CN101172159A - Acidic biological adhesion heat-variable gelling agent, its preparing method and uses - Google Patents
Acidic biological adhesion heat-variable gelling agent, its preparing method and uses Download PDFInfo
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- CN101172159A CN101172159A CNA2006101177165A CN200610117716A CN101172159A CN 101172159 A CN101172159 A CN 101172159A CN A2006101177165 A CNA2006101177165 A CN A2006101177165A CN 200610117716 A CN200610117716 A CN 200610117716A CN 101172159 A CN101172159 A CN 101172159A
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Abstract
The invention discloses acidic biologic adhesion heat-variable gelling agent, which includes (a) 12-20 wt percent of polyoxy ethylene polyoxy propylene polymer, (b) 0.5-10wt percent of polydimethyl siloxane and (c) 1.0-2.5 wt percent of acidity buffering agent. The invention is characterized in that a pH value is 3.0 to 4.5, the gelling agent is under a liquid state at the temperature less than and equal to 28 DEG C, and is under a gel state at the temperature more than and equal to 32 DEG C. The acidic biologic adhesion heat-variable gelling agent is used to prepare liquid preparation with the function of both contraception and preventative spread disease (STDs/HIV). The acidic biologic adhesion heat-variable gelling agent provides reformation and convenience for a production process, the loading and filling operation of the liquid medicine is convenient, the filling amount is accurate, and the invention particularly is suitable for GMP scale production and becomes an optimal substitute of a contraceptive sheath or lubricating additive.
Description
Technical field
The present invention relates to pharmaceutical field, relate in particular to pharmaceutic adjuvant gel and method for making thereof and purposes.
Background technology
Gel is applied to the clinical existing several years, originally mostly is hospital preparation and prepares in a small amount, because continuous expansion of range of application in recent years and commercial production levels improve constantly, the gel of existing more kind is produced in batches.Keep gluey when being room temperature, dry or liquefaction for the requirement of commercially available gel.
For example there is a kind of gel of controlling vagina pH to sell Aci-Jel on the market
TM(NJ), it is a kind of water-dispersible buffer gel, has the pH of 3.9-4.1 for Ortho-McNeilPharmaceutical Corp., Raitan, is used for recovering and keeping normal acid vagina.Though it under external room temperature or temperature environment in vivo, gel all, and the mucomembranous surface of vagina has many folds, such gel design can not cover the vaginal mucosa surface completely effectively.Though these gel design may command vaginas pH can not produce thin film or barrier layer effectively, thereby can't satisfy further treatment requirement, as catch and/or kill pathogen or the sperm that causes sexually transmitted disease (STD) (STDs) on the vaginal mucosa layer.
United States Patent (USP) 5,439 provides a kind of pharmaceutical composition that is used to prevent sexually transmitted disease (STD) 685 (Augusts 8 nineteen ninety-five).These compositionss produce foam according to being reported on the vaginal mucosa layer, contact thereby prevent to cause the microorganism of STDs to show with vagina.Yet these preparation bioadhesives are bad, can not really form barrier on the vaginal mucosa surface, therefore can not fully catch microorganism and/or the sperm that causes STDs, can not prevent that sperm from entering.
At present all gels are owing to keep gluey during room temperature, and toughness is difficult to accurate loading amount aborning, and GMP large-scale production difficulty is very big.
Therefore, this area presses for provides a kind of new medicinal gel adjuvant, and its temperature-sensitive varies with temperature the gel state that can be become by the liquid state of room temperature under the body temperature, has excellent bioadhesive; And can be accurately canned, be fit to the GMP large-scale production.
Summary of the invention
The present invention aims to provide a kind of new acidic biological adhesion heat-variable gelling agent.
Second purpose of the present invention provides the liquid preparation that contains above-mentioned acidic biological adhesion heat-variable gelling agent.
The 3rd purpose of the present invention provides the preparation method of above-mentioned acidic biological adhesion heat-variable gelling agent.
The 4th purpose of the present invention provides the medical usage of above-mentioned acidic biological adhesion heat-variable gelling agent.
The 5th purpose of the present invention provides a kind of product, can scribble the above-mentioned liquid preparation that contains acidic biological adhesion heat-variable gelling agent on this product.
In a first aspect of the present invention, a kind of acidic biological adhesion heat-variable gelling agent is provided, it contains following component:
(a) 12-20wt% polyoxyethylene polyoxypropylene polymer, alginic acid or chitosan;
(b) 0.5-10wt% polydimethylsiloxane, dimethiconol or dimethyl siloxane ether copolymer;
(c) 1.0-2.5wt% acid buffer agent,
Wherein, described gel has characteristic:
PH is 3.0-4.5; With
Described gel is liquid during in temperature≤28 ℃, is gel state during in temperature 〉=32 ℃.
In another preference, by 100 gram gels, it contains:
(a) 12-20 gram polyoxyethylene polyoxypropylene polymer, alginic acid or chitosan;
(b) 0.5-10 gram polydimethylsiloxane, dimethiconol or dimethyl siloxane ether copolymer; With
(c) 1.0-2.5 gram acid buffer agent.
In another preference, described gel 32-40 ℃ temperature is a gel state.
In another preference, the viscosity 17-22Pas when described gel is gel state.
In another preference, described gel contains 12-20wt% polyoxyethylene polyoxypropylene polymer, 0.5-10wt% polydimethylsiloxane and 1.0-2.5wt% acid buffer agent.
In another preference, described acid buffer agent 0.2-1.0M pH3.2-4.0.
In another preference, described acid buffer agent is the acetate buffer agent.
In another preference, the pH3.5-4.2 of described gel.
In another preference, described gel also contains one or more additives that are selected from down group: wetting agent, antiseptic, dispersant, stabilizing agent etc.
In another preference, described additive comprises: 0.6-10wt% wetting agent, 0.1-10wt% antiseptic.
In a second aspect of the present invention, a kind of liquid preparation that has both contraception and prevention of sexually-transmitted diseases is provided,, it contains:
(i) above-mentioned acidic biological adhesion heat-variable gelling agent; With
The active constituents of medicine, microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug.
In another preference, described liquid preparation has following characteristic:
PH is 3.0-4.5; With
Described gel is liquid during in temperature≤28 ℃, is gel state during in temperature 〉=32 ℃.
In another preference, the component of described liquid preparation (ii) is fit to the active constituents of medicine of intravaginal and/or drop rectum with drug, microbicide, or spermicide is selected from down group: nonoxynolum (NP-9), Menfegol (TS-88), hot menthylphenoxypolyethoxy ethanol (OP-9), cationic surfactant Benzalkonii Chloridum (Benzalkoniumchloride, BZK), alkyl betaine, the alkyl dimethyl amine oxide compositions, Gramicidin, polyethoxy sulfate/poly Sulfonates chemical compound, deoxidation gallbladder acyl tyrosine, mannose binding lectin, phytolaccatoxin, tea saponin, gossypol and derivant thereof, or its combination.
In another preference, described component content (ii) is 0.1-2wt%.
In another preference, the microbicide that described component (ii) is fit to intravaginal and/or drop rectum with drug be deoxidation gallbladder acyl tyrosine (Deosycholy tyrosine, DCT).
In another preference, described having both in the contraception and the liquid preparation of prevention of sexually-transmitted diseases, contained 0.1-2wt%DCT, 12-20wt% polyoxyethylene polyoxypropylene polymer, the acid buffer agent of 0.5 1 10wt% polydimethylsiloxane and 2.0-5.0wt%pH3.2-4.0.
In a third aspect of the present invention, a kind of preparation method as above-mentioned acidic biological adhesion heat-variable gelling agent is provided, it comprises step:
With 12-20wt% polyoxyethylene polyoxypropylene polymer, alginic acid or chitosan, 0.5-10wt% polydimethylsiloxane, dimethiconol or dimethyl siloxane ether copolymer and 1.0-2.5wt% acid buffer agent mixed dissolution form acidic biological adhesion heat-variable gelling agent.
In another preference, with 10-12wt%Poloxamer127,2-8wt%Poloxamer188,0.5-10wt% polydimethylsiloxane and 1.0-2.5wt% acetate buffer agent mixed dissolution form acidic biological adhesion heat-variable gelling agent.
In another preference, also can add 0.6-10wt% wetting agent and 0.1-10wt% antiseptic.
In another preference, also add 0.6-10wt% glycerol and 0.1-10wt% sodium benzoate.
In a fourth aspect of the present invention, provide a kind of as above-mentioned application of acidic biological adhesion heat-variable gelling agent in the preparation liquid preparation.
In another preference, described liquid preparation is the liquid preparation that has both contraception and prevention of sexually-transmitted diseases.
In another preference, described liquid preparation is selected from following dosage form: lotion, liniment, drop, varnish, enema, irrigating etc.
In another preference, described liquid preparation is aseptic.
In another preference, described liquid preparation is to store in the applicator of being made by polyurethane ethers plastics, and it can hold this product of 4-5ml, and single uses.
In a fifth aspect of the present invention, a kind of product is provided, described product scribbles above-mentioned liquid preparation, and it contains described liquid preparation:
(i) above-mentioned acidic biological adhesion heat-variable gelling agent; With
The active constituents of medicine, microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug.
In another preference, described product is condom and the coating that above-mentioned liquid preparation formation is arranged at its skin.
In view of the above, the invention provides a kind of new medicinal gel adjuvant, its temperature-sensitive varies with temperature the gel state that can be become by the liquid state of room temperature under the body temperature, has excellent bioadhesive; And can be accurately canned, be fit to the GMP large-scale production.
The specific embodiment
The inventor is through extensive and deep research, be surprised to find that non-ionic surface active agent, dispersant and acid ion combinations of buffers, can obtain a kind of (＜28 ℃) at normal temperatures for liquid, and at the material that can become gel state more than 32 ℃, and this material has the acidic buffer ability.Particularly, described non-ionic surface active agent is the polyoxyethylene polyoxypropylene polymer, and described dispersant is a polydimethylsiloxane.
The inventor also finds, this material as inert base, can be prepared the liquid preparation that vagina or internal rectum have both contraception and prevention of sexually-transmitted diseases.
Acidic biological adhesion heat-variable gelling agent
Acidic biological adhesion heat-variable gelling agent provided by the invention is water white transparency glue (temperature 〉=32 ℃ time), be a kind of inertia and nontoxic, change the heat-sensitive gel of gel (temperature 〉=32 ℃) with ambient temperature by aqueous (temperature≤28 ℃) into responsive to temperature.pH3.0-4.5。
Acidic biological adhesion heat-variable gelling agent provided by the invention contains substrate excipient, bioadhesive polymer, dispersant and acid buffer agent.
Described substrate excipient should be stablized in the scope of pH3.5～4.2, can use this area nonionic surfactant commonly used, it is selected from but is not limited to: polyoxyethylene polyoxypropylene polymer, Carbopol 941 (Carbomer), alginic acid, chitosan, wherein preferred poloxamer (Poloxamer), more preferably Poloxamer407 or Poloxamer127.In a preferred embodiment of the present invention, contain 15-20wt%Poloxamer127, more preferably, contain 16-18wt%Poloxamer127.
Described bioadhesive polymer can use this area nonionic surfactant commonly used, it is selected from but is not limited to: polyoxyethylene polyoxypropylene polymer, alginic acid, chitosan, wherein preferred poloxamer (Poloxamer), more preferably Poloxamer188 (being F68).In a preferred embodiment of the present invention, contain 2-8wt%Poloxamer188, more preferably, contain 4-6wt%Poloxamer188.
Described dispersant can use this area dispersant commonly used, includes but not limited to: polydimethylsiloxane, dimethiconol, dimethyl siloxane ether copolymer, preferred polydimethylsiloxane.In a preferred embodiment of the present invention, contain the 0.5-10wt% polydimethylsiloxane, more preferably, contain the 3-8wt% polydimethylsiloxane.
Described acid buffer agent can use this area acid buffer agent commonly used, includes but not limited to: acetate buffer solution, phosphate buffer, carbonic acid buffer, preferred acetate buffer solution.In a preferred embodiment of the present invention, contain the agent of 1.0-2.5wt% acetate buffer, more preferably, contain the agent of 1.5-2.0wt% acetate buffer.
Can also contain wetting agent, antiseptic, dispersant, stabilizing agent etc. in the acidic biological adhesion heat-variable gelling agent provided by the invention.
Described wetting agent can use this area acid buffer agent commonly used, include but not limited to: glycerol, soap, Polyethylene Glycol, propylene glycol, sorbitol, sodium laurylsulfate, dicaprylate sodium sulfonate, sulfonated castor oil, glyceryl triacetate, octyl palmitate, cocoyl glyceride, stearic alcohol ether, spans, preferably glycerine.In a preferred embodiment of the present invention, contain 0.6-10wt% glycerol, more preferably, contain 3-8wt% glycerol.
Described antiseptic can use this area acid buffer agent commonly used, include but not limited to: propolis, benzoic acid, sodium benzoate, parabens (parabens), ethanol, quaternary ammonium salt, sorbic acid, the glycerite more than 30%, Germall IS45, Glydant etc., preferred sodium benzoate.In a preferred embodiment of the present invention, contain the 0.1-10wt% sodium benzoate, more preferably, contain the 3-8wt% sodium benzoate.
Described stabilizing agent can use this area stabilizing agent commonly used, includes but not limited to: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose.
The present invention can use this area correctives commonly used or coloring agent etc., is selected from but is not limited to: armaticity volatile oil, natural pigment or artificial color etc.
The preparation of acidic biological adhesion heat-variable gelling agent
Acidic biological adhesion heat-variable gelling agent provided by the invention can be by obtaining substrate excipient, bioadhesive polymer, dispersant and acid buffer agent mixed dissolution.
In a preferred embodiment of the present invention, with 15-20wt%Poloxamer127,2-8wt%Poloxamer188,0.5-10wt% polydimethylsiloxane and 1.0-2.5wt% acetate buffer agent mixed dissolution form above-mentioned acidic biological adhesion heat-variable gelling agent.
In another preferred embodiment of the present invention, also can add 0.6-10wt% wetting agent and 0.1-10wt% antiseptic.
Liquid preparation
In view of the above-mentioned characteristic of acidic biological adhesion heat-variable gelling agent provided by the invention, it can be used for preparing a kind of liquid preparation, and described liquid preparation contains: (i) acidic biological adhesion heat-variable gelling agent provided by the invention; The active constituents of medicine, microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug.Described liquid preparation possesses characteristic: pH be 3.0-4.5 and during in temperature≤28 ℃ for liquid, be gel state during in temperature 〉=32 ℃.
In a preferred embodiment of the present invention, component content (ii) is 0.1-2wt%.
Active constituents of medicine, microbicide or the spermicide of described suitable intravaginal and/or drop rectum with drug are selected from down group: and nonoxynolum (NP-9), Menfegol (TS-88), hot menthylphenoxypolyethoxy ethanol (OP-9), cationic surfactant Benzalkonii Chloridum (Benzalkonium chloride, BZK), alkyl betaine and alkyl dimethyl amine oxide compositions, Gramicidin, polyethoxy sulfate/poly Sulfonates chemical compound, deoxidation gallbladder acyl tyrosine (DCT).
Liquid preparation provided by the invention can be multiple dosage form, as: lotion, liniment, drop, varnish, distillate medicinal water, enema or irrigating etc.
In one embodiment of the invention, described liquid preparation is the liquid preparation that has both contraception and prevention of sexually-transmitted diseases, and it contains: (i) acidic biological adhesion heat-variable gelling agent provided by the invention; The microbicide that (ii) is fit to intravaginal and/or drop rectum with drug be deoxidation gallbladder acyl tyrosine (Deosycholy tyrosine, DCT).
In the acidic biological adhesion heat-variable gelling agent of component (i), selected substrate excipient is Poloxamer, and it is stable in the scope of pH3.5～4.2.It is a kind of water-solubility carrier, and the compatibility of it and principal agent active ingredient DCT is good.Active ingredient DCT and gel composition do not chemically react in this gel rubber system, but because of heating up or cooling is expanded or received dilution switch as DCT.It ℃ is liquid condition that acidic biological adhesion heat-variable gelling agent is set in temperature≤28, in case enter the vagina temperature when being elevated to more than 32 ℃, can become gel state immediately.Gel heated up to expand to push and discharged DCT this moment, showed the advantage of good stability.
In the acidic biological adhesion heat-variable gelling agent of component (i), selected bioadhesive polymer also has the bioadhesion effect except the Poloxamer407 of Poloxamer188 (F68) (being the substrate excipient), the polyoxyethylene polyoxypropylene copolymer that these two kinds of Poloxamer are nonionics, its polyoxyethylene segment has hydrophobicity, thereby has the bioadhesion effect.Because its high molecular is not by mucosa absorption, cervix uteri and vaginal mucosa epithelial cell can not damaged in a large amount of use (15～25%) yet, in the external metabolic conversion that yet do not take place, are divided in the class material of GRAS (thinking safe) by U.S. FDA.
Component (i) acidic biological adhesion heat-variable gelling agent at this embodiment enters body and is stranded in the vaginal mucosa surface in order to prevent that to greatest extent active ingredient DCT is impermeable, contain a kind of dispersant-polydimethylsiloxane, it has adhesiving effect equally, and with substrate excipient (Poloxamer407), bioadhesive polymer (Poloxamer188) forms the thin film that thickness is 0.01 μ m jointly on the vaginal mucosa surface, to reach two purposes: 1, can avoid the microbiocidal activity composition DCT transvaginal mucosa in the gel to infiltrate through body, prevent that it is through liver metabolism, behind vagina or rectally, can keep the DCT time of playing a role to reach 12～24 hours, greatly improve bioavailability; 2, microbicide DCT can stop STDs/HIV by vagina and cervical mucosa epithelium to the body internal diffusion, thereby keep STDs/HIV contact with active ingredient DCT, the increase bioavailability, raising DCT is to the killing effect of sperm and STDs/HIV.
Also contain the acetate buffer agent in component (i) acidic biological adhesion heat-variable gelling agent of this embodiment, this strong ion-type acid buffer agent makes and keep intravaginal natural pH3.5～4.5 balances (normal semen pH7.2～7.8 are neutral to alkalescence) in the presence of seminal fluid.It is reported that ejaculation back vagina pH rises to pH6～7 by 3.5～4 immediately in unprotected sexual intercourse, and in 2～8 hours, maintain this alkaline level.Acidity (pH3.5～4.5) microenvironment of vagina when the liquid preparation that this embodiment provides is kept seminal fluid and existed, thereby can kill STDs/HIV by microbicide DCT in intravaginal, sperm be can kill simultaneously again, contraception and pre-preventing transmission or the danger that infects STDs/HIV realized.
Keep acid pH in intravaginal and can also help to keep natural vagina dominant microflora---lactobacillus, make vagina produce enough lactic acid, H
2O
2But, antibacterial peptide and secreted antibody etc., to keep the normal microenvironment of vagina.
In component (i) acidic biological adhesion heat-variable gelling agent of this embodiment, can also add wetting agent and antiseptic.Described wetting agent or antiseptic can be that this area is commonly used, for example glycerol, sodium benzoate etc.
In another preferred embodiment of the present invention, described having both in the contraception and the liquid preparation of prevention of sexually-transmitted diseases, contained 0.1-2%DCT, 15-20%Poloxamer407,2-8%Poloxamer188, the acetate buffer agent of 0.5-10% polydimethylsiloxane and 2.0-5.0wt%pH3.2-4.0.
In another preference of the present invention, described having both in the contraception and the liquid preparation of prevention of sexually-transmitted diseases, contained 0.1-2%DCT, 15-20%Poloxamer407,2-8%Poloxamer188, the 0.5-10% polydimethylsiloxane, the acetate buffer agent of 2.0-5.0wt%pH3.2-4.0,0.6-10% glycerol and 0.1-10% sodium benzoate.
The method that the present invention prepares liquid preparation is, with component (i) acidic biological adhesion heat-variable gelling agent provided by the invention; The active constituents of medicine, microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug mix, and sterilization forms.
In a preparation embodiment of the present invention, be that acidic biological adhesion heat-variable gelling agent provided by the invention and microbicide DCT are mixed, make the liquid preparation that has both contraception and prevention of sexually-transmitted diseases.
In another preferred for preparation example of the present invention, be with 0.1-2%DCT, 15-20%Poloxamer407,2-8%Poloxamer188, the 0.5-10% polydimethylsiloxane, the acetate buffer agent of 2.0-5.0wt%pH3.2-4.0,0.6-10% glycerol and 0.1-10% sodium benzoate mix.
In another embodiment of the present invention, provide a kind of product, scribbled a kind of liquid preparation on the described product, described liquid preparation contains: (i) acidic biological adhesion heat-variable gelling agent provided by the invention; The active constituents of medicine, microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug.Described product includes but not limited to: be coated with liquid preparation at condom, vagina and/or rectum on suppository.
The purposes of acidic biological adhesion heat-variable gelling agent
Acidic biological adhesion heat-variable gelling agent provided by the invention can be used for preparing liquid preparation, and described liquid preparation can be a skin with gel, oral cavity with gel, gel for eye, gel for nose, vaginal gel, rectum with gel etc.Described dosage form can be lotion, liniment, drop, varnish, distillate medicinal water, enema or irrigating etc.
In one embodiment of the invention, be that acidic biological adhesion heat-variable gelling agent provided by the invention is used to prepare the liquid preparation that has both contraception and prevention of sexually-transmitted diseases.This liquid preparation has following characteristic, promptly pH be 3.0-4.5 and during in temperature≤28 ℃ for liquid, be gel state during in temperature 〉=32 ℃.It is that deoxidation gallbladder acyl tyrosine (DCT) with amino acid modified technical research is microbicidal active component, adds the thermal sensitive gel of acidic biological adhesion slow release provided by the invention, and reaching provides drug effect protection in 12～24 hours.It can cover women's all ages and classes layer, comprises unmarried women, married women, climacteric women, can cover reproductive tract infection and Susceptible population, and both efficient all kinds of sexually transmitted disease (STD)s, the HIV (human immunodeficiency virus) infection of stoping can easily be practised contraception again, is difunctional vagina microbicide.
For vaginal intercourse, this liquid preparation should be inserted vagina before sexual intercourse.Hand over (opposite sex or the same sex) this product before anus is handed over, to insert rectum for anus.Hand over for vagina or anus, this product can also play the effect of lubricant.In order to increase protective effect, usually this product is coated with usefulness before sexual intercourse or other sexual activitys.As suitable, can use condom simultaneously.For further protection, can after finishing sexual activity, recoat as early as possible and use this product.
Vagina is a sour environment, and pH value is 3.5～4.5, and this is because the H of intravaginal lactobacillus and generation thereof
2O
2Due to.Generally speaking HIV/STDs and sperm can both inactivations in this sour environment.But when sexual intercourse, when seminal fluid is injected vagina, its buffer capacity makes intravaginal pH value can rise to 6.0～7.0 for some time.When pH value rises to 6.0 when above, vaginal infection takes place easily.The infection of STDs/HIV just often occurs in during the pH rising.We it is contemplated that when seminal fluid was detained vagina, this liquid preparation possessed strong ion buffer capacity, can keep about 5.0 with the mixed pH value that makes of seminal fluid.Pathogenic bacteria or sperm can both be inactivated so, also help to treat vaginal infection.
The liquid preparation that present embodiment provides, promptly the DCT microbicide is mainly used in contraception of vagina or rectum and prevention HIV/STDs, is the autonomous fugitive vagina contraceptive that uses of a kind of women.In addition, also can prevent the danger of the individual or propagation STDs/HIV infected of heterosexuality, homosexuality, bisexual love men and women by sexual intercourse.More effective when with the coupling of condom technology.
The DCT microbicide that present embodiment provides, its loading amount is between 4-5ml in the dispensing propeller of being made by polyurethane ethers plastics of packing into usually.Before sexual intercourse, back out vinyl cover and applicator is inserted vagina touch cervix uteri up to it, extracting applicator after pushing whole this product out can have sexual intercourse, and also can be coated with usefulness once more after sexual intercourse; Should be after sexual intercourse ejaculation finishes fast as far as possible additional this gel 4-5ml that pushes.All using this product before and after sexual intercourse can obtain to protect more efficiently.
After this product was inserted vagina, because the rising of temperature, gel became gel immediately by liquid state, and simultaneously, they can well fill the surface of vaginal mucosa gauffer, and forming isolation thickness is the thin film of 0.01 μ m, has brought into play the chemical barrier effect.
The DCT microbicide that present embodiment provides also can provide the protection at STDs/HIV in other types sexual intercourse (for example opposite sex or homosexual buggery).
The active component DCT of the DCT microbicide that present embodiment provides has side effect still less than present commercially available vagina spermicide (for example nonoxynolum (N-9) and benzene are pricked chlorine ammonia (BZK)).When using repeatedly, do not cause the damage of vaginal mucosa, do not cause vagina or cervix uteri surface stimulation or canceration, further reduced the danger that STDs/HIV infects.
In addition because composition matrix components self no cytotoxicity of the DCT microbicide that present embodiment provides; performance with the acid bio-adhesive slow release of strong ion-type; can buffering when seminal fluid exists, protect the sour environment of vagina, thereby reduce the danger of becoming pregnant and being caused the STDs pathogenic infection.Simultaneously vagina dominant microflora such as lactobacillus be can also protect, biological lactic acid, H produced in intravaginal
2O
2, antibacterial peptide and secreted antibody etc., to keep the normal acidic micro-environment of vagina, strengthen the natural defence capability of vagina, and have the effect of sexual reproduction device infectious disease such as prevention and treatment bacterial vaginitis.
Major advantage of the present invention is:
1. acidic biological adhesion heat-variable gelling agent provided by the invention has thermal reversibility, in the moment that arrives mucomembranous surface, because liquid state is the rough mucomembranous surface of filling fully rapidly, because surface temperature is greater than 32 ℃, become gel state this moment immediately, surface to contact forms the thin film of 0.01 μ m together, and the effect of physical barriers is played in the intrusion of isolated pathogen.
2. acidic biological adhesion heat-variable gelling agent provided by the invention has the effect of performance bioadhesive slow release system, and antimicrobial and the active composition of contraception are slowly discharged, and fully kills pathogen, continues more than 12～24 hours.
3. acidic biological adhesion heat-variable gelling agent provided by the invention when solution state, brings innovation and convenient, easy and simple to handle to production technology, and the loading amount accuracy improves, and its technological process is particularly suitable for the GMP large-scale production.
4. acidic biological adhesion heat-variable gelling agent provided by the invention has no stimulation to mucosa, and can improve the vaginal microbial flora balance, keeps the normal ph of vagina.
5. nontoxic, the nonirritant, cheap of acidic biological adhesion heat-variable gelling agent provided by the invention.
6. the liquid preparation that obtains by acidic biological adhesion heat-variable gelling agent provided by the invention, especially provided by the inventionly have both the microbicide that contraception and the liquid preparation of prevention of sexually-transmitted diseases can provide contraceptive efficacy for numerous women, at preventing STD
s/ HIV aspect and healthy reproduction aspects such as family planning, prenatal and postnatal care have social benefit; It also can provide in various sexual activity of heterosexuality, homosexuality and bisexual love vagina or rectal mucosal protection.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
The preparation acidic biological adhesion heat-variable gelling agent
19.5 kilograms of Poloxamer127 (is medical auxiliary materials technology company limited available from last Hydron) and 8 kilograms of F68 (is medical auxiliary materials technology company limited available from last Hydron) are placed agitator, the acetate buffer solution that adds 60L0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, after finishing, add 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred 1～2 hour, standing over night, centrifugal 15min removes bubble.Measure the pH and the viscosity of gel.
Result: pH is 3.5, and measuring viscosity with NDJ-1 type rotary viscosimeter (available from Shanghai Hengping Instrument ﹠ Meter Plant) is 11～22Pas.
Embodiment 2
The preparation acidic biological adhesion heat-variable gelling agent
18.5 kilograms of Poloxamer127 (is medical auxiliary materials technology company limited available from last Hydron) and 10 kilograms of F68 (is medical auxiliary materials technology company limited available from last Hydron) are placed agitator, the acetate buffer solution that adds 60L0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, after finishing, add 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred 1～2 hour, standing over night, centrifugal 15min removes bubble.Measure the pH and the viscosity of gel.
Result: pH is 3.7, and measuring viscosity with NDJ-1 type rotary viscosimeter (available from Shanghai Hengping Instrument ﹠ Meter Plant) is 11～22Pas.
Embodiment 3
The preparation acidic biological adhesion heat-variable gelling agent
11.5 kilograms of Poloxamer127 (is medical auxiliary materials technology company limited available from last Hydron) and 5 kilograms of F68 (is medical auxiliary materials technology company limited available from last Hydron) are placed agitator, the acetate buffer solution that adds 60L0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, after finishing, add 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred 1～2 hour, standing over night, centrifugal 15min removes bubble.Measure the pH and the viscosity of gel.
Result: pH is 4.2, and measuring viscosity with NDJ-1 type rotary viscosimeter (available from Shanghai Hengping Instrument ﹠ Meter Plant) is 11～22Pas.
Embodiment 4
The liquid preparation I of contraception and prevention of sexually-transmitted diseases is had both in preparation
19.5kg Poloxamer127 (is medical auxiliary materials technology company limited available from last Hydron) and 8kg F68 (is medical auxiliary materials technology company limited available from last Hydron) are placed agitator, the acetate buffer solution that adds 60L0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, after finishing, add 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred 1～2 hour, add the 0.6M acetate buffer solution 29L that contains DCT0.5kg again, continue to stir standing over night, centrifugal 15min 1 hour, remove bubble, semi-finished product.Measure the pH and the viscosity of gel next day, pH is about 3.5, and measuring viscosity with NDJ-1 type rotary viscosimeter (available from Shanghai Hengping Instrument ﹠ Meter Plant) is 11～22Pas.With the packing of plastics applicator, carry out sterility test, the qualified finished product that is.
Synthetic and the purifying process of DCT:
Deoxidation gallbladder acyl tyrosine (DCT) is the product after the Fel Sus domestica extract deoxycholic acid is modified through tyrosine, and it kills the STDs pathogen and improves several times with essence is active extremely than the prototype thing, and the zest to the vaginal mucosa epithelium reduces greatly simultaneously.It is synthetic and the purification route is as follows:
Tyrosine methyl ester hydrochloride 1.62 restrains (7mM), triethylamine 980 microlitres (7 mM), is suspended in 20 milliliters of N, dinethylformamides.NaTDC 1.96 grams (5mM), be dissolved in 20 milliliters of N, dinethylformamides, molten complete adding the former, be positioned over 0 ℃, 10 minutes, add I-hydroxybenzotriazole 1.05 grams (7mM), add dicyclohexyl carbimide 1.43 grams (7 mM) that are dissolved in 15 milliliters of N, dinethylformamide again, in 0 ℃ of stirring 3 hours, be positioned over room temperature (20 ℃) 18 hours.Add 10 dense acetic acid stopped reaction, add 20 ml distilled waters, mixture is evaporated to dried at 35 ℃.
Dry thing was suspended in 30 ml methanol/water/chloroform (70: 30: 10V/V), filter then, filtrate is adjusted to PH10 with the 1M sodium hydroxide, after 20 minutes, some floccule precipitation, discard flocky precipitate, golden yellow clear liquid obtains precipitate with 1M hydrochloric acid agitation and dropping, filter, white depositions is given a baby a bath on the third day after its birth inferior with distilled water, use the silicagel column purification then, post methanol (70: 30) balance.
The deoxidation gallbladder acyl tyrosine methanol solution evaporate to dryness of purification is used the 0.5M dissolution of sodium hydroxide, and reuse 0.5M hydrochloric acid solution obtains precipitate, and precipitate room temperature vacuum drying, the product that obtains are the deoxidation gallbladder acyl tyrosine (DCT) of purity 95%
Embodiment 5
The liquid preparation II of contraception and prevention of sexually-transmitted diseases is had both in preparation
19.5kg Poloxamer127 (is medical auxiliary materials technology company limited available from last Hydron) and 10kgF68 (is medical auxiliary materials technology company limited available from last Hydron) are placed agitator, the acetate buffer solution that adds 60L0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, after finishing, add 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred 1～2 hour, add the 0.6M acetate buffer solution 29L that contains DCT (synthetic) 1.0kg again with said method, continue to stir standing over night, centrifugal 15min 1 hour, remove bubble, semi-finished product.Measure the pH and the viscosity of gel next day, pH is about 3.5, and measuring viscosity with NDJ-1 type rotary viscosimeter (available from Shanghai Hengping Instrument ﹠ Meter Plant) is 11～22Pas.With the packing of plastics applicator, carry out sterility test, the qualified finished product that is.
Embodiment 6
The test of liquid preparation I killing microorganisms
With embodiment 4 make have both 5 times of contraception and the liquid preparation I of prevention of sexually-transmitted diseases dilutions after (1: 5) cultivate the growth of observation coccus after 1,2,5 minutes with micrococcus gonococcus (available from Shanghai medicine and biological products assay institute) effect.
The results are shown in Table 1.
Table 1: the liquid preparation I that has both contraception and prevention of sexually-transmitted diseases is to gonococcal killing action
The result shows that liquid preparation I has very strong killing action to gonococcus.
With embodiment 4 make have both 2,4,8 times of contraception and the liquid preparation I of prevention of sexually-transmitted diseases dilutions after (1: 2,1: 4,1: 8) act on 1 with treponema pallidum (available from institute of internal medicine of medical courses in general institute), cultivate after 2 minutes, observe the growth of treponema pallidum.
The results are shown in Table 2.
Table 2: have both the killing action of the liquid preparation I of contraception and prevention of sexually-transmitted diseases to treponema pallidum
-: can brake treponema pallidum+: can not brake treponema pallidum
The result shows that liquid preparation I has killing action to treponema pallidum.
With embodiment 4 make have both 2,5,10 times of contraception and the liquid preparation I of prevention of sexually-transmitted diseases dilutions after (1: 2,1: 5,1: 10) act on 1 with chlamydia trachomatis (available from Shanghai child's medical research center), 2, cultivate after 5 minutes, observe the growth of chlamydia trachomatis.
The results are shown in Table 3.
Table 3: have both the killing action of the liquid preparation I of contraception and prevention of sexually-transmitted diseases to chlamydia trachomatis
-: can brake chlamydia trachomatis+: can not brake chlamydia trachomatis
The result shows that liquid preparation I has killing action to chlamydia trachomatis.
With embodiment 4 make have both 50 times of contraception and the liquid preparation I of prevention of sexually-transmitted diseases dilutions after (1: 50) cultivate the growth of observation herpes simplex virus (available from Shanghai medicine and biological products assay institute) after 1,2 minute with the herpes simplex virus effect.
The results are shown in Table 4.
Table 4: have both the killing action of the liquid preparation I of contraception and prevention of sexually-transmitted diseases to herpes simplex virus
The result shows that liquid preparation I has killing action to herpes simplex virus.
Embodiment 7
The test of liquid preparation II killing microorganisms
Have both every test among contraception and the liquid preparation II of the prevention of sexually-transmitted diseases repetition embodiment 6 with what embodiment 5 made, come to the same thing.
Embodiment 8
Liquid preparation I buffer pH ability test
Semen sample is collected from the healthy volunteer, and screening motility of sperm, pH and volume, and the initial pH of seminal fluid is 7.92, and sperm motility rate is 86.24%.Mixed by different proportion and normal person's seminal fluid with the liquid preparation I that has both contraception and prevention of sexually-transmitted diseases that embodiment 4 makes, the pH value before and after mensuration is mixed changes and the survival rate of sperm changes, and the results are shown in Table 5.
Table 5 liquid preparation I is to the buffer capacity of people's seminal fluid and smart extremely effect
| Liquid preparation I and seminal fluid ratio | pH | 20 seconds sperm survival rates (%) |
| Seminal fluid stock solution | 7.92 | 86.24 |
| 1∶1 | 3.42 | 0 |
| 1∶4 | 4.07 | 0 |
| 1∶6 | 4.18 | 0 |
| 1∶8 | 4.81 | 0 |
| 1∶10 | 5.07 | 0 |
Because the human each average ejaculate volume of sexual intercourse is equivalent to the semen volume of about 2.5～5.0ml, the about 4～5ml of the each usually dispensing liquid preparation I of design, the average dilution factor of expecting when 1: 1 liquid preparation I and seminal fluid are than the most of sexual intercourse of representative so.
The result shows, when ratio reaches 1: 6 when (1 part of liquid preparation I and 6 parts of seminal fluid), its pH value is 4.18, illustrates that liquid preparation I has enough acidic buffer power.When thinner ratio was 1: 10, pH was that 5.07,20 seconds sperm survival rates are 0, showed that 100% sperm loses motor capacity fully, illustrated that liquid preparation I has quite effectively to kill smart effect.
Human seminal fluid's pH value is 7.2～7.8, and good buffer capacity is arranged.The mixed pH value of undiluted liquid preparation I and seminal fluid different proportion has been represented the sour buffer capacity of liquid preparation I, can keep the pH value less than 5 under the situation of the seminal fluid that has unnecessary normal amount.The sperm survival rate data that obtains in the table 1 simultaneously shows, liquid preparation I have enough also can 100% deactivation sperm when killing smart ability even having seminal fluid more than normal amount.
Embodiment 9
Liquid preparation II buffer pH ability test
The test of having both contraception and the liquid preparation II of prevention of sexually-transmitted diseases repetition embodiment 8 with embodiment 5 makes comes to the same thing.
Embodiment 10
Liquid preparation I suppresses the test of HIV-1 virus
The liquid preparation I that makes with 0.5ml embodiment 4 respectively with the HIV-1 virus (available from Pasteur Institut) of the capacity of grade in room temperature effect 10,15, after 20 minutes, each manages 100 times of liquid dilutings, get 0.5ml and add MT4 cell pipe (250,000 cells/0.5ml) 37 ℃ of effects 90 minutes, centrifugal 1500rpm * 10min, supernatant discarded (not entering the free HIV-1 of cell), add serum-free RPM1640, make cell suspension, repeat once the back and continue 37 ℃ of cultivations after 5 days, survey p24 antigen with p24 antigenic reagent box (available from the extensive and profound in meaning gloomy Science and Technology Ltd. in Beijing), calculate suppression ratio HIV-1.The results are shown in Table 6.
Table 6
| Drug dilution concentration | Medicine group p24 antigen quantity | Negative control p24 antigen quantity | Suppression ratio |
| 10 | 1.2 | 0.082 | 3.213 | 100％ |
| 15 | 1.2 | 0.060 | 2.929 | 100％ |
| 20 | 1.2 | 0.064 | 2.648 | 100％ |
| The cell contrast | 0.068 |
The result shows that liquid preparation I through 10-20 minute and HIV-1 virus function, all can reach the effect of 100% fire extinguishing HIV-1 under the condition of dilution in 1: 2.
Embodiment 11
Liquid preparation II suppresses the test of HIV-1 virus
The test of having both contraception and the liquid preparation II of prevention of sexually-transmitted diseases repetition embodiment 10 with embodiment 5 makes comes to the same thing.
Embodiment 12
Liquid preparation I mucomembranous pungency test
Generally acknowledge Eckstein experimental technique and evaluation criterion according to WHO, (available from the department of the Chinese Academy of Sciences of experimental animal section of Fudan University) is divided into 4 groups at random with 16 Female rabbits, every group 4, (the liquid preparation I that has both contraception and prevention of sexually-transmitted diseases that 1.5ml embodiment 4 makes) vagina administration is continuous 10 days once a day, put to death in the 11st day, take out vagina tissue then, make tissue slice, carry out pathologic finding.
By the histogenetic edema of vaginal mucosa, hyperemia, leukocyte infiltration, 4 kinds of pathological changes of epithelium ulcer in various degree, every with the 1-4 member record, totally 16 minutes.If total score value represents that at the 0-8 branch this medicine is an acceptable to the zest of mucosa, the score value of 9-11 is a marginal value, and 12 minutes and above total points are clinical unacceptable.The results are shown in Table 7.
Table 7
| Average score | |
| The blank group | 0.2 |
| The excipient matched group | 0.7 |
| 1％DCT | 1.6 |
| 0.5％DCT | 1.7 |
The result shows that all laboratory animal has good tolerability to liquid preparation I, does not observe intoxicating phenomenon.Do not observe macroscopic change, the histopathology scoring is table as above.
The scoring explanation: the zest of 0.5%～1.0% this product is very little, is acceptable to clinical assessment.
Embodiment 13
Liquid preparation II mucomembranous pungency test
The test of having both contraception and the liquid preparation II of prevention of sexually-transmitted diseases repetition embodiment 12 with embodiment 5 makes comes to the same thing.
Embodiment 14
Liquid preparation I is to the influence of monkey vagina lactobacillus growth breeding
Before Rhesus Macacus (available from the State Family Planning Commission's non-human primate Experimental Animal Center) experiment except that certainly healthy no pulmonary tuberculosis, also the female monkey of special survey pregnancy and examination per vagina are no abnormal, the adult female monkey of definite 9 body weight 6.8～7.4kg at last.
Test branch low dose group (the liquid preparation I 2ml that 0.25% embodiment 4 makes), middle dosage group (0.5% liquid preparation I 2ml) and three dosage groups of high dose group (1% liquid preparation I 2ml).Dosage is 2ml this product, before the detection of monkey vagina lactobacillus is chosen in administration, administration the 30th minute and the 24th hour, respectively the monkey vagina is injected the 3ml physiological saline solution, treats that sucking-off 1.0ml vagina cleanout fluid carries out the detection of lactobacillus after 5 minutes.
After SL culture medium and 3% agar of preparation in advance mixed by 1: 1 ratio, adding 6ml was the bottom culture medium in every incubator.The mixed liquid 3.5ml that got 1: 1 adds 0.5ml vagina cleanout fluid, adds behind the mixing to have spread in the incubator of finishing bottom, and room temperature is waited to coagulate.Culture dish is put into the anaerobism cylinder charge into the anaerobism mixed air, cultivated 40 hours, and counted its clump count for 37 ℃.The results are shown in Table 8.
Table 8
| Grouping | Number of animals | Before the administration (individual clump count) | Hour 0.5 (individual clump count) | 10 hours (individual clump count) |
| 0.25% liquid preparation I 2ml | 3 | 86±22 | 84±19 | 87±23 |
| 0.5% liquid preparation I2ml | 3 | 92±33 | 96±15 | 90±21 |
| 1.0% liquid preparation I2ml | 3 | 88±16 | 90±12 | 94±20 |
The result shows that liquid preparation I kills smart and suppresses at vagina and under the concentration conditions of STDs the growth and breeding of vagina lactobacillus do not seen tangible influence.
Embodiment 15
Liquid preparation II is to the influence of monkey vagina lactobacillus growth breeding
The test of having both contraception and the liquid preparation II of prevention of sexually-transmitted diseases repetition embodiment 14 with embodiment 5 makes comes to the same thing.
Embodiment 16
Liquid preparation I stability test
The liquid preparation I that embodiment 4 is made carries out stability test:
The result shows, liquid preparation I is under 40 ℃, and 6 months can degeneration, comprises outward appearance, viscosity, pH value and buffering ability, and gel state is stable.
Embodiment 17
Liquid preparation I stability test
The test of having both contraception and the liquid preparation II of prevention of sexually-transmitted diseases repetition embodiment 16 with embodiment 5 makes comes to the same thing.
Discuss
At present, the family planning policy of China is expanded to the healthy reproduction field.The level of low birth rate of statonary population is still emphasis on the one hand; On the other hand, sexually transmitted disease (STD) (STDs) has become the at present growing medical problem and the focus of All Around The World, the novel medical instrument that The World Health Organization (WHO) etc. have had development concurrently contraception about international organization and killed the STDs pathogen is introduced and is paid the utmost attention to the Research on development field, and prevention of sexually-transmitted diseases and acquired immune deficiency syndrome (AIDS) (STDs/AIDS) also become one of key task of China's population and family planning service.
China's the most frequently used Nonoxynol-9 at present is a kind of strong cytotoxicity agent, will not have specific destruction cell membrane.This character has very important disadvantages.Clinical research confirmation under the concentration in being present in the vagina contraceptive preparation usually (usually greater than 3% Nonoxynol-9) vagina and epithelium of cervix uteri can break.Nonoxynol-9 also destroys normal vaginal microbial flora, and these floras provide a kind of protection mechanism, can keep the low pH of vagina, prevents the invasion of pathogenic microorganism.Nonoxynol-9 also is partly dissolved or removes protectiveness glycoprotein layer contained in the vagina.This cytotoxicity of Nonoxynol-9, flora destructiveness and the glycoprotein effect of removing can cause vaginal injury or wound, comprise pathological changes.Some women is especially responsive to Nonoxynol-9, and only accidental use also can be subjected to the influence of these effects.Nonoxynol-9 will improve the danger that STD infects usually to the destruction of these protection mechanisms, because protection mechanism is disintegrated, pathological changes especially occur, become the easier approach that enters cell of the organism that causes STD.In addition, nonoxynolum can increase the danger of vaginitis and/or bacterial vaginosis to the destruction of these protection mechanisms.
The fugitive contraceptive of the vagina by women's Autonomous Control that has contraception and prevention STDs/HIV simultaneously is that bifunctional vagina microbicide is particularly suitable for China's national situation.So the present invention selects for use with the anti-STDs/HIV of having of amino acid modified technical research and kills the deoxidation gallbladder acyl tyrosine of active function of sperm (Deosycholytyrosine DCT) is principal agent.
Say that from vagina administration for contraception and prevention STDs/HIV purpose, must improve the bioavailability of microbicide at vagina, this microbicide should not absorbed by body, can not pass through vaginal mucosa especially, can not destroy the acidic micro-environment of normal vagina.Acidic biological adhesion heat-variable gelling agent provided by the invention is a kind of inertia and nontoxic gel.It enough stops microbicide isoreactivity composition to go into body from vaginal mucosa osmosis in degree ground, and can cover the vaginal mucosa surface with many gauffers, makes from vaginal orifice and just can effectively be protected, and this is that the ordinary gel agent is difficult to realize.
The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.
Claims (10)
1. an acidic biological adhesion heat-variable gelling agent is characterized in that, it contains following component:
(a) 12-20wt% polyoxyethylene polyoxypropylene polymer, alginic acid or chitosan;
(b) 0.5-10wt% polydimethylsiloxane, dimethiconol or dimethyl siloxane ether copolymer;
(c) 1.0-2.5wt% acid buffer agent,
Wherein, described gel has characteristic:
PH is 3.0-4.5; With
Described gel is liquid during in temperature≤28 ℃, is gel state during in temperature 〉=32 ℃.
2. acidic biological adhesion heat-variable gelling agent as claimed in claim 1 is characterized in that, described gel 32-40 ℃ temperature is a gel state.
3. acidic biological adhesion heat-variable gelling agent as claimed in claim 1 is characterized in that, it contains 12-20wt% polyoxyethylene polyoxypropylene polymer, 0.5-10wt% polydimethylsiloxane and 1.0-2.5wt% acid buffer agent.
4. acidic biological adhesion heat-variable gelling agent as claimed in claim 1 is characterized in that, it also contains one or more additives that are selected from down group: wetting agent, antiseptic, dispersant, stabilizing agent etc.
5. a liquid preparation is characterized in that it contains
(i) acidic biological adhesion heat-variable gelling agent as claimed in claim 1; With
The active constituents of medicine microbicide or the spermicide that (ii) are fit to intravaginal and/or drop rectum with drug.
6. liquid preparation as claimed in claim 5 is characterized in that, described liquid preparation has following characteristic:
PH is 3.0-4.5; With
Described gel is liquid during in temperature≤28 ℃, is gel state during in temperature 〉=32 ℃.
7. liquid preparation as claimed in claim 5, it is characterized in that, active constituents of medicine, microbicide or spermicide that described component (ii) is fit to intravaginal and/or drop rectum with drug are selected from down group: nonoxynolum, Menfegol, hot menthylphenoxypolyethoxy ethanol, cationic surfactant Benzalkonii Chloridum, alkyl betaine, alkyl dimethyl amine oxide compositions, Gramicidin, polyethoxy sulfate/poly Sulfonates chemical compound, deoxidation gallbladder acyl tyrosine, mannose binding lectin, phytolaccatoxin, tea saponin, gossypol and derivant thereof, or its combination.
8. the preparation method of an acidic biological adhesion heat-variable gelling agent as claimed in claim 1 is characterized in that, it comprises step:
With 12-20wt% polyoxyethylene polyoxypropylene polymer, alginic acid or chitosan, 0.5-10wt% polydimethylsiloxane, dimethiconol or dimethyl siloxane ether copolymer and 1.0-2.5wt% acid buffer agent mixed dissolution form acidic biological adhesion heat-variable gelling agent as claimed in claim 1.
9. the application of acidic biological adhesion heat-variable gelling agent as claimed in claim 1 in the preparation liquid preparation.
10. a product is characterized in that, described product scribbles the liquid preparation of claim 5.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102895256A (en) * | 2012-09-29 | 2013-01-30 | 广东同德药业有限公司 | Chitosan plural gel foaming agent suitable for female sperm shielding and killing dual-contraception effect and preparation method thereof |
| CN106692038A (en) * | 2017-03-02 | 2017-05-24 | 上海理工大学 | Gossypol acetate-containing thermosensitive gel preparation and preparation method and application thereof |
| CN112274480A (en) * | 2020-11-06 | 2021-01-29 | 山东莱商商贸有限公司 | Preparation method of female contraceptive antibacterial gel lubricant |
| CN114828827A (en) * | 2019-10-11 | 2022-07-29 | 赛可勒生物医学避孕法有限公司 | Vaginal contraceptive compositions for enhanced mucus barrier |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9604411A (en) * | 1994-03-28 | 1997-12-31 | Univ Columbia | Composition for inactivating irritants in fluids. |
| FR2728464B1 (en) * | 1994-12-22 | 1997-04-30 | Innothera Lab Sa | UNITAL GALENIC FORM, PROCESS FOR OBTAINING SAME AND USES THEREOF |
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2006
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102895256A (en) * | 2012-09-29 | 2013-01-30 | 广东同德药业有限公司 | Chitosan plural gel foaming agent suitable for female sperm shielding and killing dual-contraception effect and preparation method thereof |
| CN102895256B (en) * | 2012-09-29 | 2014-10-22 | 广东同德药业有限公司 | Chitosan plural gel foaming agent suitable for female sperm shielding and killing dual-contraception effect and preparation method thereof |
| CN106692038A (en) * | 2017-03-02 | 2017-05-24 | 上海理工大学 | Gossypol acetate-containing thermosensitive gel preparation and preparation method and application thereof |
| CN114828827A (en) * | 2019-10-11 | 2022-07-29 | 赛可勒生物医学避孕法有限公司 | Vaginal contraceptive compositions for enhanced mucus barrier |
| CN112274480A (en) * | 2020-11-06 | 2021-01-29 | 山东莱商商贸有限公司 | Preparation method of female contraceptive antibacterial gel lubricant |
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