CN1872026A - New medicinal preparation for vagina - Google Patents
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- CN1872026A CN1872026A CN 200510072312 CN200510072312A CN1872026A CN 1872026 A CN1872026 A CN 1872026A CN 200510072312 CN200510072312 CN 200510072312 CN 200510072312 A CN200510072312 A CN 200510072312A CN 1872026 A CN1872026 A CN 1872026A
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Abstract
A medicine in the form of liquid for vagina contains medicine, in-situ gelatinizing substance, viscosity increasing high-molecular compound, lubricant, pH regulator and antiseptic. It features that it can be quickly spread on the surface of vagina to form a gel layer.
Description
Technical field
The present invention relates to a kind of new medicinal preparation for vagina.Especially relate to a kind of vagina that can be under suitable phase changing condition changes gel state by liquid state with situ-gel (title again) preparation at the body gel.
Background technology
Along with the continuous development and progress of society, monde is more extensive between the people, the manner of intercourse is variation more, people increase greatly because of gynecological infectious diseases and the property infectious disease that infected by microbes or property contact cause, serious threat people's health, and the person of being hurt mostly is the women greatly, as bacillary, fungoid, trichomonal vaginitis, cervicitis, metritis, pelvic inflammatory disease.Especially in recent years, sexually transmitted disease (STD) has become the focus of growing medical problem and All Around The World.Because the mankind also do not find the active drug that tackles HIV virus, make the sick fashion trend of AIDS (AIDS) be difficult to control, the whole mankind has experienced grave danger of sexually transmitted disease (STD).At present, to the best of growing sexually transmitted disease (STD) (particularly AIDS disease) with perhaps be that the solution of unique reality may be exactly controlled pathophorous route of transmission, reduce pathogenic organism and propagate the danger of sexually transmitted disease (STD), thereby control and reduce the quantity of new infected individuals.As if for this reason, many countries are by freely providing condom and extensively carry out the education of " sale sex technology " to the public, and condom popularizes the purpose that can reach controlled spreading disease (particularly AIDS).But in fact, these measures fail to stop effectively popular in countries in the world of sexually transmitted disease (STD) and acquired immune deficiency syndrome (AIDS).According to a social inquiry report of the U.S., even in the high-risk group, also only have an appointment people's cover safe in utilization of 30.The difficult main cause of popularizing of condom at first is the impression that condom influence sexual life, a lot of people use of being unwilling, also have a lot of people in sexual activity for various reasons (for example carelessness, momentary impulse etc.) forget cover safe in utilization.Healthy for what shield women; new drug research persons all over the world are at the medicine that strives to find better prevention and treatment gynecological infectious diseases and property infectious disease, develop better can bring into play the dosage form that drug effect can reduce and avoid toxic and side effects again effectively.
With regard to the pharmaceutical dosage form that the vagina of having developed with regard to present people is used, roughly can be divided into three classes, the first kind is to rely on the excretory liquid of intravaginal to dissolve and dispersive medicine after the medication, as vaginal suppository, vaginal tablet, vagina effervescence agent, vaginal capsule agent; Second class is with the medicine of the substrate combination with certain viscosity, by applicating implement this type of medicine is coated the intravaginal surface, as vagina ointment, vaginal cream, vagina membrane, vagina gel; The 3rd class is a drug solution, can inject intravaginal by certain mode, as vaginal lotion, spray, effervescent liquid, pressurization effervescent liquid.By relatively, be not difficult to find out that second class and the 3rd class are all quite a lot of than the first kind aspect drug distribution.And second class and the 3rd class have his own strong points by contrast.The second class medicine tack is good but can not guarantee the medicine uniform distribution, and the medication dead angle may be arranged.Though the 3rd class medicine can guarantee the medicine uniform distribution, medicine can not continue to adhere to the intravaginal surface, runs off easily or accumulation.All there is a common defective in they, all can't avoid the too high situation of local drug concentration to occur.Therefore, to have the good and good vaginal preparation of bioadhesive of uniform distribution concurrently be the significant challenge that current drug research person is faced all the time in exploitation.
The appearance of the high molecular polymer of the high molecular polymer of temperature sensitive high molecular polymer, pH value sensitivity and ionic strength sensitivity is developed ideal vagina medicinal thing for the medicine researcheres and has been brought hope.These high molecular polymers (are commonly called " at the body gel " or " situ-gel ", this paper system is referred to as " situ-gel " for sake of convenience) have because of environmental factors and change the character that changes gel state by solution state into, utilize the drug-supplying system of this character design, not only merge the advantage of solution and gel but also avoided the two deficiency, overcome the common shortcoming of above-mentioned three class medicines, the advantage that second class and the 3rd class are possessed all concentrates in the same pharmaceutical dosage form, for the vagina rational use of drug shows very ideal application prospect.But, the substrate that the high molecular polymer (as carbomer) of existing temperature sensitive high molecular polymer (as poloxamer) or pH value sensitivity can't be formed as medicine separately because of the restriction of phase transformation characteristics, therefore, the high molecular polymer of these different qualities is carried out the composite substrate that appropriate combination obtains to have suitable phase change conditions, become the researcher prefered method.
Patent report (Suppository composition of the drug which undergo the hepaticfirst-pass effect.WO9730693 has been arranged, 1997-08-28) phase transition temperature between 30～60 ℃ poloxamer liquid, (Thermoreversible gel as a liquid pharmaceutical Carrier for a galenicformulation.EPO551626,1993-07-21) carbomer of pH sensitivity and poloxamer share and can obtain to have suitable phase transition temperature and well flow the gel that character is learned in friendship to also have patent report.Patent report is also arranged, and (2002-11-6) the poloxamer compatibility with different model uses for the ocular in-situ gel preparation with suitable phase transition temperature, patent publication No.: CN1377706A, and preparation has the ocular in-situ gel of suitable phase transition temperature.(dropped in eyes is used in body gel preparation and preparation method thereof, patent publication No.: CN1397272A 2003-2-19) prepares the dropped in eyes in-situ gel preparation with carbomer and poloxamer respectively to also have patent report.But vagina does not appear in the newspapers as yet with in-situ gel preparation.
Summary of the invention
The objective of the invention is variously to be used for the treatment of and to prevent female vagina, prevent and treat sexually transmitted disease (STD), the safety contraception, increase the moistening and lubricity of woman vagina, improve vagina medicinal thing preparation such as life quality a kind of new preparation technique is provided, promptly provide a kind of vagina with in-situ gel preparation and preparation method thereof for developing.Vagina provided by the invention with in-situ gel preparation solved easy loss that existing vagina exists with liquid pharmaceutical formulation, easily gather the crawling that exists with solid and semisolid pharmaceutical formulation, problem such as medication dead angle is arranged, the too high and untoward reaction that causes of the local drug concentration of also having avoided existing vagina medicinal thing preparation to exist.
Purpose of the present invention mainly is to have under suitable phase changing condition by reasonable use to be realized as the substrate that comprises medicine by the gelatinizing-in-situ material of liquid state transformation gel state characteristic.With the preferred situ-gel substrate of the present invention and other combinations of substances, can prepare vagina in-situ gel preparation with different clinical practice meanings.
The preferred situ-gel substrate of the present invention contains one or more can issue the high molecular polymer that looks changes in the certain environment condition, therefore can make pharmaceutical preparation of the present invention under certain storage condition, be liquid condition, behind the liquid agent form administration, sprawl and form gel layer at vagina surface rapidly, do not have the medication dead angle.Owing to the viscous effect of the gel layer that forms at vagina surface, medicine is trapped in the time lengthening of vagina surface, thereby brings into play various efficacy of drugs effectively.Because the gel layer that forms at vagina surface is evenly distributed in vagina surface, has effectively avoided too high caused zest of other drug form skewness local drug concentration and toxic and side effects.In addition; the high molecular polymer of the high molecular polymer of pH sensitivity and ionic strength sensitivity can (seminal fluid pH be about 7.2～7.8 usually at seminal fluid; and contain Na+, K and Ca++; the sexual intercourse ejaculation back vagina pH that it is reported in the end protection rises to about pH6～pH7 from about pH4 at once; and in 28 hours, maintain this high level) mix with seminal fluid when entering woman vagina gelation takes place, sperm can not be moved.
Vagina provided by the invention can contain the bioadhesive material with in-situ gel preparation, further is increased in the biological adsorptivity of vagina surface gel layer, weakens the mobility of sperm, stops that the source of disease microorganism contacts with vagina surface.
Vagina provided by the invention can also contain pH dash adjustment material with in-situ gel preparation, play a role jointly with the high molecular polymer of pH sensitivity, be neutral or weakly alkaline seminal fluid can continue to keep intravaginal natural pH balance (the normal pH scope of healthy women is in 3.5～5) when entering woman vagina.
Vagina provided by the invention can also contain greasing substance with in-situ gel preparation, continues to keep the lubricity of vaginal walls when gelation takes place.
Vagina provided by the invention can also contain contraceptive with in-situ gel preparation or/and disease-resistant source microbial medicine or/and antiseptic.
As needs, vagina provided by the invention can also add fragrance matter in right amount under the prerequisite that does not change the situ-gel characteristic with in-situ gel preparation or/and the toning material satisfies the mental impression of user.
The vagina provided by the invention basic composition of in-situ gel preparation:
Constituent content (weight %)
Gelatinizing-in-situ material 0.001～50
Tackifying macromolecular compound 0～10
Lubricant 0～10
Medicine (comprising the microgranule and the cyclodextrin clathrate that are loaded with medicine) 0～10
Antiseptic 0～10
PH dash adjustment material adjusting pH value is 2～10 amount
Water surplus
Gelatinizing-in-situ material in the above-mentioned basic composition is selected from one or more the mixture in poloxamer (Poloxamer), carbomer (Carbomer), the methylcellulose (MC, Methyl Cellulose).The poloxamer molecular weight is that 1000～16000 (comprising poloxamer 407, poloxamer 388 and poloxamers 188), carbomer molecular weight are 1 * 10
6～4 * 10
6, the methylcellulose molecular weight is 2 * 10
4～38 * 10
4
Tackifying macromolecular compound in the above-mentioned basic composition is selected from xanthan gum, hydroxypropyl cellulose, hydroxypropyl emthylcellulose (HPMC, Hydroxypropyl Methylcellulose), hydroxyethyl-cellulose, carboxymethyl cellulose, chitosan, polycarbophil, carbopol, hyaluronate sodium, polyvinyl alcohol, polyvidone, sodium alginate, polyvinyl alcohol (PVA, PolyvinylAlcohol), hyaluronic acid sodium (HA, Sodium Hyaluronat), polyvidone (PVP, Polyvidone), Smart polymergels, the mixture of one or more in Ji Leng (gellan) glue.The polyvinyl alcohol molecular weight is 3 * 10
4～20 * 10
4, the polyvidone molecular weight is 5000～70000, the hydroxypropyl emthylcellulose molecular weight is 86000.Xanthan gum is first-selected tackifying macromolecular compound.The purpose that adds the tackifying macromolecular compound is that prolong drug is in the holdup time of vagina surface for vagina surface adds protective layer.
PH dash adjustment material in the above-mentioned basic composition is selected from sodium hydroxide, hydrochloric acid, sulphuric acid, lactic acid, citric acid, potassium hydrogen tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA), acetic acid, malic acid, citric acid, sodium citrate, boric acid, sodium borate, triethanolamine etc.Usually in preparation of the present invention, can comprise several buffer agents, higher slow Zhong Nengli is provided.Certainly, alginic acid can be simultaneously as gel-type vehicle and buffer agent in the preparation of invention.
PH dash adjustment material consumption in the above-mentioned basic composition is meant the determined consumption of pH environmental requirement of vagina, and the suitable consumption that this material is used for woman vagina should be and regulates pH value is 3.5～5 amount.
Lubricant in the above-mentioned basic composition is selected from one or more the mixture in glycerol, hyaluronate sodium, Polyethylene Glycol, propylene glycol, sorbitol, the glyceryl triacetate.Glycerol is first-selected lubricant.
Medicine in the above-mentioned basic composition can be disease-resistant source microbial medicine or contraceptive, can be selected from metronidazole, povidone iodine, hibitane, Yi Qukang frustrates, the ketone health is frustrated, first nitre is frustrated, restrain mould frustrating, the fluorine health is frustrated, Te Lakang frustrates, narrowing health frustrates, frustrate for nitre, Yi Kang frustrates, ring adjoins department's amine, nystatin, tobramycin, gentamycin, neomycin, chloromycetin, dexamethasone, ciprofloxacin and salt thereof, ofloxacin, levofloxacin and salt thereof, Gatifloxacin, west arsenic chlorine plating, head is embraced the first fat, clarithromycin, clindamycin and salt thereof, matrine, beta-lactam, Tetracyclines, amino sugar formula class, vinegar class in the macro ring, chloromycetin and derivant thereof, ucleosides, ftibamzone, acyclovir, ganciclovir, quinolones, imidazoles, Niphesamide, Nonoxynol-9, benzalkonium chloride, hibitane, octoxynol 9, the hesperidin of phosphorylation, Sulfonated hesperidin, the polystyrolsulfon acid ester, the benzenesulfonic acid copolyoxymethylenes that replaces, H
2SO
4The mixture of one or more in the mandelic acid of-modification.
Medicine in the above-mentioned basic composition also can be natural extracts, protein and polypeptide class.
Antiseptic in the above-mentioned basic composition is selected from benzoic acid, sodium benzoate, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, to cutting edge of a knife or a sword essence of Niobe, diameter ethyl benzoate, to the hydrocarbon butyl benzoate, to one or more the mixture in hydrocarbon propyl benzoate, phenylmercuric nitrate, the hibitane.First-selected antiseptic is a benzoic acid.Benzoic acid also can be used as buffer agent.
The preparation method of the in-situ gel preparation that is applicable to vagina provided by the invention is as follows: by the weighing of above-mentioned prescription with contraceptive or/and antimicrobial agents or/and the antiseptic stirring and dissolving in water, add the gelatinizing-in-situ material again, the bioadhesive material, lubricant, stirring makes dissolving, be 3～9 (non-woman vagina with) with pH dash adjustment material regulator solution pH value be 3.5～5 (woman vagina with) or pH value, solution passes through filtering with microporous membrane, on filter, add water to total amount again, Quality Identification is carried out in sampling, after qualified, under gnotobasis the capacity of being sub-packed in be 1～10 milliliter the bottle in, the packing promptly.Common scope of using dosage of formulation products of the present invention is about 1～10 milliliter, and best in a woman vagina using dosage is about 3～6 milliliters.Can determine one-waw package dosage as the case may be.Certainly as need, also can adopt can be repeatedly to the high capacity inner packing bottle of vagina administration.No matter be the inner packing bottle of single dose inner packing bottle or multiple dosing, bottleneck all should be designed to insert the tubular structure of vagina.
The physicochemical character of formulation products of the present invention: external be liquid, injecting intravaginal becomes gel.
The using method of formulation products of the present invention: with the single using dosage is that 5 milliliters formulation products packing specification of the present invention is an example.It is that 5 milliliters formulation products medicinal liquid of the present invention is that the bottleneck of tubular structure injects vagina by front end with the single using dosage that user adopts prone position (lie on the back, lie on one's side or prostrate all can), continues then to keep prone position about one minute.If formulation products of the present invention is used to practise contraception, can before sexual intercourse, formulation products of the present invention be injected vagina, also can be after the sexual intercourse of unprotect measure, by the remedial measure of practising contraception to vagina injection formulation products of the present invention.
The present invention has following function respectively according to the in-situ gel preparation product of different drug regimen scheme preparations:
1, with drug regimen with inactivating pathogenic microbes effect.Its effect is, totally catches up hill and dale and kills various pathogenic microbes, effectively prevents and eliminate the infringement of originality microorganism to vagina surface, prevents the propagation of sexually transmitted disease (STD);
2, with have a drug regimen of killing the sperm effect and having the effect of pH value dash adjustment.Its effect is, neutralization in time is set in the sexual intercourse process and the intravaginal weakly alkaline seminal fluid that is is stayed in sexual intercourse afterwards, make intravaginal pH value maintain natural acidic levels (the about pH3.5 of foot～5 usually), gelatinous mass wherein also can cover the cervical orifice place, make the cervical mucus thickening, stopping that seminal fluid also can mix with seminal fluid simultaneously makes it thickening, effectively physics catch and kill in the sexual intercourse process and sexual intercourse after stay sperm (also comprising the pathogenic microbes in the seminal fluid certainly) in the tract, reach the contraception purpose, become the succedaneum of " condom ";
3, with have a drug regimen that improves woman vagina physiological environment and sexual function improving effect.Its effect is, improves life quality simultaneously increasing the moistening and lubricity of woman vagina;
4, with have the inactivating pathogenic microbes effect and have the drug regimen of killing the sperm effect and having the effect of pH value dash adjustment.Its effect is, makes the present invention possess the drug action of assembled scheme 1 and assembled scheme 2 simultaneously, promptly practises contraception and prevents the propagation of sexually transmitted disease (STD), becomes the another kind of succedaneum of " condom ";
5, with have the inactivating pathogenic microbes effect and have the drug regimen of pH value dash adjustment improved effect woman vagina physiological environment and sexual function improving effect.Its effect is that the alleviation middle aged and aged women is puckery because of the vagina interference that decrease in estrogen causes, the intravaginal pH value raises, the physiological environments such as ability drop of opposing source of disease microorganism change, and prevents and treat female vagina;
6, with the appropriate combination of first three class medicine.Its effect is to make the present invention possess the drug action of above two or three aspects simultaneously;
The in-situ gel preparation advantage of vagina that is applicable to provided by the invention is to sprawl and form gel layer at vagina surface rapidly with behind the liquid agent form administration, does not have the medication dead angle.Owing to the viscous effect of the gel layer that forms at vagina surface, medicine is trapped in the time lengthening of vagina surface, thereby brings into play various efficacy of drugs effectively.Because the gel layer that forms at vagina surface is evenly distributed in vagina surface, solved easy loss that the existing liquid pharmaceutical formulation that is used for vagina exists, easily gather the crawling that exists with solid and semisolid pharmaceutical formulation, problem such as medication dead angle is arranged, also effectively avoided the existing dosage form of vagina that is used for because of uneven too high caused zest of local drug concentration of drug distribution and toxic and side effects.The in-situ gel preparation drug regimen that is applicable to vagina provided by the invention is no cytotoxicity or extremely low cytotoxicity normally, can not produce stimulation and irritated effect to vagina, more can not cause the vagina pathological changes.Therefore the in-situ gel preparation that is applicable to vagina provided by the invention can be widely used in clinical, has the wide development prospect.
The specific embodiment
The following examples will illustrate the present invention, but not limit content of the present invention.
Embodiment 1: the in-situ gel preparation that contains Niphesamide.
Get Niphesamide 0.00025%, 21% poloxamer 407,10% poloxamers 188, and aseptic phosphate buffer solution (pH3.5～pH5) to full dose.Niphesamide is water-soluble, and poloxamer is slowly added in the above-mentioned solution under ice bath and stirring condition, and deepfreeze is preserved, until forming clear and bright solution.Said preparation has contraception and the effect of prevention cause pathogeny imcrobe infection.
Embodiment 2: the in-situ gel preparation that contains hyaluronic acid and Niphesamide.
Get Niphesamide 0.00025%, hyaluronate sodium 0.2%, 21% poloxamer 407,10% poloxamers 188, aseptic phosphate buffer solution (pH3.5～pH5) to full dose.Hyaluronate sodium is dissolved in buffer solution, again according to embodiment 1 prepared in-situ gel preparation.Said preparation has contraception and the effect of prevention cause pathogeny imcrobe infection.
Embodiment 3: contain carbomer and acyclovir and be used for the woman vagina in-situ gel preparation.
Get acyclovir 2%, benzalkonium chloride 0.02%, carbomer 934 P 0.2%, mannitol 5%, 22% poloxamer 407,10% poloxamers 188, sterilized water is to full dose.Carbomer is dispersed in the water, regulates pH to 3.5～pH5 with sodium hydroxide solution, adds medicine, benzalkonium chloride and mannitol, and poloxamer is slowly added in the above-mentioned solution under ice bath and stirring condition, and deepfreeze is preserved, until forming clear and bright solution.
Embodiment 4: contain chitosan and acyclovir and be used for the woman vagina in-situ gel preparation.
Get acyclovir 2%, benzalkonium chloride 0.02%, chitosan 1%, 21% poloxamer 407,10% poloxamers 188, aseptic phosphate buffer solution (pH3.5～pH5) to full dose.Chitosan is dissolved in buffer solution, contains chitosan according to embodiment 1 prepared again and acyclovir is used for the woman vagina situ-gel.
Embodiment 5: the in-situ gel preparation that is used for woman vagina that contains the gentamycin plasmalogen.
Gentamycin plasmalogen 1%, bromo geramine 0.02%, 21% poloxamer 407,10% poloxamers 188, aseptic phosphate buffer solution (pH3.5～pH5) to full dose.The in-situ gel preparation that is used for woman vagina that contains the gentamycin plasmalogen according to embodiment 1 prepared.
Embodiment 6: the in-situ gel preparation that is used for woman vagina that contains the amphotericin B plasmalogen.
Amphotericin B plasmalogen 0.5%, bromo geramine 0.02%, hydroxypropyl methylcellulose K4M2%, 20% poloxamer, 407,10% poloxamers 188, aseptic phosphate buffer solution (pH3.5～pH5) to full dose.Hydroxypropyl emthylcellulose is dissolved in buffer solution, contains the in-situ gel preparation that is used for woman vagina of amphotericin B plasmalogen again according to embodiment 1 prepared.
Embodiment 7: the in-situ gel preparation that is used for woman vagina that contains the hydrocortisone microsphere.
Hydrocortisone microsphere 0.5%, polyvinyl alcohol 3%, 21% poloxamer 407,10% poloxamers 188, aseptic phosphate buffer solution (pH3.5～pH5) to full dose.The hydrocortisone microsphere is dispersed in the poly-vinyl alcohol solution, contains the in-situ gel preparation that is used for woman vagina of hydrocortisone microsphere again according to embodiment 1 prepared.
Embodiment 8: the in-situ gel preparation that is used for woman vagina that contains tobramycin.
Get water for injection 39Kg, add the unreal stirring of tobramycin 0.25K and make dissolving.Get poloxamer (M12000-16000) 10Kg, be sprinkled into above-mentioned solution, standing over night adds benzene again and pricks chlorine plating 0.005Kg, the unreal stirring and dissolving of sodium chloride 0.4K.Regulating pH with boric acid is 3.5～5, and solution adds water to total amount 50Kg by 0.22 micron filtering with microporous membrane on filter.Quality Identification is carried out in sampling, and qualified back is sub-packed in the bottle under gnotobasis, and packing promptly.
Embodiment 9: the in-situ gel preparation that is used for woman vagina that contains levofloxacin hydrochloride.
Get water for injection 39Kg, add levofloxacin hydrochloride 0.1Kg, stir just dissolving.Get poloxamer (and 2000-16000) 5Kg and hydroxypropyl emthylcellulose (E50) 0.4Kg, be sprinkled into above-mentioned solution, standing over night adds ethyl hydroxybenzoate 0.015Kg again, glucose 0.4Kg, stirring and dissolving.Regulating pH with the 0.1N sodium hydroxide is 3.5～5, and solution filters by 0.22 micron microporous filter membrane, adds water to total amount 50Kg on filter.Quality Identification is carried out in sampling, and qualified back is sub-packed in the bottle under gnotobasis, and packing promptly.
Embodiment 10: the in-situ gel preparation that is used for woman vagina that contains clindamycin.
Get water for injection 45Kg, add clindamycin 0.5Kg, stir just dissolving.Get carbomer (NF940) 0.15Kg and hydrocarbon propyl methocel (E50) 0.4Kg, be sprinkled into above-mentioned solution, standing over night adds cruel 0.015Kg of Metagin and the nipalgin third cruel 0.015Kg, sodium chloride 0.4Kg, stirring and dissolving again.Regulating pH with the 0.1N sodium hydroxide is 3.5～5, and solution adds water to total amount 50Kg by 0.22 micron filtering with microporous membrane on filter.Quality Identification is carried out in sampling, and qualified back is sub-packed in the bottle under gnotobasis, and packing promptly.
Embodiment 11: the in-situ gel preparation that is used for woman vagina that contains matrine.
Get water for injection 39Kg, add matrine 0.25Kg, stir and make dissolving.Get poloxamer (and 2000-16000) 10Kg, be sprinkled into above-mentioned solution, standing over night adds benzalkonium chloride 0.005Kg again, the unreal stirring and dissolving of sodium chloride 0.4K.Regulating pH with boric acid is 3.5～5, and solution adds water to total amount 50Kg by 0.22 micron filtering with microporous membrane on filter.Quality Identification is carried out in sampling, and qualified back is sub-packed in the bottle under gnotobasis, and packing promptly.
Embodiment 12: the in-situ gel preparation that contains alginic acid and Niphesamide.
Get Niphesamide 0.00025%, 21% poloxamer 407,10% poloxamers 188,4.0% alginic acid, 3.0% xanthan gum, glycerol 8.0%, lactic acid 2.0%, citric acid 1.0%, potassium hydrogen tartrate 0.4%, benzoic acid 0.2%, sterile distilled water surplus.Niphesamide is water-soluble, stir on one side, add lactic acid, citric acid, benzoic acid, potassium hydrogen tartrate on one side, under agitation slowly add poloxamer and alginic acid in the above-mentioned solution respectively, measure pH, it is about 3.5～5 to be adjusted to pH with sodium hydroxide, continues stir about 30 minutes, or the enough time, guarantee uniform mixing.In another container, xanthan gum and glycerol are mixed, be stirred to evenly, slowly mix with above-mentioned homogeneous mixture then.The water that in mixture, adds surplus then.Stir the mixture of short time (about 20 minutes) and place the short time (about 15 minutes) then.Continue then to stir, up to obtaining the even gel denseness.Check pH, should be in about 3.5～5 scope.As needs, can add sodium hydroxide solution it is adjusted in the required scope.Said preparation has contraception and the effect of prevention cause pathogeny imcrobe infection.
Claims (13)
1. vagina is characterized in that having following basic composition with situ-gel (claiming again at the body gel) preparation:
Constituent content (weight %)
Gelatinizing-in-situ material 0.001～50
Tackifying macromolecular compound 0～10
Lubricant 0～10
Medicine (comprising the microgranule and the cyclodextrin clathrate that are loaded with medicine) 0～10
Antiseptic 0～10
PH dash adjustment material adjusting pH value is 2～10 amount
Water surplus.
2. the in-situ gel preparation of claim 1 is characterized in that it is used for woman vagina and female mammal vagina.
3. the in-situ gel preparation of claim 1 is characterized in that it is liquid condition under certain storage condition, behind the liquid agent form administration, forms gel at vagina surface rapidly.
4. the in-situ gel preparation of claim 1, wherein said gelatinizing-in-situ material are selected from one or more the mixture in poloxamer (Poloxamer), carbomer (Carbomer), the methylcellulose (MC, Methyl Cellulose).The poloxamer molecular weight is that 1000～16000 (comprising poloxamer 407, poloxamer 388 and poloxamers 188), carbomer molecular weight are 1 * 10
6～4 * 10
6, the methylcellulose molecular weight is 2 * 10
4～38 * 10
4
5. the in-situ gel preparation of claim 1, wherein said tackifying macromolecular compound is selected from xanthan gum, hydroxypropyl cellulose, hydroxypropyl emthylcellulose (HPMC, Hydroxypropyl Methylcellulose), hydroxyethyl-cellulose, carboxymethyl cellulose, chitosan, polycarbophil, carbopol, hyaluronate sodium, polyvinyl alcohol, polyvidone, sodium alginate, polyvinyl alcohol (PVA, Polyvinyl Alcohol), hyaluronic acid sodium (HA, Sodium Hyal uronat), polyvidone (PVP, Polyvidone), Smart polymer gels, the mixture of one or more in Ji Leng (gellan) glue.The polyvinyl alcohol molecular weight is 3 * 10
4～20 * 10
4, the polyvidone molecular weight is 5000～70000, the hydroxypropyl emthylcellulose molecular weight is 86000.Xanthan gum is first-selected tackifying macromolecular compound.The purpose that adds the tackifying macromolecular compound is to add protective layer for the body cavities surface, and prolong drug is in the holdup time of vagina surface.
6. the in-situ gel preparation of claim 1, wherein said pH dash adjustment material is selected from sodium hydroxide, hydrochloric acid, sulphuric acid, lactic acid, citric acid, potassium hydrogen tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA), acetic acid, malic acid, citric acid, sodium citrate, boric acid, sodium borate, triethanolamine etc.Usually in preparation of the present invention, can comprise several buffer agents, higher slow Zhong Nengli is provided.Certainly, alginic acid can be simultaneously as gel-type vehicle and buffer agent in the preparation of invention.
7. the in-situ gel preparation of claim 1, wherein said pH dash adjustment material consumption is meant the determined consumption of pH environmental requirement of vagina, the suitable consumption that is used for woman vagina should be and regulates pH value is 3.5～5 amount.
8. the in-situ gel preparation of claim 1, wherein said lubricant are selected from one or more the mixture in glycerol, hyaluronate sodium, Polyethylene Glycol, propylene glycol, sorbitol, the glyceryl triacetate.Glycerol is first-selected lubricant.
9. the in-situ gel preparation of claim 1, wherein said medicine can be disease-resistant source microbial medicine or contraceptive, can be selected from metronidazole, povidone iodine, hibitane, Yi Qukang frustrates, the ketone health is frustrated, first nitre is frustrated, restrain mould frustrating, the fluorine health is frustrated, Te Lakang frustrates, narrowing health frustrates, frustrate for nitre, Yi Kang frustrates, ring adjoins department's amine, nystatin, tobramycin, gentamycin, neomycin, chloromycetin, dexamethasone, ciprofloxacin and salt thereof, ofloxacin, levofloxacin and salt thereof, Gatifloxacin, west arsenic chlorine plating, head is embraced the first fat, clarithromycin, clindamycin and salt thereof, matrine, beta-lactam, Tetracyclines, amino sugar formula class, vinegar class in the macro ring, chloromycetin and derivant thereof, ucleosides, ftibamzone, acyclovir, ganciclovir, quinolones, imidazoles, Niphesamide, Nonoxynol-9, benzalkonium chloride, hibitane, octoxynol 9, the hesperidin of phosphorylation, Sulfonated hesperidin, the polystyrolsulfon acid ester, the benzenesulfonic acid copolyoxymethylenes that replaces, H
2SO
4The mixture of one or more in the mandelic acid of-modification.
10. the in-situ gel preparation of claim 1, wherein said medicine can be a natural extracts.
11. the in-situ gel preparation of claim 1, wherein said medicine can be protein and polypeptide class.
12. the in-situ gel preparation of claim 1, wherein said antiseptic are selected from benzoic acid, sodium benzoate, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, to cutting edge of a knife or a sword essence of Niobe, diameter ethyl benzoate, to the hydrocarbon butyl benzoate, to one or more the mixture in hydrocarbon propyl benzoate, phenylmercuric nitrate, the hibitane.First-selected antiseptic is a benzoic acid.Benzoic acid also can be used as buffer agent.
13. the vagina of claim 1 preparation method of in-situ gel preparation, the step that this method comprises: by the weighing of the described prescription of claim 1 with medicine (comprising the microparticulate system and the cyclodextrin clathrate that are loaded with medicine) or/and the antiseptic stirring and dissolving in water, add the gelatinizing-in-situ material again, the tackifying macromolecular compound, lubricant, stirring makes dissolving, with pH dash adjustment material regulator solution pH value, solution passes through filtering with microporous membrane, add water to total amount by filter again, Quality Identification is carried out in sampling, after qualified, in the sub-bottling, packing promptly under gnotobasis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510072312 CN1872026A (en) | 2005-05-30 | 2005-05-30 | New medicinal preparation for vagina |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510072312 CN1872026A (en) | 2005-05-30 | 2005-05-30 | New medicinal preparation for vagina |
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| Publication Number | Publication Date |
|---|---|
| CN1872026A true CN1872026A (en) | 2006-12-06 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510072312 Pending CN1872026A (en) | 2005-05-30 | 2005-05-30 | New medicinal preparation for vagina |
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| Country | Link |
|---|---|
| CN (1) | CN1872026A (en) |
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| CN101703504B (en) * | 2009-07-08 | 2011-07-20 | 济南宏瑞创博医药科技开发有限公司 | Medicinal composition for vagina |
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