CN105263472A - Topical pharmaceutical composition comprising tenofovir, an antibacterial agent and,optonally ciclopirox - Google Patents
Topical pharmaceutical composition comprising tenofovir, an antibacterial agent and,optonally ciclopirox Download PDFInfo
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- CN105263472A CN105263472A CN201380054028.7A CN201380054028A CN105263472A CN 105263472 A CN105263472 A CN 105263472A CN 201380054028 A CN201380054028 A CN 201380054028A CN 105263472 A CN105263472 A CN 105263472A
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Abstract
The present invention relates in general to a topical pharmaceutical composition comprising an antiretroviral agent in combination with a bactericidal agent and optionally an antifungal agent, particularly for use as a contraceptive.
Description
Invention field
The present invention relates to the local medicine composition comprising antiretroviral agent and antibacterial and the optional antifungal existed, it is in particular as contraceptive.The present invention also openly prepares the method for described local medicine composition, and some purposes of described compositions.
Background technology
Oral contraceptive is the most common form of reversible contraception.About 30% current use oral contraceptive in Women of childbearing age, and 80% during its childbearing age, use oral contraceptive sometimes in all women.Oral contraceptive both provided the contraceptive efficacy of height, provided again a series of non-contraception health benefits, such as, reduced menstrual cramps, preventing ovarian cancer and carcinoma of endometrium, dystopy pregnancy and inflammatory pelvic disease.According to estimates, every 100, there are 1614 user to avoid because of the preventive effect of oral contraceptive in hospital when front in 000 oral contraceptive user.The method also has excellent safety, is reflected in formation component (estrogen and progestogen) and declines steadily.
But, oral contraceptive needs to use barrier approach to prevent to increase the sexually transmitted disease (STD) by candidal colpitic prevalence, need the frequency of life-time service and no matter sexual intercourse, relatively costly, reduce libido, cause irreversible chloasma (plaque-like facial pigmentation) when user exposes in the sun, and cause slight exception, such as Thyroid Hormones Levels raises.
Except oral contraceptive, can also adopt from physical method to chemical method, even other contraceptive methods various of operation method.Men's and female condom, barrier film, intrauterine device, vasectomy, tubal ligation are these class methods of minority.
In addition, acquired immunodeficiency disease (AIDS) is one of most dangerous and fatal disease, and has been considered to epidemic now.It is caused by HIV (human immunodeficiency virus) (HIV), and this virus can shift in every way or infect, but major way is by unshielded sexual intercourse and blood transfusion.
Contraception is for preventing conceived method, but it is applicable to the object by pre-preventing transmission prevention of sexually-transmitted diseases (STD) (mainly AIDS) equally.
Vaginal infection (vaginitis) is common, and (sexually transmitted disease (STD), Gardnerella or gonorrhea cause by candidiasis (yeast infection), chlamydia.Most of vaginal infection can be divided into: yeast infection, trichomonacide or bacterial vaginosis.These symptoms infected can comprise rubescent, swelling, stimulation, the secretions of pruritus and exception or abnormal smells from the patient.
This type of vaginal infection can use antifungal tablet or emulsifiable paste to treat usually.
But, do not have a kind of method to ensure fully to prevent HIV spread in said method, and have minimum opportunistic infection AIDS all the time.Some drugs part such as antiretroviral agent or antifungal (Drug-InducedReactivationofApoptosisAbrogatesHIV-1Infecti on, the people such as HartmutM.Hanauske-Abel, PLOSONE, in JIUYUE, 2013,8th volume, 9th phase, e74414) can by blocking the generation of the reproduction process restriction HIV of HIV.This makes again virus concentration decline steadily.
Tenofovir is this type of drug moiety a kind of, and with its prodrug forms tenofovir disoproxil fumarate (or PMPA) as antiretroviral agent, it is nucleotide analog reverse transcriptase inhibitors.Known tenofovir blocks requisite reverse transcriptase in virus produces, and stops copying of virocyte thus, thus containment virus.It is chemically being called ({ [(2R)-1-(6-amino-9H-purine-9-base) the third-2-base] oxygen base } methyl) phosphonic acids, and its chemical constitution is as follows.
Tenofovir can be used as in tablet and the form of oral powder
be purchased.
the combination of tenofovir as tablet and emtricitabine, and
it is the combination of tenofovir as tablet and emtricitabine and Sustiva.According to the order of severity of disease, the every daily dose of recommendation of the tenofovir in these preparations is in the scope of 150mg-300mg.
Ciclopirox is broad-spectrum antifungals, and is chemically being called 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H)-pyridone, 2-ethylaminoethanol salt.
Ciclopirox is pyridone ketone antifungal, and it is by polyvalent cation (Fe
3+or Al
3+) chelating work, thus cause the suppression of metal-dependent enzymes being responsible for peroxide degradation in fungal cell.
EP1773296 discloses the vaginal jellies preparation of the tenofovir comprised as antiretroviral agent.
" Invaginalfluid; bacteriaassociatedwithbacterialvaginosiscanbesuppressedw ithlacticacidbutnothydrogenperoxide ", DierdreEO ' Hanlon, ThomasRMoench and RichardACone, BMCInfectiousDiseases2011,11:200 disclose and use lactic acid antagonism bacterial vaginosis.
" GelsasvaginaldrugdeliverysystemsReviewArticle ", InternationalJournalofPharmaceutics, the 318th volume, 1-2 phase, on August 2nd, 2006,1-14 page, J.dasNeves, M.F.Bahia
US20050037033 discloses for preventing the propagation of Sex transmitted pathogen and/or common vaginal infection or being used for the treatment of the Synergistic microbicidal compositions comprising ciclopirox olamine of Sex transmitted pathogen and/or common vaginal infection.
WO9602226 discloses the pharmaceutical composition comprising 1-hydroxyl-2-pyridone (such as ciclopirox or Octopirox) and the combination as the crotamiton of activity of antifungal agents reinforcing agent.
WO9717075 discloses the local of ciclopirox or ciclopirox olamine and the surfactant being used for the treatment of the dermatosis of being induced by Pityrosporum oval can vesicatory compositions.
Reformulatedtenofovirgelforuseasadualcompartmentmicrobic ide, the people such as CharleneS.Dezzutti, JAntimicrobChemotherapy, 1-4,2012.
InVitroandExVivoTestingofTenofovirShowsItIsEffectiveAsan HIV-1Microbicide, the people such as LisaC.Rohan, PLoSONE, in February, 2010, the 5th volume, the 2nd phase, e9310.
Prior art discloses the tenofovir for antiretroviral purposes in vaginal jellies preparation.The lactic acid being used for the treatment of bacterial vaginosis is also disclosed in another prior art.Prior art discloses the ciclopirox preparation being used for the treatment of fungal infection in addition.
But, it should be noted, not prior art discloses the combination of tenofovir, lactic acid and ciclopirox.And any prior art does not all disclose the purposes of this combination yet, particularly as contraceptive.
We have recognized that the compositions needing to be used for the treatment of the virus of the above-mentioned type and the improvement of bacteriological infection.We also recognize the method needing the improvement promoting or provide contraception.
Goal of the invention
The object of this invention is to provide the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide the local medicine composition of combination and optional one or more the pharmaceutically acceptable excipient existed comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed and one or more the pharmaceutically acceptable excipient optionally existed for vaginal application.
Another object of the present invention is to provide the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed guaranteeing high effect.
Another object of the present invention is to provide the stable local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide the method for the preparation of the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide the method by using the local medicine composition contraception comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide and promotes contraception, the propagation of prevention retroviral infection and the method for the treatment of bacterial vaginosis by using the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
Another object of the present invention is to provide the purposes of local medicine composition as contraceptive of the ciclopirox comprising tenofovir, at least one or multiple antibacterial and optional existence.
Another object of the present invention is to provide the local medicine composition of the ciclopirox comprising tenofovir, at least one or multiple antibacterial and optional existence for promoting practise contraception, the prevent propagation of retroviral infection and the purposes for the treatment of bacterial vaginosis.
Summary of the invention
According to an aspect of the present invention, providing package is containing the local medicine composition of tenofovir, at least one antibacterial and the optional ciclopirox existed.
Preferably, described compositions also comprises ciclopirox.
Tenofovir, described at least one antibacterial and ciclopirox can be the form of pharmaceutically acceptable derivates, comprise such as pharmaceutically acceptable salt, solvate, complex, hydrate, dehydrate, isomer, ester, tautomer, enantiomer, polymorph or prodrug.
Suitably, compositions of the present invention comprises one or more pharmaceutically acceptable excipient.The form of described compositions preferably in gel.Particularly preferably vaginal jellies, that is, be suitable for those gels that topical vaginal is used.
In one aspect of the method, the present invention is also provided for the method for the local medicine composition preparing the form in vaginal jellies of the present invention, and described method comprises:
A) preparation comprises the medicine phase of tenofovir, at least one antibacterial and one or more pharmaceutically acceptable excipient;
B) ciclopirox solution is prepared together with one or more pharmaceutically acceptable excipient;
C) by step b) ciclopirox Solution Dispersion to step medicine a) mutually in form described gel.
In one aspect of the method, the invention provides a kind of method providing or promote contraception, described method comprises to there being the patient of these needs to use local medicine composition of the present invention.
The present invention also provides the method for the treatment of retroviral infection or bacteriological infection, particularly bacterial vaginosis, and described method comprises to there being the patient of these needs to use local medicine composition of the present invention.
In another aspect of the present invention, provide as medicine, in particular as contraceptive, or for promoting the local medicine composition as herein defined of practising contraception.
The present invention is also provided for the local medicine composition as herein defined for the treatment of retroviral infection or bacteriological infection, particularly bacterial vaginosis.
According to an aspect of the present invention, providing package contains the local medicine composition of tenofovir or its any pharmaceutically acceptable derivates, at least one or multiple antibacterial or its any pharmaceutically acceptable derivates and the ciclopirox optionally existed or its any pharmaceutically acceptable derivates.
According to another aspect of the present invention, be provided for preparing the method for the local medicine composition comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed and one or more the pharmaceutically acceptable excipient optionally existed.
According to a further aspect of the invention, the method by using the local medicine composition contraception comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed is provided.
According to a further aspect of the invention, provide by using the propagation of local medicine composition prevention retroviral infection and the method for the treatment of bacterial vaginosis that comprise tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
According to a further aspect of the invention, providing package contains the purposes of local medicine composition as contraceptive of tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
According to a further aspect of the invention, providing package contains the local medicine composition of tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed for preventing the propagation of retroviral infection and treating the purposes of bacterial vaginosis.
Detailed description of the invention
Contraception is used to prevent pregnancy and sexually transmitted disease (STD).Many methods can be used for contraception; Respectively there is the Pros and Cons of himself.Men's and female condom, lady's barrier film, hormone oral contraceptive, intrauterine device, vasectomy, tubal ligation are some contraceptive devices, but do not have a kind of method to provide in them to assure fully and guarantee to prevent pregnancy and infectivity to spread disease completely.
The present inventor has been found that the combination of tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed is inclined to because acid buffering character shows spermicide when mixing with seminal fluid.In addition, this combination strengthens contraceptive effect, thereby eliminates pregnancy or propagates the chance of this type of sexually transmitted disease (STD), and treat bacterial vaginosis.
According to the present invention, antibacterial can include but not limited to following in one or more: lactic acid, citric acid, fumaric acid, tartaric acid, malic acid, acetic acid, its mixture etc.Preferably, described antibacterial can be lactic acid.If needed, two or more antibacterial can be used.
Term " tenofovir ", " antibacterial " and " ciclopirox " use in a broad sense, not only comprise " tenofovir free alkali " or " ciclopirox free alkali " etc. itself, and comprise its pharmaceutically acceptable derivates.Suitable pharmaceutically acceptable derivates comprises its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable isomer, pharmaceutically acceptable ester, pharmaceutically acceptable dehydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable polymorph, pharmaceutically acceptable prodrug, pharmaceutically acceptable tautomer and/or pharmaceutically acceptable complex.
Term " lactic acid " also uses in a broad sense, not only comprises " lactic acid moieties " own, and comprises its pharmaceutically acceptable derivates.Suitable pharmaceutically acceptable derivates comprises its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable isomer, pharmaceutically acceptable ester, pharmaceutically acceptable dehydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable polymorph, pharmaceutically acceptable prodrug, pharmaceutically acceptable tautomer and/or pharmaceutically acceptable complex.
Compositions of the present invention can such as comprise in racemic lactic acid, the lactic acid of the form of D (-) lactic acid or L (+) lactic acid, or the pharmaceutically acceptable salt of one of free acid form, or the hydrate of one of free acid or salt form or solvate.In appropriate circumstances, same principle is also applicable to other acid, such as, and citric acid, fumaric acid, tartaric acid, malic acid and acetic acid.
Preferably, lactic acid can described compositions gross weight about 1%-about 10% amount exist.
Term " ciclopirox " also uses in a broad sense, not only comprises " ciclopirox " own, and comprises its pharmaceutically acceptable derivates.Suitable pharmaceutically acceptable derivates comprises its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable isomer, pharmaceutically acceptable ester, pharmaceutically acceptable dehydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable polymorph, pharmaceutically acceptable prodrug, pharmaceutically acceptable tautomer and/or pharmaceutically acceptable complex.
Term " pharmaceutically acceptable derivates " refer to have compared with active part equal or close to the pharmaceutical active compounds of equal physiological function.As used herein, term " pharmaceutically acceptable derivates " comprises any pharmaceutically acceptable ether, stereoisomer (comprising enantiomer, diastereomer, the mixture of stereoisomerism enrichment or racemic mixture) and can provide any other compound of (directly or indirectly) this compounds or its antiviral activity metabolite or residue when delivering medicine to receiver.
The example of the pharmaceutically acceptable salt of tenofovir and its pharmaceutically acceptable derivates comprises the salt derived from suitable alkali, and described alkali is such as alkali metal (such as sodium), alkaline-earth metal (such as magnesium), ammonium and NX
4 +(wherein X is C
1-C
4alkyl).The pharmaceutically acceptable salt of hydrogen atom or amino comprises the salt of organic carboxyl acid (such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid); The salt of organic sulfonic acid (such as methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid); And the salt of mineral acid (such as hydrochloric acid, sulphuric acid, phosphoric acid and sulfamic acid).The pharmaceutically acceptable salt of the compound of hydroxyl comprises the anion of described compound and suitable cat ions as Na
+and NX
4 +(wherein X is independently selected from H or C
1-C
4alkyl) combination.
For therapeutic use, the salt of active component can be pharmaceutically acceptable, and namely they are the salt derived from pharmaceutically acceptable acid or alkali.But the salt of unacceptable acid or alkali also can be used for such as preparing or the pharmaceutically acceptable compound of purification on physiology.All salt, whether derived from pharmaceutically acceptable acid or alkali all within the scope of the present invention.
As used herein, term " prodrug " refers to when delivering medicine to biosystem because the reaction of spontaneous chemical reaction, enzymatic chemical reaction and/or metabolic chemistry produces any compound of drug substance (active component).
" prodrug moiety " to be referred in general metabolism process in cell by hydrolysis, enzymatic lysis or the functional group of instability that is separated by active inhibitory compound by some additive methods.Prodrug moiety may be used for strengthening dissolubility, absorption and lipotropy, thus improves drug delivery, bioavailability and effect.Therefore, " prodrug " is the covalent modified analog of therapeutical active compound.
Tenofovir is when with its any prodrug forms, highly effective when namely PMEA [9-(2-phosphonomethoxyethyl) adenine)], PMPA [(1R)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine], tenofovir disoproxil fumarate or fumaric acid tenofovir Chinese mugwort draw phenol amine ester (tenofoviralafenamidefumarate) administration.
In in preferred at one, tenofovir is the form that tenofovir disoproxil fumarate or fumaric acid tenofovir Chinese mugwort draw phenol amine ester.
Preferably, tenofovir can described compositions gross weight about 1%-about 5% amount exist.
Ciclopirox preferably provides with the form of the ethanolamine salt of ciclopirox (being called ciclopirox olamine).Therefore, preferred local medicine composition of the present invention comprises the ciclopirox of the form in ciclopirox olamine.
Preferably, ciclopirox can described compositions gross weight about 0.05%-about 5% amount exist.
Aforementioned particularly preferred local medicine composition of the present invention comprises tenofovir disoproxil fumarate, lactic acid and the ciclopirox olamine optionally existed and one or more pharmaceutically acceptable excipient.
Another particularly preferred local medicine composition of the present invention comprises fumaric acid tenofovir Chinese mugwort and draws phenol amine ester, lactic acid and the ciclopirox olamine optionally existed and one or more pharmaceutically acceptable excipient.
Preferably, in above-mentioned often kind of situation, ciclopirox olamine is present in described local medicine composition.
In in preferred at one, local medicine composition of the present invention can comprise tenofovir disoproxil fumarate, lactic acid and the optional ciclopirox olamine existed in the dosage form being suitable for vaginal application.
In one aspect of the method, local medicine composition of the present invention can comprise the ciclopirox olamine that fumaric acid tenofovir Chinese mugwort is drawn phenol amine ester, lactic acid and optionally exists in the dosage form being suitable for vaginal application.
The local medicine composition comprising tenofovir, lactic acid and the optional ciclopirox existed of the present invention can in the dosage form being suitable for vaginal application, such as but not limited to gel, tablet, capsule, vaginal suppository, tampon, emulsifiable paste, paste, jelly, tablet, foam, film, ring, implant or spray etc.Preferably, local medicine composition of the present invention can be the form of vaginal jellies.
The local medicine composition comprising tenofovir, lactic acid and the optional ciclopirox existed of the present invention can be the form of Co ntrolled release preparation, delayed release preparation, prolongation delivery formulations, pulsation-releasing preparation and rapid release and Co ntrolled release slurriable combination etc.Prepare described compositions, to make it to produce the speed release of active ingredients of valid density in site of administration.
The aspect of the general expectation of the local medicine composition form of vaginal jellies (preferably in) comprises the acceptance of safety (such as, isotonic water gel), effect, stability and patient.Preparation aspect comprises best retention time, suitable drug diffusion and targeted delivery of drugs more specifically.
Local medicine composition of the present invention is preferably in the dosage form being suitable for vagina or rectal administration.Therefore, such as, described local medicine composition can the form of vaginal jellies or rectal gel provide.
But local medicine composition of the present invention can be provided with the form of such as gel, tablet, capsule, vaginal suppository, tampon, emulsifiable paste, paste, jelly, foam, film, ring, spray, suppository, enema, ointment, solution or suspensoid by those skilled in the art as required.
It should be understood that the pH of described compositions can be changed by those skilled in the art as required.Local medicine composition of the present invention preferably has the pH of 3.0-4.5.
If needed, local medicine composition of the present invention can also comprise the antiretroviral agent that at least one is selected from protease inhibitor, nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors and integrase inhibitor.Those skilled in the art will know that suitable operable medicament.
Local medicine composition in vaginal jellies form of the present invention is easy to use, and carefully think out, patient is painless, and cost effectively and successive administration safety.Local medicine composition in vaginal jellies form of the present invention also allows automedication, minimum to the interference of physical function and daily life.
The rheological equationm of state of gel successfully has considerable influence to practising contraception.Along with the denseness of used product increases, its effect is also owing to becoming more viscous and more anti-sperm migration and therefore reduce sperm to arrive the ability of the site of fertilization and increase.
According to an aspect of the present invention, the local medicine composition in vaginal jellies form guarantees high effect because of local application.
Vaginal jellies of the present invention can extend original position retention time, therefore can reduce application times.Ideally, preparation will be retained in biological surface, and medicine will be released close to absorbing film, and therefore bioavailability improves.
Local medicine composition of the present invention has lubricity, therefore convenient in coitus.The degree of lubrication provided by pharmaceutical composition of the present invention is its important determiner that is acceptable and that use.
Local medicine composition in vaginal jellies form of the present invention provides enough lubrications, to guarantee the compliance of patient.
The described local medicine composition comprising tenofovir, lactic acid and the optional ciclopirox existed can also comprise the suitable excipient that can be used for preparing vaginal jellies compositions of the present invention.
It should be understood that compositions of the present invention can comprise one or more pharmaceutically acceptable excipient usually.The suitable excipient that can be used for described local medicine composition includes but not limited to gellant, chelating agen, antiseptic, biological adhesive or polymer, viscosity improver or regulator, wetting agent/lubricant, surfactant, pH adjusting agent, solvent/co-solvent and tension regulator or penetrating agent.
The suitable gellant that can be used for described local medicine composition include but not limited to xanthan gum, sodium alginate (ManugelDMB),
eTD2020, polycarbophil, polysaccharide, natural gum, arabic gum, Tragacanth, starch, cellulose derivative is carboxymethyl cellulose such as, hydroxypropyl emthylcellulose, hydroxypropyl emthylcellulose (MethocelK4M), methacrylate polymers, polyvinylpyrrolidone, bentonite, alginic acid, carbomer, ethyl cellulose, gelatin, guar gum, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxyethylmethyl-cellulose, mountain Yu's pyrene acid glyceride, algae extract, natural gum, polysaccharide, poly(ethylene oxide), poloxamer, pectin, aminosal, comprise polymer or its ester that side hangs hydroxy-acid group, comprise the anhydride of the dicarboxylic acids group that side hangs polymer and based on the block copolymer etc. of oxirane and/or expoxy propane or its mixture.
Preferably, one or more gellant can described compositions gross weight about 0.05%-about 10% amount exist.
The chelating agen that can be used for local medicine composition includes but not limited to disodiumedetate, condensed phosphoric acid sodium, diethylene-triamine pentaacetic acid etc. or its combination.
Preferably, chelating agen can described compositions gross weight about 0.01%-about 1% amount exist.
The antiseptic that can be used for described local medicine composition includes but not limited to hydroxybenzoate (p-Hydroxybenzoate, such as methyl parahydroxybenzoate, propyl p-hydroxybenzoate), benzylalcohol, benzoic acid, chlorphenesin, sorbic acid, phenyl phenol etc. or its combination.
Preferably, one or more antiseptic can described compositions gross weight about 0.05%-about 2% amount exist.
The biological adhesive or the polymer that can be used for described local medicine composition include but not limited to hydroxyethyl-cellulose, gelatin, carbopol, polycarbophil, cross-linked poly-methyl methacrylate, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, ethyl cellulose, Polyethylene Glycol, hyaluronan, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, methylcellulose, starch etc. or its combination.
Suitable wetting agent and/or lubricant provide slickness and lubricity, thus promote filling and the distribution of described local medicine composition.
The lubricant that can be used for described local medicine composition includes but not limited to that polyhydric alcohols is as glycol, and polysaccharide, such as glycerol, ethylene glycol, propylene glycol, butanediol, diethylene glycol, dipropylene glycol, diglycerol, sorbitol, maltose alcohol, trehalose, Raffinose, xylitol, mannitol, Polyethylene Glycol, propylene glycol, polyglycereol, cholesterol, Squalene, fatty acid, octyldodecanol, myristyl alcohol, carbamide, lanoline, lactic acid, ester is isopropyl stearate such as, isopropyl myristate, isopropyl palmitate and isopropyl laurate etc. or its combination.
Preferably, lubricant can described compositions gross weight about 2%-about 20% amount exist.
Viscosity improver or regulator improve the formation of gel.The suitable viscosity improver or the regulator that can be used for described local medicine composition include but not limited to polyolefin, polyethylene, polypropylene, poly alpha olefin, ethylene-propylene copolymer, maleylation (maleneated) derivant of material herein, polyisobutylene, maleic anhydride and its diene derivatives, polymethacrylates, maleic anhydride-styrene copolymers and ester and its diene derivatives, the hydrogenated copolymer of styrene-butadiene, ethylene-propylene copolymer, polyisobutylene, hydrogenated styrene isoprene polymer, hydrogenated isoprene polymer, polymethacrylates, polyacrylate, alkyl styrenes, alkenyl aryl conjugated diene copolymer, polyolefin, the ester of maleic anhydride-styrene copolymers, with the ethylene-propylene copolymer that the product of maleic anhydride and amine is functionalized, with amine-functionalized polymethacrylates, the styrene-maleic anhydride copolymer reacted with amine, polymethacrylate polymer, esterified polymer, the esterified polymer of vi-ny l aromatic monomers and unsaturated carboxylic acid or derivatives thereof, olefin copolymer, ethylene-propylene copolymer, polyisobutylene etc. or its combination.
Suitable tension regulator or penetrating agent in order to mate the permeability (mosm) of physiological fluid include but not limited to glycerol, sodium chloride, potassium chloride, mannitol, sucrose, lactose, fructose, maltose, glucose, anhydrous glucose, propylene glycol, glycerol etc. or its combination.
Suitable both sexes, nonionic, cation or anion surfactant can be included in local medicine composition of the present invention.
According to the present invention, surfactant can include but not limited in following material one or more: Cortex cocois radicis oleoyl diethanolamine (coconutfattyaciddiethanolamide), Polysorbate, sodium lauryl sulphate (sodium lauryl sulfate), lauryl dimethyl amine oxide, docusate sodium, cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols, polyoxyethylene sorbitan, octoxinol, N, N-dimethyl dodecylamine-N-oxide, cetyl trimethyl ammonium bromide, polyoxyethylene 10 lauryl ether, Brij, cholate (NaTDC, sodium cholate), polyoxyethylene castor oil, nonyl phenol ethoxylate, cyclodextrin, lecithin, methylbenzethonium chloride, carboxylate, sulfonate, petroleum sulfonate, alkylbenzenesulfonate, naphthalene sulfonate, alkene sulfonate, alkyl sulfate, sulfate, sulfated natural oils and fat, sulphated esters, sulfated alkanolamide, ethoxylation and Sulfated alkyl phenol, the aliphatic alcohol of ethoxylation, polyoxyethylene surfactant, carboxylate, macrogol ester, Isosorbide Dinitrate and its ethoxylated derivative, the glycol ester of fatty acid, carboxylic acid amides, monoalkanolamine condensates, polyoxyethylene fatty acid amide, quaternary ammonium salt, there is the amine of amido link, polyoxyethylene alkyl amine and polyxyethylated cycloaliphatic amines, the quaternary ethylenediamine of N, N, N, N-, 2-alkyl-1-ethoxy-2-imidazoline, N-cocoyl-3-alanine/sodium salt, N-Adeps Bovis seu Bubali base-3-iminodipropionate salt, N-carboxymethyl-n-dimethyl-n-9-octadecylene base ammonium hydroxide, n-cocoamidoethyl-n-hydroxyethyl glycine sodium salt etc. or its combination.
Preferably, one or more surfactants can described compositions gross weight about 0.05%-about 20% amount exist.
The suitable pH adjusting agent or the buffer agent that can be used for described local medicine composition include but not limited to acidulant (such as hydrochloric acid, acetic acid, citric acid, tartaric acid, propanoic acid), sodium hydroxide, sodium phosphate, ammonia solution, triethanolamine, sodium borate, sodium carbonate, potassium hydroxide etc. or its combination.
Preferably, one or more buffer agents can described compositions gross weight about 0.1%-about 2% amount exist.
Can be used for the suitable solvent/co-solvent of described local medicine composition, solubilizing agent or vehicle include but not limited to water, glycerol, Cortex cocois radicis oleoyl diethanolamine, medium chain and/or long-chain fatty acid or glyceride, monoglyceride, diglyceride, triglyceride, structuring triglyceride, soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Semen Maydis oil monoglyceride, Semen Maydis oil diglyceride, Semen Maydis oil triglyceride, Polyethylene Glycol, capryl-caproyl base polyethyleneglycol glyceride (caprylocaproylmacroglycerides), caproyl90, propylene glycol, polyoxyethylene sorbitan fatty acid esters, castor oil derivatives, Oleum Ricini, Oleum Gossypii semen, olive oil, safflower oil, Oleum menthae, Oleum Cocois, palmit seed oil, Cera Flava, oleic acid, methanol, ethanol, isopropyl alcohol, butanols, acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone or its mixture.
Preferably, one or more solvents can described compositions gross weight about 0.05%-about 20% amount exist.
In this case, described local medicine composition not only contains the compositions being suitable for vaginal application, and is suitable for the compositions of rectum and applied dermally under being encompassed in scope of the present invention.
The preparation used for rectum can be rendered as suppository, enema,retention, ointment, emulsifiable paste, solution, tablet, aerosol, jelly, suspensoid, gel or the foam and transdermal skin patches with suitable substrate.
In the context of the present invention, it should be understood that term local comprises and be administered to body cavity and skin.
Therefore, the local medicine composition comprising tenofovir, lactic acid and the optional ciclopirox existed of the present invention is administered to the body cavity of such as anus or vagina.In an especially preferred embodiment, described local medicine composition is administered to vagina.
The local medicine composition comprising tenofovir, lactic acid and the optional ciclopirox existed of the present invention can relate to and locally applies to vagina, to promote contraception, the propagation of prevention retroviral infection and treatment bacterial vaginosis in vaginal intercourse process.Therefore, provide compositions of the present invention for promoting contraception, prevention retroviral infection and prevention or treatment bacterial vaginosis.
Usually, local application is before beginning vaginal intercourse, and before beginning vaginal intercourse, 0-60 minute, preferred 0-5 minute carry out suitably.
In the present invention, suitably, pH remains between 3.0 and 4.5.Preferably, the pH of described local medicine composition is between 3.8 and 4.2 ± 0.2.
Local medicine composition of the present invention can also comprise sweeting agent, spice and can improve this type of excipient any of aesthstic attractive force of described compositions.
In another aspect of the present invention, described local medicine composition can also be the form of nano-emulsion.In nano-emulsion to be average droplet size be 50-1000nm and droplet size is the Emulsion of 100nm and 500nm.Granule can be used as Water-In-Oil and oil-in-water form exists.Nano-emulsion can by any method, obtain such as but not limited to high pressure homogenizing, phase transition temperature technology and Micro Fluid.
Nano-emulsion can comprise the suitable excipient that can be used for preparing described nano-emulsion, such as but not limited to oil, emulsifying agent, antioxidant, tension regulator, pH adjusting agent and antiseptic.
In another aspect of the present invention, described local medicine composition can also be the form of nano suspension.Nano suspension is size in aqueous vehicles lower than the very thin colloidal state of 1 μm, the solid drug particles of two-phase dispersion.
In another aspect of the present invention, described local medicine composition can also be the form of solid lipid nano-particles.
In another aspect of the present invention, described local medicine composition also can comprise micelle.Micelle is the aggregation of the surfactant molecule be dispersed in liquid colloid.When the surfactant existed is higher than CMC (critical micelle concentration), they as emulsifying agent, can allow usually the compound dissolution of insoluble (in solvent for use).
In another aspect of the present invention, the described local medicine composition form that can also discharge in response to some events such as vagina or coitus in ano in wherein active part.Such as, described compositions can contain compositions in vesicle or liposome, and described vesicle or liposome are destroyed by the mechanism of sexual intercourse.Liposome is microcosmic vesicle, due to the key component of liposome and the similarity of natural membranes, wherein can mix multi-medicament nontoxic with biodegradable preparation to be formed.It allows high Premeabilisation of cells, the efficient targeting of the tissue of macrophage enrichment and the remarkable improvement of drug pharmacokinetics.Local medicine composition of the present invention provides activating agent sending to the improvement of the cell of infection, and reduce the toxic action relevant with said composition, thus show effect and the safety of the improvement of medicine, to promote contraception, the propagation of prevention retroviral infection and treatment bacterial vaginosis.
According to one embodiment of the invention, described local medicine composition can be included in the active substance in nano-scale range.
The nanosized surface area exposure of granule that makes increases, thus increases rate of dissolution.Nano-particle of the present invention can by any method, and such as but not limited to grinding, precipitate, homogenize, atomizing freeze drying, supercritical fluid technology, PRINT (particle replication in non-wetted template), capillary aerosol generator, supersound process and spraying dry obtain.
According to one embodiment of the invention, use together with the antiretroviral active component that the local medicine composition of the form in vaginal jellies also can be extra with one or more.These antiretroviral drugs can belong to any one of following kind of apoplexy due to endogenous wind: protease inhibitor, nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors and integrase inhibitor.
The suitable protease inhibitor (PI) of local medicine composition used in the present invention can comprise Saquinavir; Ritonavir; Viracept see nelfinaivr; Amprenavir; Lopinavir; Indinavir; Viracept see nelfinaivr; Atazanavir; LASINAVIR BMS-234475 Lasinavir [INN; Palinavir; Tipranavir; That Wei of furan mountain; Prezista; Tipranavir; N-cycloalkyl glycine, Alpha-hydroxy aryl butyramide; Alpha-hydroxy-γ-[[(carbocyclic ring or heterocyclic substituted) is amino) carbonyl] alkanamides derivant; γ-hydroxyl-2-(fluoroalkyl amino carbonyl)-1-piperazine pentanamide; Dihydropyrone derivatives and α-and beta-amino acids hydroxyethylamino sulfonamide; And the 1B derivant of N-aminoacid replacement.
The suitable nucleoside reverse transcriptase inhibitor (NRTI) of pharmaceutical composition used in the present invention can comprise zidovudine; Didanosine; Stavudine; Lamivudine; Abacavir; Adefovirdipivoxil; Lobucavir; Entecavir; A Lita shore; Emtricitabine; Zalcitabine; Right Elvucitabine; Alovudine; Amdoxovir; Elvucitabine; Phosphazide (phosphazid); Racivir; Stampidine; β-L-FD4 (also referred to as β-L-D4C and called after β-L-2', 3'-dideoxy-5-fluorine cytidine); DAPD, purine nucleosides, (-)-β-D-2,6-diaminopurine dioxolanes; And lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-beta-D-Su Shi-furan pentose base) adenine.
The suitable nucleotide reverse transcriptase inhibitors (NtRTI) of pharmaceutical composition used in the present invention can comprise adefovirdipivoxil.
The suitable non-nucleotide reverse transcriptase inhibitors (NNRTI) of pharmaceutical composition used in the present invention can comprise nevirapine, rilpivirine, Delavirdine, efavirenz, etravirine (etravirine), furopyridine-thiopyrimidine (furopyridine-thiopyrimide); Capravirine; 5-(3,5-Dichlorobenzene base)-sulfo--4-isopropyl-1-(4-pyridine radicals) methyl isophthalic acid H-imidazoles-2-ylmethyl carbonic ester); Emivirine (1-(ethoxyl methyl)-5-(1-Methylethyl)-6-(phenyl methyl)-(2,4 (1H, 3H)-hybar X); (+)-calanolide A A and B ((+)-calanolideA and B), coumarin derivative; Reach a Wei Lin; 4-{4-[4-((E)-2-vinyl)-2,6-dimethylphenylamino] pyrimidine-2--amino] benzonitrile; 12-ethyl-8-[2-(1-hydroxyquinoline-4-base oxygen base) ethyl]-5-methyl isophthalic acid 1,12-dihydro-5H-1,5,10,12-tetra-azepine dibenzo [a, e] cyclo-octene-6-ketone; The bromo-3-of 7-[2-(2,5-Dimethoxyphenyl) ethyl]-3,4-dihydro-1H-pyridos [1,2-a] [-1,3,5] triazine-2-thioketone and 1-(5-bromopyridine-2-base)-3-(2-thiophene-2-base ethyl) thiourea.
The suitable integrase inhibitor of pharmaceutical composition used in the present invention can comprise Merck, dust for lattice Wei.
Antiretroviral agent of the present invention can use derived from the form of mineral acid or organic acid salt or ester.These salt include but not limited to following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate, digluconate, cyclopentane propionate, lauryl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochlorate, hydrobromate, hydriodate, 2-isethionate (isethionate), lactate, maleate, mesylate, nicotinate, 2-naphthalene sulfonate, oxalates, embonate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, rhodanate, tosilate and undecylate.Such as, and Basic nitrogen-containing groups can be quaternized with reagent, described reagent such as elementary alkyl halide, the chloride of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate, such as dimethyl, diethyl, dibutyl and diamyl sulfate; Long chain halide, the chloride of such as decyl, lauryl, myristyl and stearyl, bromide and iodide; Aralkyl halide, such as benzyl and phenylethyl bromide, and other.
The present invention is also provided for the method for the local medicine composition prepared in vaginal jellies form, and described method comprises:
A) preparation comprises the medicine phase that tenofovir and at least one antibacterial and one or more are selected from the excipient of vehicle, pH adjusting agent, chelating agen and gellant;
B) preparation comprises the solution of ciclopirox, one or more vehicles, antiseptic;
C) by step b) ciclopirox Solution Dispersion to step medicine a) mutually in form described gel.
The present invention also provides the method by using the local medicine composition contraception comprising tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
The present invention also provides by using the propagation of local medicine composition prevention retroviral infection and the method for the treatment of bacterial vaginosis that comprise tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
The present invention goes back the purposes of local medicine composition as contraceptive that providing package contains tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed.
The present invention goes back providing package and contains the local medicine composition of tenofovir, at least one or multiple antibacterial and the optional ciclopirox existed for preventing the propagation of retroviral infection and treating the purposes of bacterial vaginosis.
The following example only for illustration of object of the present invention, and is not intended to limit the scope of the invention by any way.
Embodiment 1
The preparation of organic facies:
1. glycerol is heated.
2. methyl parahydroxybenzoate and propyl p-hydroxybenzoate added and be dissolved in the glycerol of heating.
3. the solution cooling will obtained in step 2.
4. hydroxyethyl-cellulose added and be dispersed in from the solution that step 3 obtains, to obtain thick dispersion.
The preparation of medicine phase:
1. disodiumedetate is dissolved in water.
2. lactic acid added and dissolve in the solution obtained in step 1.
3. tenofovir is disperseed in the solution obtained in step 2.
4. use sodium hydroxide and hydrochloric acid by pH regulator to 3.8-4.5, until obtain the solution of tenofovir.
The preparation of gel:
1. medicine is added in organic facies, mutually with continuous stirring to obtain gel.
Embodiment 2
The preparation of organic facies:
1. glycerol is heated.
2. methyl parahydroxybenzoate and propyl p-hydroxybenzoate added and be dissolved in the glycerol of heating.
3. the solution cooling will obtained in step 2.
4. polycarbophil added and be dispersed in from the solution that step 3 obtains, to obtain thick dispersion.
The preparation of medicine phase:
1. disodiumedetate is dissolved in water.
2. lactic acid added and dissolve in the solution obtained in step 1.
3. tenofovir is disperseed in the solution obtained in step 2.
4. use sodium hydroxide and hydrochloric acid by pH regulator to 3.8-4.5, until obtain the solution of tenofovir.
The preparation of gel:
1. medicine is added in organic facies, mutually with continuous stirring to obtain gel.
Embodiment 3
The preparation of tenofovir medicine phase
1) disodiumedetate is dissolved in pure water;
2) citric acid, lactic acid and tenofovir are added in the solution obtained in step (1);
3) hydrochloric acid is added in the solution obtained in step (2) to dissolve tenofovir;
4) pH of the solution obtained in step (3) is regulated with sodium hydroxide solution;
5) xanthan gum is added in the solution obtained in step (4), to form the gel without agglomerate.
The preparation of ciclopirox olamine solution
1) glycerol and propylene glycol are added in pure water, and heat;
2) methyl parahydroxybenzoate, propyl p-hydroxybenzoate, Cortex cocois radicis oleoyl diethanolamine and polysorbate 60 are added in the solution obtained in step (1).
The preparation of gel:
1) added with continuous stirring in organic facies mutually by medicine, to obtain gel, and required volume pure water is supplied, and measures pH.
It will be apparent for a person skilled in the art that and can carry out various substituting and amendment to invention disclosed herein, and do not deviate from scope of the present invention.Therefore, be understood that, although specifically disclose the present invention by preferred embodiment and the optional feature existed, those skilled in the art can take the modifications and variations of concept disclosed herein, and these type of modifications and variations are considered within the scope of the invention.
It should be understood that wording used herein and term are for purposes of illustration, and should not be construed as restriction." comprising " used herein, " comprising " or " having " and its variant are intended to comprise project listed thereafter and its equivalent and sundry item.
Must be noted that as in this specification and in the appended claims use, unless the context clearly dictates otherwise, otherwise English singulative " a ", " an " and " the " comprise a plurality of indicant.Therefore, such as, mention that " cosolvent " refers to single cosolvent or the combination etc. of two or more cosolvent.
Claims (28)
1. local medicine composition, it comprises tenofovir, at least one antibacterial and the optional ciclopirox existed.
2. local medicine composition according to claim 1, wherein said compositions comprises ciclopirox.
3. the local medicine composition described in claim 1 or 2, one or more wherein in tenofovir, described at least one antibacterial and ciclopirox are the form of pharmaceutically acceptable derivates, and it comprises pharmaceutically acceptable salt, solvate, complex, hydrate, dehydrate, isomer, ester, tautomer, enantiomer, polymorph or prodrug.
4. the local medicine composition described in claim 1,2 or 3, wherein tenofovir is the form that tenofovir disoproxil fumarate or fumaric acid tenofovir Chinese mugwort draw phenol amine ester.
5. the local medicine composition described in claim 1,2,3 or 4, wherein tenofovir exists with the amount of the about 1%-about 5% of the gross weight of described compositions.
6. the local medicine composition described in arbitrary aforementioned claim, wherein said antibacterial is selected from lactic acid, citric acid, fumaric acid, tartaric acid, malic acid and acetic acid.
7. the local medicine composition described in arbitrary aforementioned claim, wherein said antibacterial comprises lactic acid.
8. the local medicine composition described in arbitrary aforementioned claim, wherein said antibacterial comprises in racemic lactic acid, the lactic acid of the form of D (-) lactic acid or L (+) lactic acid.
9. the local medicine composition described in arbitrary aforementioned claim, wherein lactic acid exists with the amount of the about 1%-about 10% of the gross weight of described compositions.
10. the local medicine composition described in arbitrary aforementioned claim, wherein ciclopirox is the form of ciclopirox olamine.
Local medicine composition described in 11. arbitrary aforementioned claim, wherein ciclopirox olamine exists with the amount of the about 0.05%-about 5% of the gross weight of described compositions.
Local medicine composition described in 12. arbitrary aforementioned claim, it comprises tenofovir disoproxil fumarate, lactic acid and the optional ciclopirox olamine existed.
Local medicine composition according to any one of 13. claim 1-11, it comprises fumaric acid tenofovir Chinese mugwort and draws phenol amine ester, lactic acid and the optional ciclopirox olamine existed.
Local medicine composition described in 14. claim 12 or 13, it comprises ciclopirox olamine.
Local medicine composition described in 15. arbitrary aforementioned claim, it comprises one or more pharmaceutically acceptable excipient, one or more pharmaceutically acceptable excipient described be selected from chelating agen, antiseptic, biological adhesive, viscosity improver, wetting agent/lubricant, surfactant and pH adjusting agent and tension regulator one or more.
Local medicine composition described in 16. arbitrary aforementioned claim, wherein said compositions is in the dosage form being suitable for vagina or rectal administration.
Local medicine composition described in 17. arbitrary aforementioned claim, wherein said compositions provides with the form of gel, tablet, capsule, vaginal suppository, tampon, implant, emulsifiable paste, paste, jelly, foam, film, ring, spray, suppository, enema, ointment, solution or suspensoid.
Local medicine composition described in 18. arbitrary aforementioned claim, wherein said compositions is the form of nano-emulsion or nano suspension, or as solid lipid nano-particles or micelle.
Local medicine composition described in 19. arbitrary aforementioned claim, it is the form of vagina or rectal gel.
Local medicine composition described in 20. arbitrary aforementioned claim, the pH of wherein said compositions is 3.0-4.5.
Local medicine composition described in 21. arbitrary aforementioned claim, it also comprises the antiretroviral agent that at least one is selected from protease inhibitor, nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors and integrase inhibitor.
22. for the preparation of the method for local medicine composition in vaginal jellies form described in arbitrary aforementioned claim, and described method comprises:
A) preparation comprises the medicine phase of tenofovir and at least one antibacterial and one or more pharmaceutically acceptable excipient;
B) ciclopirox solution is prepared together with one or more pharmaceutically acceptable excipient;
C) by step b) ciclopirox Solution Dispersion to step medicine a) mutually in form described gel.
23. provide or promote the method for practising contraception, and described method comprises to there being the patient of these needs to use local medicine composition according to any one of claim 1-21.
24. treatment retroviral infections or the methods of bacteriological infection, particularly bacterial vaginosis, described method comprises to there being the patient of these needs to use local medicine composition according to any one of claim 1-21.
Local medicine composition according to any one of 25. claim 1-21, it is used as medicine.
Local medicine composition according to any one of 26. claim 1-21, it is used as contraceptive.
Local medicine composition according to any one of 27. claim 1-21, it is used for the treatment of retroviral infection or bacteriological infection, particularly bacterial vaginosis.
28. substantially as the local medicine composition herein as described in reference embodiment.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/GB2013/053001 WO2014041378A2 (en) | 2012-09-14 | 2013-11-14 | Topical pharmaceutical composition |
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| Publication Number | Publication Date |
|---|---|
| CN105263472A true CN105263472A (en) | 2016-01-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380054028.7A Pending CN105263472A (en) | 2013-11-14 | 2013-11-14 | Topical pharmaceutical composition comprising tenofovir, an antibacterial agent and,optonally ciclopirox |
Country Status (2)
| Country | Link |
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| KR (1) | KR20160072829A (en) |
| CN (1) | CN105263472A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112891323A (en) * | 2020-01-22 | 2021-06-04 | 首都医科大学附属北京地坛医院 | anti-HIV (human immunodeficiency virus) external disinfectant and preparation method thereof |
| CN113194945A (en) * | 2018-08-23 | 2021-07-30 | 光州科学技术院 | Use of ciclopirox for inhibiting HBV core assembly |
-
2013
- 2013-11-14 KR KR1020157007557A patent/KR20160072829A/en not_active Application Discontinuation
- 2013-11-14 CN CN201380054028.7A patent/CN105263472A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113194945A (en) * | 2018-08-23 | 2021-07-30 | 光州科学技术院 | Use of ciclopirox for inhibiting HBV core assembly |
| CN112891323A (en) * | 2020-01-22 | 2021-06-04 | 首都医科大学附属北京地坛医院 | anti-HIV (human immunodeficiency virus) external disinfectant and preparation method thereof |
| CN112891323B (en) * | 2020-01-22 | 2023-08-18 | 首都医科大学附属北京地坛医院 | anti-HIV external disinfectant and preparation method thereof |
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| KR20160072829A (en) | 2016-06-23 |
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