CN101683316A - Temperature responsive bio-adhesive in situ gel sustained-release preparation for vagina - Google Patents
Temperature responsive bio-adhesive in situ gel sustained-release preparation for vagina Download PDFInfo
- Publication number
- CN101683316A CN101683316A CN200810200716A CN200810200716A CN101683316A CN 101683316 A CN101683316 A CN 101683316A CN 200810200716 A CN200810200716 A CN 200810200716A CN 200810200716 A CN200810200716 A CN 200810200716A CN 101683316 A CN101683316 A CN 101683316A
- Authority
- CN
- China
- Prior art keywords
- vagina
- preparation
- gel
- poloxamer
- carrageenan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicinal preparation, relating to a temperature responsive bio-adhesive in situ gel sustained-release preparation for vagina drug administration. The preparationis composed of poloxamer, carrageenan, at least one optional gel substrate material, such as polyacrylic acid and the like and at least one drug with effective treating amount. The preparation combines the reversed-phase gelation properties of poloxamer and the bio-adhesive property and antiviral activity of carrageenan, and can obviously improve the sustained-release effect of the gel and can maintain effective drug concentration for above 12 hours in the vagina in vivio. The preparation has the advantages of convenient drug administration and favourable sustained release and is suitable fortreating diseases of female reproductive system, in particular to sexually transmitted sex microorganism infection.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of bioadhesive in-situ gel sustained-release preparation that is used for vagina administration and preparation method thereof.
Background technology
Female genital disease is a common gynecological disease, and infection can betide down reproductive tract such as vulvitis, vaginitis and cervicitis; Also can attack reproductive tract and be internal genitalia and cause pelvic inflammatory disease.According to the interrelated data statistics, the adult women of China 70% has gynecological inflammation in various degree.It should be noted that at present reproductive tract viral infection and sexually transmitted disease (STD) are in rising trend, not only threaten women health itself but also leave troubles to the children offspring, pathogen can cause intrauterine infection by Placenta Hominis, the birth process birth canal infects, and by links such as sucklings after giving birth to, infect fetus and neonate, cause serious consequences such as miscarriage, premature labor, congenital development deformity, mental retardation.In order to guarantee WomanHealth and children's health of future generation, infect and to pay much attention to preventing and treating disease in the female sexual system.
Vagina administration is one of important route of administration of treatment disease in the female sexual system, and it can directly be delivered to the part, affected part with medicine, has local concentration height, advantage that systemic side effects is little.Present existing vagina medicinal agent type roughly can be divided into three classes: the first kind is a solid dosage forms, comprise vaginal suppository, vaginal tablet, vagina effervescence agent, vaginal capsule agent, per vaginam endocrine liquid dissolves and dispersive medicine after medication, the easiest intravaginal problem pockety that occurs of such preparation; Second class is a semi-solid preparation, comprise vagina ointment, vaginal cream, vagina membrane, vagina gel, need it be coated the intravaginal surface by applicating implement, though such preparation is good in the tack on vaginal mucosa surface, but be difficult to guarantee to be coated with evenly, occur medication dead angle (for example fornix vaginae portion) easily, and administration is convenient inadequately; The 3rd class is a solution, as vaginal lotion, spray, effervescent liquid, pressurization effervescent liquid, need inject intravaginal by apparatus, and preparation is the easiest is evenly distributed for such, but tack is poor, runs off easily.Therefore, exploitation has convenient drug administration concurrently, uniform distribution is good and bioadhesion is strong vaginal preparation is the task of top priority.
The solution that appears as this problem of situ-gel has brought dawn.Situ-gel is the aqueous solution of the high molecular polymer of the high molecular polymer of temperature sensitive high molecular polymer, pH value sensitivity and ionic strength sensitivity, can change gel state into by solution state in the stimulation of adapt circumstance factor.This drug-supplying system, the advantage of fusion solution and gel can be avoided the inherent shortcoming of above-mentioned three class preparations, has a good application prospect.
Temperature-sensitive situ-gel is the class situ-gel the most widely of research at present, wherein poloxamer class high polymer is wherein to study and use maximum gellike materials, existing disclosed patent: with poloxamer is the patent (for example Supository composition of the drug which undergo the hepaticfirst-pass effect.WO9730693) of single gel substrate, have by patent (the ocular in-situ gel preparation with suitable phase transition temperature of poloxamer compatibility use to have suitable phase transition temperature with different model, patent publication No.: CN1377706A,), have poloxamer and other biological adhesiveness macromolecule are share to obtain the patent (for example Thermoreversible gel as a liquid pharmaceutical carrier fora galenic formulation.EP0551626) of bioadhesive situ-gel, also has the situ-gel that poloxamer and other macromolecule couplings with special properties is used for specific use with acquisition, for example the cross-linked polysaccharides coupling of poloxamer and high-hydroscopicity is obtained to be used for gel (the Wound gels of wound healing, US 7,083,806), with gel (the Hydrogel compositions for controlled deliveryof virus vectors and methods of use thereof.6 that poloxamer and collagen coupling is obtained to be used for viral vector, 333,194).The route of administration that relates to comprises that dosing eyes (sees above CN1377706A; Dropped in eyes is used in body gel preparation and preparation method thereof, CN1397272A) and the administration by the health tract, comprise oral cavity, nasal cavity, rectum and vagina administration (RECTALAND VAGINAL SUPPOSITORIES CONTAINING BIOADHESIVE BROMOCRIPTINE AND POLOXAMERWO2006099877; A kind of heat-sensitive gel preparation and preparation method thereof CN 1814253A; New medicinal preparation for vagina, CN 1872026A; A kind of temperature sensitive vagina in-situ gel preparation, CN 1593386A).
Though based on the patent of the situ-gel of poloxamer class contained comprise vagina administration multiple non-injection through the cavity/canal drug administration approach, and with various macromolecules (carbopol for example, hydroxy methocel, alginic acid, cross-linked polysaccharides, share collagen protein etc.) also has reports more, but studies show that, dissolved quite fast in the dissolution in vitro experiment of poloxamer gellike under the condition of contact simulated body fluid and 37 ℃, for gelling temperature proper ('s more than 20 ℃) 20%poloxamer 407 gels, be 1cm when gel face and liquid contact surface are long-pending
2The time, dissolution velocity is about 0.133g/ hour, and the release of medicine also is subjected to the dissolved control of gel substantially, and gel dissolves that medicine has just all discharged when complete.This medicine carrying in-situ gel its slow release effect behind subcutaneous injection is limited, compare with solution injection group, effective blood drug concentration has only prolonged 2 hours (Liu, Lu et al.2007), this illustrates simple poloxamer gel owing to its character soluble in water, so dissolving is very fast under the situation of contact body fluid.Although a lot of documents and patent have all proposed to wherein adding the macromolecule that can increase gel viscosity, but there is document (El-Kamel2002) to show, the high molecular adding of methylcellulose, hydroxypropyl emthylcellulose etc. is very little to the retarding action of gel dissolving and drug release, and in fact these high molecular addings not only fail effectively to prolong the gel time of staying in vivo, can increase the viscosity of original flavor gel under liquid condition on the contrary, make administration become more difficult.According to previous patent and document, the adding of poloxamer 188 can be regulated the gelling temperature of poloxamer 407 situ-gels, but according to the result of certain research previous experiments, the dissolving of poloxamer 407-poloxamer 188 pluralgel is also faster than the dissolving of poloxamer 407 gels.Therefore, the too fast problem of dissolving has limited the practical application based on the situ-gel of poloxamer 407.Although there has been couple poloxamer to carry out some trials (US7 for example, 008, the 628 End modified thermal responsive hydrogels of chemical modification, 2006-3-7), but cost is higher, complex process, and also new material needed comprehensive evaluation before coming into operation.Therefore, seek suitable natural polymer,, remain one of direction that this area research makes great efforts by realizing improving the purpose of slow release effect with the physical mixed of poloxamer gel.
Carrageenan is the general designation of the Sargassum polysaccharides that extracts Chondrus (Chondrus), Eucheuma (Eucheuma), China fir Trentepohlia (Gigartina) and the husky Lepidium kind Sargassums such as (Hypnea) from red algae.On chemical constitution, carrageenan be a kind of be the sulfuric acid ester of galactan, it is a kind of galactose and 3 by sulfateization or non-sulfuric acid baseization, the 6-Anhydrogalactose. is by α-1,3-glycosidic bond and β-1,4 glycosidic bond alternately is formed by connecting.Though it is used mainly aspect food industry, but increasing experimental evidence shows, carrageenan has good prospects for application at pharmaceutical field, because carrageenan not only can be used as source abundant, with low cost thickening agent and gel-type vehicle (Tomida, Nakamura et al.1994), the more important thing is that it also has good bioadhesive, antimicrobial acivity and good safety.The most basic bioadhesive Material card POP is similar, there is the sulfate of a large amount of formed hydrogen bonds to exist in the carrageenan molecule, and hydrogen bond is the ingredient of the mechanism of adhering to, and the height ionizing can form better adhesiveness, therefore carrageenan has bioadhesive, and the experiment of carrying out with animal nasal mucosa and gastric mucosa is verified this point (Bertram andBodmeier 2006).Carrageenan has good microbicide effect, can be by forming negative electricity peplos on the mononuclear cell surface, stop the transhipment of mononuclear cell from the vaginal secretion to the mucosa of having infected enveloped virus (for example HIV and HSV), thereby play antiviral effect (Perotti, Pirovano et al.2003), the carrageenan preparation has obtained support (the Zacharopoulos and Phillips 1997 of moving experimental data to the inhibitory action of HSV and HIV vaginal infection; Maguire, Zacharopoulos et al.1998).The data of existing zoopery and I phase clinical experiment show, concentration does not have tangible zest (Elias, Coggins et al.1997 up to the gel of 2% carrageenan to female genital tract; Coggins, Blanchard et al.2000).
At present, not appearing in the newspapers about share with poloxamer and carrageenan as yet is temperature sensitive vagina situ-gel and preparation method thereof of substrate.
Summary of the invention
The purpose of this invention is to provide a kind of temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation.
Another object of the present invention provides a kind of method for preparing described preparation.
Contain natural polymer in the situ-gel provided by the present invention with bioadhesive and antimicrobial acivity, have responsive to temperature type gel rubber material and, alternative, the third has the acrylic acid high polymer of bioadhesive.
Described in-situ gel sustained-release preparation contains the effective dose of medicine thing that is applicable to vagina administration, treatment disease in the female sexual system, and contained drug content is 0.01%～10% (w/w); Gel matrix material, it comprises a kind of or more than one poloxamer and carrageenan; Or further contain at least a polyacrylic acid with bioadhesive.
Described medicine is selected from antiviral agent (as acyclovir, recombinant alpha-human interferon), antifungal (as metronidazole), antibacterial (as clindamycin), antimycotic agent (as matrine), spermicide (as nonoxynolum) and hormone medicine (as estradiol); Described poloxamer is selected from poloxamer 407, and its content is 15%～25% (w/w) and/or poloxamer 188, and content is 1～15% (w/w); Described carrageenan is for extracting the mixture from plants such as chondrus ocellatus Holmes, and its content is 0.1～1% (w/w).
Described polyacrylic is selected from Polycarbophil, carbomer, Carbopol 934, Carbopol 974, Carbopol971 etc., and content is 0.01～1%.
Described preparation at room temperature is liquid, is semi-solid gel when body temperature, said preparation can discharge medicine lentamente with zero order kinetics; Medicine wherein constantly disengaged in 12 hours;
Described preparation, it further comprises antiseptic, and as parabens, its content is 0.005%～0.2% (w/w).
Purpose of the present invention is achieved through the following technical solutions:
Earlier carrageenan is dissolved in postcooling in hot pure water or the buffer, obtain the carrageenan storing solution of appropriate concentration, according to recipe quantity, with carrageenan storing solution dissolving poloxamer gellike substrate and, alternative, acrylic acid high polymers such as carbopol, 4 ℃ leave standstill components dissolved such as treating poloxamer and carbopol after, make it evenly to obtain blank gel-type vehicle 4 ℃ of stirrings.An amount of medicine is added in the above-mentioned blank gel, continue stirring and obtain uniform dispersion.
In one embodiment of the invention, carrageenan is a κ type carrageenan, and poloxamer 407 provides (model is Pluronic F127) by BASF.In another embodiment of the invention, containing acrylic acid high polymer is Carbopol934.
Poloxamer 407 (Poloxamer 407) is one of the most frequently used thermo-responsive hydro gel material, the block copolymer of forming by polyoxyethylene (PEO) and polyoxypropylene (PPO), be white particle, its 15% or the aqueous solution of higher concentration have the character of reversible heat-sensible gelation, when low temperature liquid, when being heated to gelling temperature when above, then form the clear gel of semi-solid; But gel is transformed into solution again after temperature descends.Therefore can be used as the host material of situ-gel drug-supplying system.
Carrageenan (CAS 9000-07-1, Carrageen) being a kind of Sulfated polysaccharide. it is a kind of hydrocolloid that obtains by among the various members in the shirt algae section of Bostrychia montagnei Rhodophyceae or the red tail feather dish section. it is by galactose and 3, and the sulphuric acid vinegar of 6-Anhydrogalactose. copolymer is formed. be not have the powder of the yellow of aroma and flavor to white. dissolve in the dense atmosphere sodium solution of hot water and heat. be insoluble in oils and the organic solvent. it is used as emulsifying agent, bonding other, extender, stabilizing agent, thickening agent, gelling is other, suspending agent, loose aperient and be used for oral and local medicine; Its Castor Oil skin .. it both with medicine, also manufactured and mirror is sold with cereal product. the example of its trade name comprises Aguagel SP339, Cl-10, CM-80, Carcked 15 Bleached Irish Moss, Genu Carrageenan, Genugel series, Genuvisco, Soageena, Soageena LX7, Soageena LX26, Soageena WX87, Stamere CKOS, Stamere-325, Stamere-350, Stamere-3505, stamere Nl.Carrageenan is soluble in hot water, dissolves in 30 parts of water and to form thickness limpid or slightly with the solution of lacteous at 80 ℃, is 4 to have good stability between 10 the time at pH value.There are some researches show that carrageenan has bioadhesive, and can suppress of the infection of enveloped viruses such as HSV, HIV at vagina.
Preparation of the present invention prepares by following method and step::
1) in about 50 ℃ to 70 ℃ water or buffer, dissolves the carrageenan postcooling to room temperature, so that first kind of mixture to be provided;
2) in water, disperse poloxamer and, alternative, at least a polyacrylic acid family macromolecule, add first kind of an amount of mixture again, be statically placed in 4 ℃ of refrigerators, treat solids dissolving after, stir about 30min under 4 ℃ of conditions makes it evenly, so that second kind of mixture to be provided;
3) in second kind of mixture, add appropriate amount of drug, stir,, promptly obtain temperature sensitive bioadhesive vagina in-situ gel preparation until the abundant or even suspendible of medicine dissolution.
Slow release vagina situ-gel delivery system of the present invention is based on the synergistic function of carrageenan and poloxamer, they produce complicated network structure, can not only promote bioadhesive, also form a kind of diffusion barrier, thereby increased the pharmaceutically-active persistent period drug migration.Wherein, the anti-phase gelling property of poloxamer 407 has been given this formulation temperature sensitivity, and this preparation is liquid below 20～35 ℃ at gelling temperature, convenient drug administration, improve compliance, and can form semi-solid gel, be trapped in intravaginal and slowly release for a long time in intravaginal; The adding of carrageenan not only can overcome based on the gel of poloxamer 407 meets the too fast problem of body fluid dissolving, and the release of medicine from the poloxamer gel of obviously slowing down prolongs onset time; And can further improve the bioadhesive of preparation; The inherent resisting pathogenic microbes activity of carrageenan can make this preparation have the viral infection resisting effect concurrently, and the disease in the female sexual system that is used for preferably is treated, particularly spreading through sex intercourse property infected by microbes aspect.
Though also have the method for other intravaginal drug administration at present, but still a kind of delivery system of needs, its administration easily, can provide the lasting release of activating agent, can adhere on the vaginal wall for a long time and can too fastly not come off, leak or cause the form of administration of stimulation.Preparation of the present invention can provide the administration of the medicine that reaches 12 hours. and the medicine example that can be formulated in the prolonged release bioadhesive vaginal gel dosage form of the present invention comprises, but be not limited to, treat colpitic antibiotic, antiviral agent, the antifungal of treatment fungal infection, the spermicide of contraception usefulness, the pruritus that the treatment vagina is fullyed recover from an illness and itched, the Humectant and the emollient of treatment vagina drying, the corticosteroids of treatment inflammation, the mould resistant of treatment mycete and yeast infection, hormone and hormone replacement thing therapy (HRT) with treatment premenstrua syndrome (PMS).The medicine that relates to is a kind of of following medicine or their compound recipe: acyclovir, recombinant alpha-human interferon, clindamycin, matrine, first nitre sound of crying or vomiting, for nitre sound of crying or vomiting, clindamycin, gram mould sound of crying or vomiting, fluconazol, ketoconazole, itraconazole, miconazole, policresulen, nystatin, hachimycin, chloromycetin, chlortetracycline, nonoxynolum, estradiol etc.
Preparation of the present invention shows through external experiment: have good controlled external slow release effect.When with the suspension medicine carrying, drug release at least 9 hours meets zero order kinetics, the release of medicine from the gel of carrageenan and poloxamer (poloxamer407, trade name Pluronic F127) combination gained is obviously than the gel that poloxamer is only arranged slow (Fig. 1).Itself can not form gel the carrageenan of respective concentration.As seen two kinds of gel rubber materials are used in combination and obviously are better than the two independent use.Though the adding of carbopol is accelerated drug release, but still slower than the gel that poloxamer is only arranged.Only have the gel of poloxamer to dissolve quickly with stable speed in drug release process, the release of visible medicine is subjected to the dissolved control of gel, and this point has also obtained the support of lot of documents.By contrast, preparation of the present invention not significantly dissolving in 8 hours at least, the adding of carbopol is slightly accelerated the dissolving of gel, but still very slow.Therefore, the slow release effect of the excellence of carrageenan and poloxamer combination gained gel is based on slower gel dissolution velocity, and the release of medicine mainly is subjected to the course of dissolution of gel to control (Fig. 2).The drug release process that carries the gel of acyclovir with dissolved state has shown more obvious DIFFUSION CONTROLLED feature (Fig. 3), because the dissolving of carrageenan and poloxamer combination gained gel is slower, so the release of medicine is obviously slower.Based on The above results, the slow release effect of preparation of the present invention has benefited from slower gel dissolution velocity, is applicable to that various medicines are with suspension (dissolubility is less and required dosage is bigger) or with dissolved state (dissolubility is big and required dosage is less) medicine carrying.The mouse animal experiment that preparation of the present invention carries out shows, the local retention effect behind the vagina administration good (Fig. 4), and local retention effect is the most obvious during wherein with carrageenan-poloxamer-three kinds of material couplings of carbopol.The acyclovir major part that run off after with suspensoid form vagina administration 3h, as seen this medicine there is no specificity with the vagina part and combines, and the result confirms, can both obtain intravaginal retention effect preferably when preparation of the present invention is used for most drug.
Disclosed gel dosage form can be mixed with the dosage form that contains the acyclovir between the 1mg to 30mg in every g gel easily, drops in the scope of utilizing by common commercial product.This slow release vagina situ-gel dosage form is designed to be packaged in the pipe that can easily liquid quantitative ground be injected vagina.This preparation can satisfy the requirement of twice of medication every day.Before administration, preparation should be placed in the refrigerator or shady and cool place, make it keep liquid, it is more convenient to feed vagina than other administering modes (vagina insert, tablet, gel).Said preparation solidifies rapidly under the stimulation at body temperature after the administration, slowly release in ensuing about 12 hours, if use this prescription between the lights, that the medicine that then whole evening, institute's slow release came out should be able to provide is constant, than other administering modes (vagina insert, tablet, lotion) higher at intravaginal drug level.
Preparation provided by the invention has the following advantages: (1) has reverse thermal sensitivity, administration is convenient especially, can be controlled at room temperature to the body temperature be converted into solid-state critical temperature (gelling temperature) from liquid state by accurate prescription, therefore can feed vagina easily with liquid form, under the stimulation of body temperature, solidify rapidly, be implemented in intravaginal permanent delay.(2) adding of carrageenan makes the preparation slow release effect outstanding, and it is little obviously to be better than common thermo-responsive hydro gel preparation (not having the poloxamer gel with the carbopol coupling) (3) composition zest, and safety is good.(4) carrageenan itself has the activity of virus such as anti-HIV, HSV, can with the active substance Synergistic, be specially adapted to vagina administration.(5) raw material sources are extensive, and are with low cost.
Description of drawings
Fig. 1 carries the drug release process in the gel of acyclovir with suspension.
Fig. 2 carries the course of dissolution of the gel of acyclovir with suspension.
Fig. 3 carries the drug release process of the gel of acyclovir with dissolved state.
Fig. 4 acyclovir carries out the local percent that is detained of vagina of different time points after the mouse vagina administration with the different dosing system.
The specific embodiment
Following examples are to be used for illustrating of the present invention, should not be considered to limitation of the present invention by any way.
The preparation of embodiment 1 blank gel I
Take by weighing an amount of kappa-carrageenan and be dissolved in 70～80 ℃ the pure water, stir and make it abundant dissolving, cool to room temperature, promptly get the carrageenan storing solution (0.25%, w/w).In 4 parts (weight ratios) 0.25% carrageenan storing solution, add 1 part of Poloxamer 407, leave standstill at 4 ℃ and treat to stir after the solid constituent dissolving, obtain uniform mixture, be blank gel I.The gelling temperature of this embodiment is about 22～23 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
The preparation of embodiment 2 blank gel II
The carrageenan storing solution join method with embodiment 1.In 4 parts (weight ratios) 0.25% carrageenan storing solution, add 1 part of Poloxamer 407 and The addition of C arbopol 934P-NF, leave standstill at 4 ℃ and treat to stir after the solid constituent dissolving, obtain uniform mixture, be blank gel II.The gelling temperature of this embodiment is about 23～24 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
The preparation of embodiment 3 blank gel III
Identical among experimental arrangement and the embodiment 1. but when in the carrageenan storing solution, adding Poloxamer407 and Carbopol 934, adding an amount of methyl parahydroxybenzoate.The gained gel is blank gel III.The gelling temperature of this embodiment is about 22～23 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Identical among experimental arrangement and the embodiment 1 stirs add an amount of acyclovir (ACV, 60 orders) in the blank gel I of gained after, and making its final medicament contg is 30mg ACV/g gel, and wherein ACV exists with suspension.The gelling temperature of this embodiment is about 22～23 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Identical among experimental arrangement and the embodiment 2 stirs add an amount of acyclovir (ACV, 60 orders) in the blank gel II of gained after, and making its final medicament contg is 30mg ACV/g gel, and wherein ACV exists with suspension.The gelling temperature of this embodiment is between 23～24 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Identical among experimental arrangement and the embodiment 3. stir add an amount of acyclovir (ACV) in the blank gel III of gained after, making its final medicament contg is 30mg ACV/g gel.The gelling temperature of this embodiment is between 23～24 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Identical among experimental arrangement and the embodiment 6 just when preparation carrageenan storing solution, replaces pure water with the phosphate buffer of pH 7.The gelling temperature of this embodiment is between 23～24 ℃.
Identical among experimental arrangement and the embodiment 5 just is increased to 0.5% to the consumption of Carbopol 934P.The gelling temperature of this embodiment is between 24～25 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.5
Embodiment 9 blank gel IV
To prepare 10 gram gels is example, accurately every kind of composition of weighing. the 0.0285g carrageenan is dissolved in the pure water of 70～80 ℃ of 10g, stirs and make it abundant dissolving, cool to room temperature promptly gets the carrageenan storing solution.In the above-mentioned carrageenan storing solution of 7g, add 2g Poloxamer407 and 1g Poloxamer 188, leave standstill at 4 ℃ and treat to stir after the solid constituent dissolving, obtain uniform mixture, be blank gel IV.The gelling temperature of this embodiment is between 32～33 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Poloxamer?188 10
Identical among experimental arrangement and the embodiment 9 stirs after the blank gel IV of gained adds an amount of acyclovir (ACV, 60 orders) at last, and making its final medicament contg is 30mg ACV/g gel.The gelling temperature of this embodiment is between 32～33 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Poloxamer?188 10
Embodiment 11
Identical among experimental arrangement and the embodiment 3. stir after the blank gel III of gained adds an amount of metronidazole at last, making its final medicament contg is 8mg metronidazole/g gel, and this gel can be used for the treatment of fungal infection of vagina.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Metronidazole 0.8
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 12
Identical among experimental arrangement and the embodiment 3. stir after the blank gel III of gained adds an amount of clindamycin at last, making its final medicament contg is 20mg clindamycin/g gel, and this gel can be used for the treatment that vaginal bacteria infects.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 13
Identical among experimental arrangement and the embodiment 3. stir after the blank gel III of gained adds an amount of matrine at last, making its final medicament contg is 20mg matrine/g gel, and this gel can be used for the treatment of vagina fungal infection.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 14
Identical among experimental arrangement and the embodiment 3 stirs after the blank gel III of gained adds an amount of matrine at last, and making its final medicament contg is 0.625mg estradiol/g gel, and this gel can be used for the treatment of vagina drying.
Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Estradiol 0.0625
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 15
Identical among experimental arrangement and the embodiment 3 stirs after the blank gel III of gained adds an amount of recombinant alpha-human interferon at last, and making its final medicament contg is 1.25 * 10
6IU recombinant alpha-human interferon/g gel, this gel can be used for the treatment of female genital tract viral infection.The gelling temperature of this embodiment is between 23～24 ℃.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Recombinant alpha-human interferon 1.25 * 10
7IU/100g
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Identical among experimental arrangement and the embodiment 3 adds at the blank gel III of gained at last and stirs after appointing menthylphenoxypolyethoxy ethanol in right amount, and making its final medicament contg is that 25mg appoints menthylphenoxypolyethoxy ethanol/g gel, and this gel can be used for contraception.Wherein each component weight percentage is as follows:
Reagent
Percetage by weight (%)
Appoint menthylphenoxypolyethoxy ethanol 2.5
Kappa-carrageenan 0.2
Poloxamer?407 20
Carbopol?934?P-NF 0.2
Methyl parahydroxybenzoate 0.1
Claims (10)
1, a kind of temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation, it is characterized in that containing the effective dose of medicine thing that is suitable for vagina administration, treatment disease in the female sexual system, gel matrix material, and/or at least a polyacrylic acid with bioadhesive; Contained drug content is 0.01%～10%w/w; Described gel matrix material comprises a kind of or more than one poloxamer and carrageenan; Described poloxamer is selected from poloxamer 407, and its content is 15%～25% (w/w), and/or poloxamer 188, and its content is 1～15% (w/w).
2, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that described carrageenan for extracting mixture from plants such as chondrus ocellatus Holmes, its content is 0.1～1%w/w.
3, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that described medicine is selected from antiviral agent, antifungal, antibacterial, antimycotic agent, spermicide and hormone medicine.
4, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 3, it is characterized in that described antiviral agent is selected from acyclovir or recombinant alpha-human interferon; Antifungal is a metronidazole; Antibacterial is a clindamycin; Antimycotic agent is a matrine; Spermicide is a nonoxynolum; Hormone medicine is an estradiol.
5, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that described preparation at room temperature for liquid, is a semi-solid gel when body temperature, said preparation discharges medicine lentamente with zero order kinetics.
6, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that the medicine of described preparation constantly disengaged in 12 hours.
7, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that described polyacrylic acid is selected from Polycarbophil, carbomer, Carbopol 934, Carbopol 974 or Carbopol971, content is 0.01～1%w/w.
8, the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 7 is characterized in that described polyacrylic content is 0.01～1%w/w.
9, by the described temperature sensitive bioadhesive vagina in-situ gel sustained-release preparation of claim 1, it is characterized in that described preparation also comprises antiseptic, its content is 0.005%～0.2%w/w.
10, a kind of temperature sensitive bioadhesive vagina of claim 1 preparation method of in-situ gel sustained-release preparation is characterized in that it comprises following steps:
1) in 50 ℃ to 70 ℃ water or buffer dissolving carrageenan postcooling to room temperature, so that first kind of mixture to be provided;
2) in water, disperse poloxamer and, alternative, at least a polyacrylic acid family macromolecule, add first kind of an amount of mixture again, be statically placed in 4 ℃ of refrigerators, treat solids dissolving after, stir about 30min under 4 ℃ of conditions makes it evenly, so that second kind of mixture to be provided;
3) in second kind of mixture, add appropriate amount of drug, stir,, promptly obtain temperature sensitive bioadhesive vagina in-situ gel preparation until the abundant or even suspendible of medicine dissolution.
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| CN200810200716A CN101683316B (en) | 2008-09-26 | 2008-09-26 | Temperature responsive bio-adhesive in situ gel sustained-release preparation for vagina |
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| CN101683316B CN101683316B (en) | 2012-10-24 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102204887A (en) * | 2011-06-09 | 2011-10-05 | 浙江浙北药业有限公司 | In-situ formed acyclovir spraying agent and preparation method thereof |
| CN103239389A (en) * | 2013-06-03 | 2013-08-14 | 南京泽恒医药技术开发有限公司 | Preparation method of progestin sustained-release gel for treating threatened abortion |
| CN103462883A (en) * | 2013-09-06 | 2013-12-25 | 武汉理工大学 | Matrine diatomic alcohol plastid temperature-sensitive gel and preparation method thereof |
| CN106075446A (en) * | 2016-06-24 | 2016-11-09 | 青岛中腾生物技术有限公司 | A kind of slow release gynecological gel and preparation method thereof |
| CN106309354A (en) * | 2015-06-24 | 2017-01-11 | 复旦大学 | Nasal-delivery temperature-sensitive in-situ gel sustained-release preparation comprising ketorolac tromethamine |
| CN113248800A (en) * | 2021-05-24 | 2021-08-13 | 广州市尚信净化工程有限公司 | Carboxymethylated carrageenan gel and preparation method thereof |
| CN115569109A (en) * | 2022-09-20 | 2023-01-06 | 郑州伊品医药科技有限公司 | Sustained-release gynecological antibacterial gel and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1311873C (en) * | 2004-06-30 | 2007-04-25 | 上海复康医药科技发展有限公司 | Temperature sensitive gel formulation for in situ vagina uses |
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2008
- 2008-09-26 CN CN200810200716A patent/CN101683316B/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102204887A (en) * | 2011-06-09 | 2011-10-05 | 浙江浙北药业有限公司 | In-situ formed acyclovir spraying agent and preparation method thereof |
| CN102204887B (en) * | 2011-06-09 | 2013-05-29 | 浙江浙北药业有限公司 | In-situ formed acyclovir spraying agent and preparation method thereof |
| CN103239389A (en) * | 2013-06-03 | 2013-08-14 | 南京泽恒医药技术开发有限公司 | Preparation method of progestin sustained-release gel for treating threatened abortion |
| CN103462883A (en) * | 2013-09-06 | 2013-12-25 | 武汉理工大学 | Matrine diatomic alcohol plastid temperature-sensitive gel and preparation method thereof |
| CN103462883B (en) * | 2013-09-06 | 2015-05-27 | 武汉理工大学 | Matrine diatomic alcohol plastid temperature-sensitive gel and preparation method thereof |
| CN106309354A (en) * | 2015-06-24 | 2017-01-11 | 复旦大学 | Nasal-delivery temperature-sensitive in-situ gel sustained-release preparation comprising ketorolac tromethamine |
| CN106075446A (en) * | 2016-06-24 | 2016-11-09 | 青岛中腾生物技术有限公司 | A kind of slow release gynecological gel and preparation method thereof |
| CN113248800A (en) * | 2021-05-24 | 2021-08-13 | 广州市尚信净化工程有限公司 | Carboxymethylated carrageenan gel and preparation method thereof |
| CN115569109A (en) * | 2022-09-20 | 2023-01-06 | 郑州伊品医药科技有限公司 | Sustained-release gynecological antibacterial gel and preparation method thereof |
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|---|---|
| CN101683316B (en) | 2012-10-24 |
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