CN1290493C - Local therapy for skin virus infection - Google Patents
Local therapy for skin virus infection Download PDFInfo
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- CN1290493C CN1290493C CN 95121116 CN95121116A CN1290493C CN 1290493 C CN1290493 C CN 1290493C CN 95121116 CN95121116 CN 95121116 CN 95121116 A CN95121116 A CN 95121116A CN 1290493 C CN1290493 C CN 1290493C
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Abstract
The present invention relates to a pharmaceutical preparation containing an aphidicolin or the derviation of the aphidicolin. The pharmaceutical preparation is used for partially curing the skin viral infection. The pharmaceutical preparation contains the aphidicolin or the derviation of the aphidicolin and an acceptable vehicle for partial use in medicine. The present invention also relates to a method for treating the skin viral infection, and comprises the preparation application on the region of skin viral infection. The preparation is used for curing the viral infection of the papilloma in a concrete executive plan.
Description
The present invention is relevant a kind of pharmaceutical preparation that contains aphidicolin (aphidicolin) or derivatives thereof, and it is used for the topical treatment of skin viral infection, as: the infection that causes by human papillomavirus and herpesvirus.
But many is the skin infection disease topical therapeutic of feature with the skin injury.Cause the virus of skin injury for example to comprise: papillomavirus and herpesvirus.These two kinds of viruses all are DNA viruses, need archaeal dna polymerase when duplicating between infection period.This paper will be example with the papillomavirus, go through this class skin infection, rely on the virus of archaeal dna polymerase.
Papillomavirus is no tunicle, twenty body DNA viruses, and it can infect the squamous epidermis cell.This virion comprises the ring-type distrand DNA molecule of one 8000 base, and it is contained in the globular protein skin.The genomic organizational structure of papillomavirus then keeps to heavens.
Papillomavirus has strict product species specificity, and produces squamous epidermis tumor and fiber skin tumor in its host.Identified at present the human papilloma virus's (hereinafter being called " HPVs ") more than 70 kinds.HPV-1 can cause palm wart, and HPV-6 and HPV-11 then cause throat papilloma and condyloma latum (reproduction wart), and this is infectious modal the 4th disease of property.HPV-16, HPV-18, HPV-31 and HPV-33 can cause the reproduction wart, and relevant with the intraepithelial neoplastic development of genitals.These neoplasia may develop into various carcinoma gradually, comprise cervical cancer, and 500,000 people's death are arranged every year approximately.
The standard method of antiviral therapy is to suppress virus replication by suppressing varial polymerases.This method once was used to develop many medicines that are applicable to the treatment herpesvirus infection.For example: to form the triphosphate derivant, it is suppressing more effective than suppressing human dna polymerase on the herpes virus DNA polymerase to vidarabine (vidarabine) in the endocellular phosphorus acidify.Similarly, acycloguanosine (acyclovir) passes through herpes specificity thymidine kinase and phosphorylation, to form ACG (acycloguanosine) monophosphate, forms the ACG triphosphate through host's tyrosine phosphorylation again.This derivant is the inhibitor of the more effective varial polymerases of comparison human dna polymerase.In these each examples, being used for the selected medicine sufficient to guarantee of virus replication can be because of suppressing the host DNA polymerase, and produces overdosage toxicity.
The effect of duplicating is can not carry out selectivity to suppress to papillomavirus, has dna polymerase activity because still find no the virus protein of expressing when infecting papillomavirus.In addition, the HPV that carries out in acellular dubbing system duplicates and researchs and proposes in recent years, and HPVs uses one or more host's polymerases to duplicate.Guo people such as (Kuo) points out in 269 J.Biol.Chem.24058-65 (1994), when using HPV-11 to duplicate the source, effectively the effect of duplicating will depend on virus protein E1 and E2, human dna polymerase-α reaches-δ, replication protein A and topoisomerase I and II (topoisomerases).
Having multiple processing to be used for the treatment of HPV at present infects.Can adopt anti-mitosis medicine Kang Di Loews (Condylox) with the outer reproduction wart of topical therapeutic.Yet according to doctor's reference manual, about 65% patient has local untoward reaction in the clinical trial, as: pain, itch, burning sensation, inflammation, bleed or fester.In addition, the Kang Di Loews can not be used for the treatment of the wart of perianal or mucosa.Injection of interferon-α and laser surgery also can be used to handle papilloma virus infection in the affected part.Yet these two kinds handle equal pain, costliness and recurrence rate height.Another shortcoming of these methods is to be carried out by the doctor.When if the medicine that can be applied to intravital or external infringement place of patient is arranged, then will be more more favourable than existing therapy.
Aphidicolin (ten tetrahydrochysenes-3,9-dihydroxy-4,11b-dimethyl-8,11a-methylene-11aH-ring [α] naphthalene-4 in heptan, 9-dimethanol) be a kind of by the aphid cephalophore (
Cephalosporum aphidicola) antibiotic that produced, it is the potent inhibitor of cell DNA anabolic effect.This effect is owing to the inhibitory action to the mammalian DNA polymerase.Specifically, aphidicolin can suppress the activity of eukaryotic DNA polymerase-α, δ and ∈.Aphidicolin also can suppress duplicating of herpes simplex virus (hereinafter being called " HSV ") in tissue culture and rabbit eyes.This effect even appear at has in the variant of resistance other antiviral agent, as: the HSV variant that phosphonoformic acid is resistance.In addition, confirmed that aphidicolin can suppress the varial polymerases that HSV and vaccine virus produce.
Although aphidicolin has strong antiviral activity, do not see its purposes in medical treatment.Particularly, there are several problems to hinder the purposes of aphidicolin in antiviral therapy.At first, there is not bioavailability during the aphidicolin oral administration medicine supplying.The second, aphidicolin is insoluble in water, so need inject big quantity of fluid during systemic treatment.This problem is resolved by developing water dissolubility aphidicolin (aphidicolin glycinate).
The past aphidicolin suffer from the medical application another more serious problems be when general is offerd medicine, because of suppressing the toxicity that the host DNA polymerase produces.People such as Sessa find to be subjected to the local toxicity and the neurotoxicity symptom of dose limitation in the aphidicolin glycinate I of ovarian cancer patients clinical trial phase.[people such as Sessa, 83 J.Natl.CancerInstitute 1160-64 (1991)].The author points out in conclusion, and the clinical development of aphidicolin glycinate should be used in combination and studies (document is with above-mentioned) at this medicine and the antineoplastic agent cisplatin (cisplatin) of checking and approving use clinically.In the document of delivering after a while, people such as Damia have inquired into the effect (people such as Damia, 30 Cancer Chemother.Pharmacol.459-464s) of this compositions in the mice that suffers from the Mus reticulosarcoma.Wherein observe the active middle equivalent force of cisplatin, but it does not support the clinical application (document is with above-mentioned) of aphidicolin glycinate and cisplatin combination not illustrate that aphidicolin can be locally applied to treat viral infection yet.
The invention provides a kind of topical pharmaceutical formulation that contains the aphidicolin or derivatives thereof, be used for the treatment of viral infection.Find that aphidicolin medicine former with it had high toxicity when general is used though the present invention is based on, this medicine can be used as the topical antiviral therapeutic agent effectively.
Preparation of the present invention is local to contain the aphidicolin or derivatives thereof in excipient pharmaceutically acceptable.Use the definition of " aphidicolin " speech to comprise that having archaeal dna polymerase suppresses active aphidicolin derivant in the literary composition.The concentration of aphidicolin must be enough high, to guarantee having enough aphidicolins to enter in the cell, to suppress the required dna polymerase activity of virus replication.
In a specific embodiments, the concentration of aphidicolin is enough to suppress host's polymerase.Be used for the treatment of in the preferable preparation of cutaneous papillomatosis poison infection, aphidicolin concentration is enough to suppress eukaryotic DNA polymerase-α, δ and ∈.In another specific embodiments, the concentration of aphidicolin is enough to suppress varial polymerases.This concrete scheme is applicable to the virus of treatment as HSV-1 and HSV-2.
Excipient of the present invention can be any pharmaceutically acceptable part excipient.Suitable excipient comprises liquid, gel, aerosol, powder, paste, cream, ointment machin aliphatic alcohol/propylene glycol substrate such as (FAPG).Preferable excipient is the liquid preparation that contains DMSO, poly alkylene glycol and alcohols.
The present invention also provides a kind of method of topical therapeutic viral infection, comprises the pharmaceutical preparation that the skin part local application of infective virus is contained aphidicolin.This topical preparation is suitable for to use in one day 2 times.In some cases, treatment once just can reach the recovery from illness effect.Yet treatment is general to be continued at least about 7 days.In addition, behind the infringement transference cure, continue treatment a period of time again, recur again preventing.
When the present invention with for example: the method for the treatment of the reproduction wart at present is relatively the time, and advantage of the present invention is just apparent.Topical preparation of the present invention is different from currently used reproduction wart local treatment, can not produce any significant untoward reaction.In the clinical trial of part with the aphidicolin preparation, Most patients is all pointed out and is infected relevant pain and the phenomenon of itching reduces.In addition, therapy of the present invention is opposite with plain injection of affected part internal interference and laser surgery, and the patient is in and just can treats.
The present invention is based on and find that aphidicolin and derivant thereof are applicable to the topical therapeutic viral infection.Aphidicolin is the potent inhibitor of virus and eukaryotic DNA polymerase (comprising human dna polymerase-α, δ and ∈).Because this effect can influence and be the class polymerase, therefore aphidicolin will be failed as the systemic treatment agent.Have now found that, can utilize topical pharmaceutical formulation, the aphidicolin or derivatives thereof of valid density is introduced in the cell of infective virus and can not caused excessive general toxicity.
As mentioned above, " aphidicolin " speech comprise the aphidicolin derivant as, for example: can be in vivo (in the cell or extracellular) change into the prodrug of aphidicolin.The prodrug example comprises that wherein one or more hydroxyls have been modified into ester, ether or carboxylate derivatives, or the like derivant.The aphidicolin glycinate is for being applicable to ester derivant example of the present invention.
The invention provides a kind of in the suitable local topical preparation of containing aphidicolin in excipient.The concentration of aphidicolin is wanted enough height, with when administered formulation is to the position of infective virus, suppresses dna polymerase activity in the cell.The present invention also provides the method for treatment skin viral infection, and this method is included in infection site and uses the topical pharmaceutical formulations that contains aphidicolin.
Viral infection
Topical preparation of the present invention can be used for treatment and is used for the caused skin infection of the necessary any virus of virus replication (as: papillomavirus) by eucaryon polymerase-α, δ and/or ∈.In addition, because aphidicolin also suppresses viral dna polymerase, so topical preparation can be used for treating herpesvirus, as, for example: the caused skin infection of HSV-1 and HSV-2.
The local aphidicolin preparation of using
Preparation of the present invention is local to contain aphidicolin in excipient pharmaceutically acceptable.The concentration of aphidicolin must be enough to make the inhibition concentration of aphidicolin to be sent in the cell at infective virus position, just must have the aphidicolin of capacity to enter in the cell, to suppress the required dna polymerase activity of virus replication.During the treatment papilloma virus infection, intracellular aphidicolin concentration must be enough to suppress the activity of host DNA polymerase.In a specific embodiments, the concentration of aphidicolin can suppress host polymerase-α, δ and ∈.
Usually, the concentration range of aphidicolin is decided by specific viral infection, at about 1 μ M (0.34 mcg/ml) to about 15mM (5.10 mg/litre) scope.For example: the concentration range that is fit to the treatment papilloma virus infection is that about 1 μ M (0.34 mcg/ml) is to about 1mM (0.34 mg/ml).Preferably, aphidicolin concentration at about 50 μ M (17 mcg/ml) between about 800 μ M (0.27 mg/ml), better, at about 100 μ M (34 mcg/ml) between the 500 μ M (0.17 mg/ml).Yet suitable aphidicolin concentration can and change according to specific virus infection to be treated.For example: when treatment HSV-1 and HSV-2, can use aphidicolin concentration up to 15mM (5.10 mg/ml).Specific virus is infected optimal dosage to be determined by the correlation technique expert.
Excipient can be any pharmaceutically acceptable part excipient.Many this excipient are known, select appropriate excipients according to certain drug and site of administration.Appropriate excipients comprises liquid preparation, gel, aerosol, powder, paste, cream, ointment, and the substrate of aliphatic alcohol/propylene glycol (FAPG) etc.
Liquid preparation can comprise glycerol, Polyethylene Glycol, hexane-1,2,6-triol, polyvinyl alcohol, lauryl alcohol, myristyl alcohol, spermol, stearyl alcohol, oleyl alcohol, lanoline, anhydrous lanolin, lanolin derivative, lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid, cholesteryl ester, ethylene glycol and/or propylene glycol monoester, glyceryl monoesters, emulsive glyceryl monostearate, Sorbitol and/or anhydrous sorbitol ester, vegetable oil, sulfated oil, isopropyl myristate, isopropyl palmitate voluntarily, or the like.
The polymer that is applicable to the excipient of gel base comprises, for example: tragcanth, carrageenin, pectin, agar, alginic acid, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, Bentonite, aluminium-magnesium silicate, laponite, carbopol (Carbopol) (with the carboxy vinyl polymer of allyl sucrose interlinkage), and compositions.
Suitable aerosol excipient comprises: solution aerosol, powder aerosol, emulsion aerosol and semi-solid aerosol.The powder based excipient can comprise Talcum, zinc oxide, starch, Kaolin, or the like.Suitable paste can comprise many kinds of preparations as: zinc oxide, starch, calcium carbonate, Talcum, salicylic acid, and dithranol in lipid substrate.Cream can be the emulsion of Water-In-Oil or oil-in-water.Suitable ointment can comprise hydroxyl matter, fat and fixed oil radicals matter, silicone, absorption base, emulsifying base, water-soluble base, or the like.Excipient can be a FAPG substrate also, for example comprises: stearyl alcohol, propylene glycol, Polyethylene Glycol and glycerol.
When topical preparation comprises incompatible mixtures of liquids, in preparation, can comprise surfactant, to form uniform and stable preparation.Suitable surfactant example comprises: alkyl sulfate, glyceryl monostearate, polyoxyethylene sorbitan monostearate and monoleate (polysorbate 80) and Polyethylene Glycol.
Other reagent that are widely used in topical preparation comprise cetin and can improve the relevant esters of cream denseness; Stearic acid and stearyl alcohol can be used as lubricant, softening agent and defoamer; And methylcellulose and tragcanth, it is used as suspending agent in paste and ointment.Any this additive all can be contained in the topical preparation of the present invention.At last, topical preparation also can comprise antiseptic, for example: the methyl ester of para amidocyanogen benzoic Acid and propyl ester (methyl-with propyl-p-hydroxybenzoate (paraben)).
Select for use the factor of considering in the excipient to comprise: the dissolubility of therapeutic agent in excipient and stability, excipient are to the chemistry that promotes chemosmotic ability and excipient, horny layer and activating agent and the interaction of physics.Therefore the present invention includes the aphidicolin suspension, in topical preparation, can use aphidicolin quite not to be soluble in wherein excipient.Yet the excipient with the solubilized aphidicolin is good usually.
Excipient should make wherein, and aphidicolin (about 8 to 18 hours usually) during carrying out the aphidicolin treatment keeps stable.Aphidicolin is preferably in and keeps stable at least about 2 years in the excipient.Preparation can be kept at (about 4 ℃) in the refrigerator, to add stiff stability.
In a specific embodiment scheme, therefore excipient and horny layer hydration promote the aphidicolin infiltration.In addition, selected excipient preferably can alleviate the zest of infection site.
Topical preparation of the present invention is not necessarily aseptic.Yet, with sterile preparation for well, so excipient preferably aseptic or after being combined into topical preparation, can sterilize.Topical preparation can be by any usual method sterilization that does not destroy aphidicolin or excipient.Suitable sterilizing methods comprises filtration and irradiation.In addition, by the above-mentioned antiseptic that in preparation, comprises, to reduce or to prevent germ contamination.
In a specific embodiments, excipient comprises dimethyl sulfoxine (DMSO).A kind of change of this concrete scheme be in the excipient except DMSO, also comprise poly alkylene glycol and a kind of alcohol.Another kind of change is then for comprising about 5%DMSO in the excipient, about 45% polypropylene glycol, and about 50% ethanol.
Another provides and continues to discharge in the specific embodiments of aphidicolin, and excipient comprises, and contains the cream of stearyl alcohol and spermol.A kind of change of this specific embodiments is also to comprise propylene glycol and Polyethylene Glycol-100 (PEG-100) stearate in the cream.In the another kind of change, cream comprises 25% stearyl alcohol, 25% spermol, 12% propylene glycol, 10%PEG-100 stearate, 7.96% polysorbate 60,5% sorbitan monostearate, 5% tristerin, 5% mineral oil, 5% distilled water, 0.025% methyl metagin, reaches 0.015% propyl group metagin.
Combination excipient composition and active component and technology are known, and they are applicable to the present invention and do not have different with prior art.
The treatment of skin viral infection
At infection site, mainly refer to skin lesion place, use topical pharmaceutical formulations of the present invention and treat skin viral infection.Any giver of knowing, as: cotton ball can be used for applying preparation.It is aseptic that giver is preferably.
Optimum medication can along with the type of viral infection with the position and different; Yet administration every day just can provide good result 2 times usually.Therefore, topical preparation generally uses once in the morning, between the lights or on use once again.Preparation is continuous administration 7 days at least usually, or preferably is applied to till any infringement transference cure.In addition, after waiting to damage transference cure, can continue to treat a period of time, recur again preventing.
When the treatment skin lesion, directly use topical preparation at damaging part and surrounding skin thereof.For example, if during 1 inch of the about diameter of damaging part, then use topical preparation on interior skin on every side for about 0.5 inch at damaging part.
In the specific embodiments, adopt this therapy with the caused reproduction wart of treatment papillomavirus.Therefore, topical preparation is applied directly over any wart and surrounding skin thereof.Interior giving birth to and external all available this method treatment of infringement.In other specific embodiments, use this therapy with treatment HSV-1 and HSV-2.
By following concrete but example that do not limit further specifies the present invention.With the method for present explanation is can actual operator, then is that laboratory is carried out with the method for past tense explanation.
Example 1 clinical trial
Carry out clinical trial of the present invention.Follow the trail of 40 female reproduction wart patients, the patient age scope was by 22 to 50 years old.All patients accept local with the processing of aphidicolin preparation, once reach morning at dusk once.With cotton ball preparation is applied to the wart place.
Preparation contains 100 μ M or 500 μ M aphidicolins, 5%DMSO, 45% propylene glycol and 50% ethanol (v/v).For the preparation preparation, get proper volume DMSO, propylene glycol and ethanol mixed together.Add the solid aphidicolin to mixture, under room temperature, stir and spend the night, to guarantee that aphidicolin dissolves fully.Owing to contain high concentration ethanol in the preparation, therefore unnecessary the sterilization.
Each is handled and the results are shown in Table I and II, and is incorporated into Table III.Nympha, vaginal vestibule, pudendum, and the infringement of inside such as perineum belong to external damage (" E "), and the infringement of external genitalia fornix, the cloudy fornix in back, vaginal wall and vagina neck belongs to inner damage (" I ").
The effect of Table I .500 μ M aphidicolin treatment reproduction wart
| The patient | Infringement number and position | The reduction degree of treatment back infringement area (infecting the HPV area) | Sick time (moon) before the treatment | ||||
| E | I | 100％ | ＞50％ | ＜50％ | Trace | ||
| 1 | 0 | 1 | X | 2 | |||
| 2 | 2 | 0 | X | 2 | |||
| 4 | 0 | 2 | X | 3 | |||
| 6 | 3 | 0 | X | 1+ | |||
| 8 | 1 | 1 | X | 1+ | |||
| 10 | 2 | 2 | X | 4+ | |||
| 12 | 0 | 1 | X | 3 | |||
| 14 | 1 | 1 | X | 1+ | |||
| 16 | 2 | 0 | X | 5 | |||
| 18 | 1 | 2 | X | 1 | |||
| 20 | 1 | 1 | X | 2 | |||
| 23 | 1 | 2 | X | 2 | |||
| 25 | 0 | 2 | X | 6 | |||
| 28 | 1 | 1 | X | 50 | |||
| 30 | 4 | 1 | X | 12 | |||
| 32 | 2 | 1 | X | 1 | |||
| 34 | 1 | 1 | X | 4 | |||
| 36 | 1 | 1 | X | 3 | |||
| 37 | 0 | 1 | X | 2 | |||
| 40 | 1 | 1 | X | 48 | |||
The effect of Table II .100 μ M aphidicolin treatment reproduction wart
| The patient | Infringement number and position | The reduction degree of treatment back infringement area (infecting the HPV area) | Sick time (moon) before the treatment | ||||
| E | I | 100％ | ＞50％ | ＜50％ | Trace | ||
| 3 | 1 | 1 | X | 7 | |||
| 5 | 2 | 1 | X | 3 | |||
| 7 | 1 | 2 | X | 2 | |||
| 9 | 1 | 1 | X | 2+ | |||
| 11 | 0 | 1 | X | 2 | |||
| 13 | 1 | 1 | X | 6 | |||
| 15 | 2 | 1 | X | 3 | |||
| 17 | 2 | 1 | X | 3 | |||
| 19 | 1 | 2 | X | 5 | |||
| 21 | 1 | 2 | X | 3 | |||
| 22 | 0 | 1 | X | 1 | |||
| 24 | 2 | 0 | X | 5 | |||
| 26 | 0 | 1 | X | 4 | |||
| 27 | 1 | 2 | X | 3 | |||
| 29 | 0 | 2 | X | 5 | |||
| 31 | 1 | 1 | X | 3 | |||
| 33 | 1 | 1 | X | 2 | |||
| 35 | 2 | 1 | X | 5 | |||
| 38 | 1 | 2 | X | 2 | |||
| 39 | 1 | 1 | X | 3 | |||
Table III. the clinical trial synthesis result
| Solution | Case load | The result | |||
| 100% recovery from illness | ＞50% recovery from illness | ＜50% recovery from illness | Can ignore | ||
| 500μM | 20 | 3(15％) | 7(35％) | 10(50％) | 0(0％) |
| 100μM | 20 | 0(0％) | 9(45％) | 7(35％) | 4(20％) |
Some patient has the calcination sensation during administered formulation.Yet 80% above patient no longer includes pain and itches sensation and the minimizing of vagina Excreta.The patient of 100% recovery from illness is all no longer long wart after treatment finishes 2 months.
Claims (13)
1, a kind of local skin pharmaceutical preparation, it comprises:
(a) aphidicolin of 50～800 μ M, this concentration are enough to suppress intracellular dna polymerase activity at the viral infection skin part of administered formulation;
(b) pharmaceutically acceptable part excipient, described excipient is selected from gel, aerosol, powder, paste, emulsifiable paste, ointment machin FAPG substrate.
2, local skin pharmaceutical preparation according to claim 1, wherein said preparation contains the aphidicolin glycinate.
3, local skin pharmaceutical preparation according to claim 1, wherein the concentration of aphidicolin is 100 μ M to 500 μ M.
4, local skin pharmaceutical preparation according to claim 1, wherein said excipient comprises surfactant.
5, local skin pharmaceutical preparation according to claim 1, wherein said excipient is the emulsifiable paste that comprises stearyl alcohol and spermol.
6, local skin pharmaceutical preparation according to claim 5, wherein said emulsifiable paste also comprise propylene glycol and Polyethylene Glycol-100 stearate.
7, local skin pharmaceutical preparation according to claim 6, wherein said excipient is the emulsifiable paste that comprises following ingredients:
(a) 25% stearyl alcohol;
(b) 25% spermol;
(c) 12% propylene glycol;
(d) 10% PEG-100 stearate;
(e) 7.96% polysorbate 60;
(f) 5% sorbitan monostearate;
(g) 5% tristerin;
(h) 5% mineral oil;
(i) 5% distilled water;
(j) 0.025% methyl parahydroxybenzoate; And
(k) 0.015% propyl p-hydroxybenzoate.
8, aphidicolin is used to prepare the purposes of medicine, and described medicine is used for the treatment of the skin part that is subjected to papilloma virus infection.
9, purposes according to Claim 8, the position of wherein said papilloma virus infection are the reproduction warts.
10, according to Claim 8 or 9 purposes, wherein said medicine comprises aphidicolin and the pharmaceutically acceptable part excipient of 50～800 μ M, and described excipient is selected from liquid, gel, aerosol, powder, paste, emulsifiable paste, ointment machin FAPG substrate.
11, aphidicolin is used to prepare the purposes of medicine, and described medicine is used for the treatment of the skin part that is subjected to herpesvirus infection.
12, according to the purposes of claim 11, wherein said skin part is selected from the viral infection of HSV-1 and HSV-2.
13, according to the purposes of claim 11 or 12, wherein said medicine comprises aphidicolin and the pharmaceutically acceptable part excipient of 50～800 μ M, and described excipient is selected from liquid, gel, aerosol, powder, paste, emulsifiable paste, ointment machin FAPG substrate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43759395A | 1995-05-09 | 1995-05-09 | |
| US437,593 | 1995-05-09 | ||
| US437593 | 1995-05-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1135332A CN1135332A (en) | 1996-11-13 |
| CN1290493C true CN1290493C (en) | 2006-12-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95121116 Expired - Fee Related CN1290493C (en) | 1995-05-09 | 1995-12-20 | Local therapy for skin virus infection |
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| Country | Link |
|---|---|
| CN (1) | CN1290493C (en) |
| TW (1) | TW306878B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3915549A1 (en) * | 2020-05-26 | 2021-12-01 | Merck Patent GmbH | Senescence inducers for use in the treatment and/or prevention of virus induced diseases |
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| US11058699B2 (en) * | 2008-07-01 | 2021-07-13 | Wisconsin Alumni Research Foundation | Method and compositions for inhibition of double stranded DNA viruses |
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1995
- 1995-06-30 TW TW84106769A patent/TW306878B/en active
- 1995-12-20 CN CN 95121116 patent/CN1290493C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3915549A1 (en) * | 2020-05-26 | 2021-12-01 | Merck Patent GmbH | Senescence inducers for use in the treatment and/or prevention of virus induced diseases |
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| Publication number | Publication date |
|---|---|
| TW306878B (en) | 1997-06-01 |
| CN1135332A (en) | 1996-11-13 |
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Applicant after: TCW Pharmaceutical Co., Ltd. Applicant before: TCW Pharmaceutical Co., Ltd. |
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Correction item: Service bar Correct: delete False: deemed to have been withdrawn Number: 30 Page: 255 Volume: 17 |
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Granted publication date: 20061220 Termination date: 20100120 |