspending agent (Suspension) dosage form of different promoter

According to the preparation method of embodiment 33, the acyclovir (ACV) that takes by weighing 5% weight percent is dissolved in the 94% weight percent ethylene glycol (EG), evenly sneaks into the Fructus Gleditsia (Gleditsia sinensis Lam.) of 1% weight percent.

The modulation of embodiment 37 solutions (Solution) dosage form

The acyclovir (ACV) that takes by weighing 0.1% weight percent is dissolved in the suitable quantity of water, makes it dissolve mixing fully with ultrasonic oscillator.

Embodiment 38 modulation contain solution (Solution) dosage form of different promoter

According to the preparation method of embodiment 37, in acyclovir (ACV) solution, evenly sneak into the glycyrrhizic acid (Glycyrrhizin) of 0.1% weight percent.

Embodiment 39 modulation contain solution (Solution) dosage form of different promoter

According to the preparation method of embodiment 37, the acyclovir (ACV) that takes by weighing 0.05% weight percent is dissolved in the suitable quantity of water.

Embodiment 40 modulation contain solution (Solution) dosage form of different promoter

According to the preparation method of embodiment 39, in acyclovir (ACV) solution, evenly sneak into Fructus Gleditsia (the Gleditsia sinensis Lam.) Extract of 0.005% weight percent.

Embodiment 41

According to ointment, gel, suspending agent, the solution preparation method of embodiment 1～37,, replace acyclovir (ACV) to be prepared into percutaneous absorption type with vidarabine (Vidarabine), trifluridine (Trifluridine) antiviral agents.

Embodiment 42

The method for preparing percutaneous absorption type according to embodiment 1～37, with monoterpenes glycoside body, triterpenes glycoside body, triterpenes saponin, tannic acid, quintessence oil, replace contained glycyrrhizic acid (Glycyrrhizin), enoxolone (18-β-Glycyrrhetinic acid) in the Radix Glycyrrhizae wherein; Oleanolic acid in Fructus Forsythiae, Flos Caryophylli, Fructus Jujubae, the Fructus Corni Chinese medicine (Oleanolic acid); Pinene in Fructus Foeniculi, the Semen Myristicae ((+)-α-Pinene); Fructus Gleditsia (Gleditsia sinen-sis Lam.); Ursolic acid in uva ursi, Fructus Corni, the Fructus Jujubae (Ursoic acid).

Embodiment 43

The amniotic membrane that when upper and lower two interlayers of in-vitro percutaneous penetration test device clip human body skin, pregnant woman childbirth, takes off, or the skin of big ICR of Serpentis whole bark, 25 days, the skin of 80 age in days guinea pigs (guinea pig) and female 7 to 9 weeks or the female nude mice of Balb/C kind (Nude Mice) is as test skin (film) material, therein as the infiltration barrier, utilize metal clip to be fixed with the research antiviral drugs.Carry out 72 hours penetration test with various percutaneous absorption types, and at the sodium chloride solution sample of each setting-up time by sample tap (sampling port) extraction 200 μ l, analyze the content of main composition through high pressure liquid chromatography (HPLC) method (HPLC), converse the medicine amount of penetrating according to calibration trace, judge the degree of disengaging of preparation.

Embodiment 44

Percutaneous absorption type is covered in the rabbit ear, after 72 hours, measures acyclovir (ACV) concentration of this each layer of ear cortex.Through containing the body of promoter dosage form with assessment in, acyclovir (ACV) concentration of high pressure liquid chromatography (HPLC) method (HPLC) analyzing blood and various internal organs penetrates and situation that each organ distributes.

Claims (11)

1, a kind of antiviral percutaneous medicament compositions that contains the Chinese medicine extra conductant ingredient, comprising the antiviral agents of main composition 0.1% to 30%, 0.05% to 20% Chinese medicine extra conductant ingredient, and necessary percutaneous absorbs excipient.

2, pharmaceutical composition according to claim 1, wherein antiviral drugs be selected from acyclovir, ganciclovir, Dan Xike and, my Ah, Ka Bao and, the enlightening enemy and, the enlightening enemy according to, phosphorus is good and, uncommon, the zidovudine of card enemy treasured, deoxyguanosine, cytosine arabinoside, enlightening enemy, enlightening be fixed like ladder, deoxyribosylthymine, bromovinyl deoxyuridine, fluorine iodocytosine, I. D. C, BrdU, trifluridine, thymine arabinoside, the good alkene of phosphorus, ribavirin, Lei Baomai, Oman, take turns gracefully decide, tromantadine, I, Moroxydine, enviroxime, foscarnet sodium in winter.

3, pharmaceutical composition according to claim 2, wherein antiviral agents is to be selected from bromovinyl deoxyuridine, acyclovir, vidarabine, ganciclovir, trifluridine, trifluridine, fluorine iodocytosine.

4, pharmaceutical composition according to claim 3, wherein antiviral agents is to be acyclovir.

5, pharmaceutical composition according to claim 1, wherein this Chinese medicine extra conductant ingredient is to be selected from triterpenes saponin, quintessence oil, triterpenes, tannic acid.

6, pharmaceutical composition according to claim 1, wherein this Chinese medicine extra conductant ingredient is to be selected from contained triterpenes saponin constituent in the Chinese medicines such as Radix Glycyrrhizae, Fructus Gleditsia and Poria; Or be selected from contained derived essential oil in the Chinese medicines such as Cortex cinnamomi japonici (Ramulus Cinnamomi), the Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis, Pericarpium Citri Reticulatae, Rhizoma Chuanxiong, Fructus Aurantii Immaturus, Herba Artemisiae Scopariae, Flos Matricariae chamomillae, the Radix Aucklandiae, Herba Schizonepetae, Fructus Foeniculi, Flos Caryophylli, Folium eucalypti globueli (Eucalyptus globulus Labill.), senea, Fructus Evodiae, Pericarpium Zanthoxyli, Herba Asari, Herba Houttuyniae, Fructus Schisandrae Chinensis, Fructus Alpiniae Oxyphyllae, the sand that contracts; Or be selected from the contained triterpenes components of Chinese medicine such as Rhizoma Alismatis, Radix Kansui, tragcanth, Semen Persicae, Rhizoma Cimicifugae, Cortex Mori; Or be selected from contained tannic acid component in the Chinese medicines such as Fructus Gleditsia, Radix Paeoniae, Cortex cinnamomi japonici (Ramulus Cinnamomi) and Radix Et Rhizoma Rhei.

7, pharmaceutical composition according to claim 1, wherein this Chinese medicine extra conductant ingredient is to be selected from Fructus Forsythiae, Fructus Corni, Flos Caryophylli, the oleanolic acid that Chinese medicines such as Fructus Jujubae are contained, or be selected from the contained ursolic acids of Chinese medicine such as uva ursi, Fructus Corni, Fructus Jujubae.

8, pharmaceutical composition according to claim 1 wherein comprises 2%～99.95% excipient and comprises Polyethylene Glycol, sodium carboxymethyl cellulose, glycerol and ethylene glycol.

9, a kind of antiviral agents percutaneous medicament compositions that contains the herbal mixture extra conductant ingredient is selected from Fructus Gleditsia or oleanolic acid, 0.1～30% antiviral agents, and necessary excipient comprising 0.05% to 20%.

10, pharmaceutical composition according to claim 1, wherein antiviral agents is acyclovir (ACV).

11, pharmaceutical composition according to claim 1 is to comprise ointment, suspending agent, gel, solution, spray, patch topical administration preparation.

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