CN101683316B - 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
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- CN101683316B CN101683316B CN200810200716A CN200810200716A CN101683316B CN 101683316 B CN101683316 B CN 101683316B CN 200810200716 A CN200810200716 A CN 200810200716A CN 200810200716 A CN200810200716 A CN 200810200716A CN 101683316 B CN101683316 B CN 101683316B
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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 preparation is 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 for treating 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 through Placenta Hominis, and the birth process birth canal infects, and through 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 that WomanHealth and children of future generation are healthy, 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 types: 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, and intravaginal problem pockety appears in such preparation the most easily; Second type is 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, what be difficult to guarantee to be coated with is even; Occur medication dead angle (for example fornix vaginae portion) easily, and administration is convenient inadequately; The 3rd type is solution, like 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 responsive high molecular polymer of responsive high molecular polymer of temperature sensitive high molecular polymer, pH value and ionic strength, 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 above-mentioned three types of inherent shortcomings of preparation, has a good application prospect.
Temperature-sensitive situ-gel is the one type of 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 through poloxamer compatibility and use patent (ocular in-situ gel preparation with suitable phase transition temperature 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 aliquid pharmaceutical carrier fora galenic formulation.EP0551626) of bioadhesive situ-gel, also have poloxamer and other macromolecule couplings, for example the cross-linked polysaccharides coupling acquisition of poloxamer and high-hydroscopicity is used for gel (the Wound gels of wound healing to obtain to be used for the situ-gel of specific use with special properties; US7; 083,806) obtains to be used for gel (the Hydrogel compositions for controlled deliveryof virus vectors and methods of use thereof.6 of viral vector with poloxamer and collagen coupling; 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 through 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 CN1814253A; New medicinal preparation for vagina, CN1872026A; A kind of temperature sensitive vagina is used in-situ gel preparation, CN1593386A).
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 share also of various macromolecules (for example carbopol, hydroxy methocel, alginic acid, cross-linked polysaccharides, the collagen protein etc.) reports that have more; But research shows; 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%poloxamer407 gel, 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 receives the dissolved control of gel basically, 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 the solution injection groups; Effective blood drug concentration has only prolonged 2 hours (Liu; Lu et al.2007), this explains 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 poloxamer188 can be regulated the gelling temperature of poloxamer407 situ-gel; But according to the result of certain research previous experiments, the dissolving of poloxamer 407-poloxamer188 pluralgel is also faster than the dissolving of poloxamer407 gel.Therefore, the too fast issues limit of dissolving based on the practical application of the situ-gel of poloxamer407.Although there has been couple poloxamer to carry out some trials (US7 for example, 008, the 628End modified thermal responsive hydrogels of chemical modification; 2006-3-7); But cost is higher, complex process, and also new material needed comprehensively to estimate before coming into operation.Therefore, seek suitable natural polymer,, remain one of direction that this area research makes great efforts through realizing improving the purpose of slow release effect with the physical mixed of poloxamer gel.
Carrageenan is the general designation of the Sargassum polysaccharides of Chondrus (Chondrus), Eucheuma (Eucheuma), China fir Trentepohlia (Gigartina) and husky Lepidium kind extracting algae such as (Hypnea) from red algae.Say from 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 through 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, so 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 through 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 Phillips1997 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 that the temperature sensitive vagina of substrate is with situ-gel and preparation method thereof.
Summary of the invention
The purpose of this invention is to provide a kind of temperature sensitive bioadhesive vagina and use the in-situ gel sustained-release preparation.
Another object of the present invention provides a kind of method for preparing said preparation.
Contain natural polymer in the situ-gel provided by the present invention with bioadhesive and antimicrobial acivity, the gel rubber material with responsive to temperature type with, 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.
Said medicine is selected from antiviral agent (like acyclovir, recombinant alpha-human interferon), antifungal (like metronidazole), antibacterial (like clindamycin), antimycotic agent (like matrine), spermicide (like nonoxynolum) and hormone medicine (like 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, Carbopol934, Carbopol974, 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 like parabens, its content is 0.005%～0.2% (w/w).
The object of the invention is realized through following technical scheme:
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 with; 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 K 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 (Poloxamer407) 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, be liquid when low temperature; 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 (CAS9000-07-1, Carrageen) is 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 the powder that does not have 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 be used as emulsifying agent, bonding not, other, the suspending agent of extender, stabilizing agent, thickening agent, gelling, loose aperient and be used for oral and local medicine; Its Castor Oil skin .. it both with medicine, also made and mirror is sold with cereal product. the instance of its trade name comprises Aguagel SP339, Cl-10, CM-80, Carcked15Bleached Irish Moss, Genu Carrageenan, Genugel series; Genuvi sco; 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.Existing research shows that carrageenan has bioadhesive, and can suppress the infection of enveloped viruses such as HSV, HIV at vagina.
Preparation of the present invention prepares through 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 with, 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 and use in-situ gel preparation until the fully perhaps 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, the lasting release of activating agent can be provided, 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. can be formulated in medicine instance in the prolonged release bioadhesive vaginal gel dosage form of the present invention including, but not limited to fully recover from an illness mould resistant and the hormone and the hormone replacement thing therapy (HRT) of treatment premenstrua syndrome (PMS) of corticosteroids, treatment mycete and yeast infection of Humectant and emollient, treatment inflammation of the pruritus of itching, treatment vagina drying of, antifungal, the spermicide of contraception usefulness, the treatment vagina of treating colpitic antibiotic, antiviral agent, treatment fungal infection.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 fit zero-order at least 9 hours; 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.It is thus clear that two kinds of gel rubber materials are used in combination and obviously are superior to 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 in drug release process, to dissolve with stable rapid speed ground, the release of visible medicine receives 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 receives 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 significantly DIFFUSION CONTROLLED characteristic (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, visible this medicine does not have specificity with the vagina part and combines, and result's confirmation 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 in every g gel, contains the acyclovir between the 1mg to 30mg easily, drops in the scope of utilizing through common commercial product.This slow release vagina situ-gel dosage form is designed and is 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, should preparation 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 through 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 superior to 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 explaining 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 Poloxamer407, 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
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 Poloxamer407 and The addition of C arbopol934P-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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Carbopol934P-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 Carbopol934, 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Pol?oxamer407 20
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Identical among experimental arrangement and the embodiment 1 stirs after in the blank gel I of gained, adding an amount of acyclovir (ACV, 60 orders), 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Identical among experimental arrangement and the embodiment 2 stirs after in the blank gel II of gained, adding an amount of acyclovir (ACV, 60 orders), 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Pol?oxamer407 20
Carbopol934P-NF 0.2
Identical among experimental arrangement and the embodiment 3. stir after in the blank gel III of gained, adding an amount of acyclovir (ACV), 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Pol?oxamer407 20
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Identical among experimental arrangement and the embodiment 6 is just when preparation carrageenan storing solution, with the phosphate buffer replacement pure water of pH7.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 Carbopol934P.The gelling temperature of this embodiment is between 24～25 ℃.Wherein each component weight percentage is following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Carbopol934P-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 10g70～80 ℃, 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 Poloxamer188, 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Embodiment 11
Identical among experimental arrangement and the embodiment 3. after the blank gel III of gained adds an amount of metronidazole, stir 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 following:
Reagent
Percetage by weight (%)
Metronidazole 0.8
Kappa-carrageenan 0.2
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 12
Identical among experimental arrangement and the embodiment 3. after the blank gel III of gained adds an amount of clindamycin, stir 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 13
Identical among experimental arrangement and the embodiment 3. after the blank gel III of gained adds an amount of matrine, stir 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 following:
Reagent
Percetage by weight (%)
Kappa-carrageenan 0.2
Carbopol934P-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 following:
Reagent
Percetage by weight (%)
Estradiol 0.0625
Kappa-carrageenan 0.2
Carbopol934P-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 following:
Reagent
Percetage by weight (%)
Recombinant alpha-human interferon 1.25 * 10
7IU/100g
Kappa-carrageenan 0.2
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Embodiment 16
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 following:
Reagent
Percetage by weight (%)
Appoint menthylphenoxypolyethoxy ethanol 2.5
Kappa-carrageenan 0.2
Carbopol934P-NF 0.2
Methyl parahydroxybenzoate 0.1
Claims (4)
1. a temperature sensitive bioadhesive vagina is used the 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 at least a polyacrylic acid with bioadhesive; Contained drug is an acyclovir, and its content is 0.01%～10% (w/w); Described gel matrix material comprises poloxamer and carrageenan; Described poloxamer is selected from poloxamer 407; Its content is 15%～25% (w/w), and/or poloxamer 188, and its content is 1%～15% (w/w); Carrageenan is for extracting the mixture from the chondrus ocellatus Holmes plant; Its content is 0.1%～1% (w/w), and described polyacrylic acid is selected from Polycarbophil, Carbopol 934, Carbopol 974 or Carbopol 971, and content is 0.01～1% (w/w); Prepare through following step:
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 at least a polyacrylic acid, add first kind of an amount of mixture again, be statically placed in 4 ℃ of refrigerators, treat the solids dissolving after, under 4 ℃ of conditions, stir 30min, make 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 and use in-situ gel preparation until the fully perhaps even suspendible of medicine dissolution.
2. use the in-situ gel sustained-release preparation by the described temperature sensitive bioadhesive vagina of claim 1, it is characterized in that said preparation at room temperature for liquid, is a semi-solid gel when body temperature, said preparation discharges medicine lentamente with zero order kinetics.
3. use the in-situ gel sustained-release preparation by the described temperature sensitive bioadhesive vagina of claim 1, it is characterized in that the medicine of said preparation constantly disengaged in 12 hours.
4. use the in-situ gel sustained-release preparation by the described temperature sensitive bioadhesive vagina of claim 1, it is characterized in that described preparation also comprises antiseptic, its content is 0.005%～0.2% (w/w).
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| 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 |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1593386A (en) * | 2004-06-30 | 2005-03-16 | 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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| CN1593386A (en) * | 2004-06-30 | 2005-03-16 | 上海复康医药科技发展有限公司 | Temperature sensitive gel formulation for in situ vagina uses |
Non-Patent Citations (4)
| Title |
|---|
| Rūta Masteiková,et al.Stimuli-sensitive hydrogels in controlled and sustained drug delivery.《MEDICINA》.2003,第39卷(第2期),19-24. * |
| 说明书第2页第12-13，18-20行 |
| 说明书第3页实施例3. |
| 邢梦龙.藻类、微生物的多糖研究与医药工业上的应用.《上海医药情报研究》.2000,(第56期),16-18. * |
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