A kind of pharmaceutical composition for treating senile vahinitis and temperature sensitive slow-releasing gel used and systemPreparation MethodTechnical field
The present invention relates to senile vahinitis field of medicine preparing technology more particularly to a kind of senile vahinitis for the treatment ofPharmaceutical composition and its temperature sensitive slow-releasing gel used and preparation method.
Background technology
Senile vahinitis (Senile Vaginitis, SV) is mainly in postclimacteric elderly woman, because ovarian function declinesIt moves back, estrogen level reduces, and vagina mucosa loses estrogen and supports to protect and vaginal wall atrophy occur, and mucous membrane is thinning, and epithelium is thinPhenomena such as intracellular glycogen content is reduced, and intravaginal pH value rises to 5.0~7.0 by normal 3.8~4.4 causes vagina localResistance reduces, and pathogenic bacteria invasion breeding causes inflammation.A small number of women are since chemicotherapy leads to hypo-ovaria, or due to ovumAfter nest resection estrogen reduce or hyposecretion and cause senile vahinitis.In addition, estrogen level reduces, the moon can be causedRoad biological community structure and function are difficult to the pathologic reversed variation, lead to vaginal dysbacteriosis, to be distributed in vaginaThe condition of invasion and breeding is provided with the pathogenic bacteria in the external world, and then causes the inflammation of vagina part.
Senile vahinitis cardinal symptom increases for vaginal fluid and pruritus vulvue, burning heat sensation.Inspection is shown in vagina in oldYear sexually revises, epithelial atrophy, and pleat disappears, and smooth muscle layer is thinning, and vagina contraction power reduces etc..Vaginal mucosa hyperemia is shown as,Mucous membrane petechial hemorrhage or sheet bleeding, are shown in superficial ulcer sometimes.Clinic is usually to supplement to the principle of reatment of senile vahinitisEstrogen enhances vagina resistance, inhibits bacterial growth.
The drug for the treatment of senile vahinitis is disclosed in currently available technology can be prepared into thermo-sensitive gel dosage form.It utilizesHigh molecular material after gelling agent is made with certain drug in it, can be such that drug is administered in liquid form the sensibility of temperature, andIt is adhered to therapentic part, when therapentic part temperature is constant (30~35 DEG C), medicament gelling agent forms the gel of semi-solid state.This technology can make drug be uniformly dispersed in therapentic part, increase medicament contact area, and not easily to fall off or outflow, reach increasingThe purpose of strong curative effect.But the gelling agent there are administration number of times frequent, the poor situation of patient's compliance.
Invention content
The purpose of the present invention is to provide a kind of pharmaceutical composition for treating senile vahinitis and its temperature sensitive sustained-release gelsAgent and preparation method, this it is temperature sensitive it is slow-releasing gel used make senile vaginitis patients reduce times for spraying, increase its compliance.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
It is described the present invention provides a kind of pharmaceutical composition for treating senile vahinitis, including active component and auxiliary materialActive component includes the raw material of following parts by weight：
5~20 parts of nitroimidazoles medicine, 1~5 part of quinolone drugs, 0.01~0.08 part of estrogen drugs, sugar5~20 parts of 0.05~0.2 part of corticoid drug and glucose.
Preferably, the auxiliary material includes the raw material of following parts by weight：1~50 part of matrix, 0.1~10 part of moisturizer, anti-corrosionThe pH value of 4~88 parts of 0.01~0.5 part of agent and pH buffer solutions, described pharmaceutical composition is 3.5~4.8.
Preferably, the nitroimidazoles medicine is one or more of metronidazole, Tinidazole and Ornidazole；The quinolinePromise ketone drug is one or more of Ofloxacin, lavo-ofloxacin, Ciprofloxacin and pefloxacin；The estrogensDrug is one or more of diethylstilbestrol, estradiol, estriol and ethinyloestradiol；The glucocorticoid medicine is that ground is filled inOne or more of meter Song, hydrocortisone and prednisone.
Preferably, the matrix includes chitosan, carbomer, poloxamer, sodium carboxymethylcellulose, polycarbophil and seaOne or more of mosanom.
Preferably, the moisturizer is glycerine and/or propylene glycol；The preservative is methyl hydroxybenzoate, ethyl hydroxy benzoate, oxybenzeneOne or more of propyl ester, benzalkonium bromide and benzoic acid.
Preferably, the pH buffer solutions are Acetate-acetate buffer solution.
Preferably, the dosage form of described pharmaceutical composition be ointment, capsule, gelling agent, powder, effervescent tablet, suppository orSolution.
The present invention provides the pharmaceutical compositions of the treatment senile vahinitis described in said program to prepare treatment old ageApplication in the drug of property vaginitis.
The temperature sensitive slow-releasing gel used of senile vahinitis drug is treated the present invention provides a kind of, includes following per 1000mLRaw material：50~200g of nitroimidazoles medicine, 10~50g of quinolone drugs, 0.1~0.8g of estrogen drugs, sugared cortex0.5~2g of hormone medicine, 50~200g of glucose, 100~300g of PLURONICS F87,100~400g of poloxamer188,The pH of 30~60g of sodium carboxymethylcellulose, 5~15g of moisturizer, 1.5~2.5g of preservative, 500~900mL of purified water and surplusBuffer solution, pH value are 3.5~4.8.
The present invention provides the temperature sensitive slow-releasing gel used preparations of the treatment senile vahinitis drug described in said programMethod includes the following steps：
1) it takes sodium carboxymethylcellulose to mix swelling with purified water, obtains component A；
2) the component A obtained in PLURONICS F87, poloxamer188 and step 1) is stirred, obtains component B；
3) by nitroimidazoles medicine, quinolone drugs, estrogen drugs, glucocorticoid medicine, glucose,After the component B obtained in moisturizer, preservative and step 2) is stirred, pH buffer solutions are added, obtain temperature sensitive sustained-release gelAgent.
In step 2) 0~4 DEG C is stood alone as with the temperature being stirred described in step 3).
Beneficial effects of the present invention
The method of the present invention can pointedly solve the various symptoms of senile vahinitis, from improve estrogen level,Eliminate pathogenic flora, reduce vagina pH, adjust vaginal flora etc. treatment is various caused by being reduced due to estrogen levelSenile vahinitis.It is of the present invention treatment senile vahinitis drug it is temperature sensitive it is slow-releasing gel used have disperse in vaginal canalThe characteristics of uniformly and being sustained, and the contact area of drug and tissue is made to increase, bioavilability is improved, reaches enhancing and treatsThe purpose of effect realizes good therapeutic effect to improve treated effect.And said preparation, which also has, to be not easy to flow out chamberRoad, not pollution clothes, times for spraying is less, easy to use, the preferable advantage of patient's compliance.
Specific implementation mode
It is described the present invention provides a kind of pharmaceutical composition for treating senile vahinitis, including active component and auxiliary materialActive component includes the raw material of following parts by weight：5~20 parts of nitroimidazoles medicine, 1~5 part of quinolone drugs, estrogen5~20 parts of 0.01~0.08 part of class drug, 0.05~0.2 part of glucocorticoid medicine and glucose；Preferably, the activityComponent includes the raw material of following parts by weight：9~16 parts of nitroimidazoles medicine, 2~4 parts of quinolone drugs, Alora9~16 parts of 0.03~0.06 part of object, 0.1~0.15 part of glucocorticoid medicine and glucose；It is furthermore preferred that the activearmIt point include the raw material of following parts by weight：11~14 parts of nitroimidazoles medicine, 3 parts of quinolone drugs, estrogen drugs11~14 parts of 0.04~0.05 part, 0.12~0.14 part of glucocorticoid medicine and glucose.
In the present invention, the nitroimidazoles medicine is one or more of metronidazole, Tinidazole and Ornidazole, excellentIt is selected as metronidazole.Metronidazole is the representative drug in nitroimidazoles medicine, main in addition to for anti-trichomonal and anti-AmoebaBe used for system or local infection caused by treating or preventing anaerobic bacteria, as alimentary canal, female reproductive system, skin and soft tissue,The anaerobic infection at the positions such as bone and joint.There is preferable antibacterial action to following anaerobic bacteria:1. Bacteroides, including it is fragile quasi-Bacillus；2. fusobacterium；3. Clostridium, including clostridium tetani；4. part Eubacterium；5. peptococcus and disappearingChange streptococcus etc..
In the present invention, the quinolone drugs is in Ofloxacin, lavo-ofloxacin, Ciprofloxacin and pefloxacinOne or more, preferably Ofloxacin.Ofloxacin belongs to quinolone drugs, with the DNA of bacterium(DNA) it is target spot, inhibits DNA gyrases, further result in the irreversible lesion of DNA of bacteria, reach antibacterial effect.Common drugThere are Ofloxacin, Norfloxacin, lavo-ofloxacin, Ciprofloxacin etc..There is bactericidal effect to a variety of gram-negative bacterias, is widely used inDisease of the genitourinary system, gastrointestinal disease and respiratory tract, skin histology gram-negative bacterial infection treatment.
In the present invention, the estrogen drugs be diethylstilbestrol, estradiol, estriol and ethinyloestradiol in one kind orIt is several, preferably diethylstilbestrol.Diethylstilbestrol is artificial synthesized nonsteroidal estrogen substance, can be generated and natural estradiolIdentical all pharmacology and therapeutic effect.It is mainly used for various diseases caused by estrogen is low or deficiency disease and hormonal balance disorderDisease.
In the present invention, the glucocorticoid medicine is one kind in dexamethasone, hydrocortisone and prednisoneOr several, preferably dexamethasone.Dexamethasone is glucocorticosteroid hormone, and derivative has hydrocortisone, prednisone etc., mainIt is anti-inflammatory to act on, the reaction for mitigating and preventing tissue to inflammation, the performance to reduce inflammation, and eliminates oedema, reduces exudation.
In the present invention, glucose can cause local penetration pressure difference, improve the dry and astringent environment of intravaginal, moisten vagina, moltenLiquid pH can improve intravaginal acid-base value between 3.2~6.5, be conducive to vagina beneficial bacterium and breed, while also having trophism.
Auxiliary material described in the pharmaceutical composition for the treatment of senile vahinitis of the present invention includes the raw material of following parts by weight：4~88 parts of 1~50 part of matrix, 0.1~10 part of moisturizer, 0.01~0.5 part of preservative and pH buffer solutions, described pharmaceutical compositionPH value be 3.5~4.8；Preferably, the auxiliary material includes the raw material of following parts by weight：5~30 parts of matrix；Moisturizer 2~8The pH value of 10~70 parts of part, 0.1~0.4 part of preservative and pH buffer solutions, described pharmaceutical composition is 3.8~4.5；More preferably, the auxiliary material includes the raw material of following parts by weight：9~20 parts of matrix；4~6 parts of moisturizer, 0.2~0.3 part of preservative and pHThe pH value of 20~50 parts of buffer solution, described pharmaceutical composition is 4.2.
In the present invention, the matrix includes chitosan, carbomer, poloxamer, sodium carboxymethylcellulose, polycarbophilOne or more of with sodium alginate, preferably poloxamer.Matrix refers to institute of the material system in addition to analyteIt is the excipient and carrier of drug to have ingredient, matrix, and the quality and therapeutic effect of drug are had a major impact.Wherein carboxymethylCertain slow releasing function is all had after sodium cellulosate and poloxamer swelling, is common slow-release material in pharmacy.ThisOutside, it can control gelling agent phase transition temperature after the mixing of different model poloxamer.
In the present invention, the moisturizer is glycerine and/or propylene glycol, preferably glycerine.Glycerine is common moisturizer,It can play the role of moisturizing, lubrication.
In the present invention, the preservative is in methyl hydroxybenzoate, ethyl hydroxy benzoate, Nipasol, benzalkonium bromide and benzoic acidOne or more, preferably methyl hydroxybenzoate and Nipasol.Preservative can effectively inhibit the breeding of microorganism in drug.
In the present invention, the pH buffer solutions are Acetate-acetate buffer solution, are that pharmacy often uses buffer solution；The vinegarSteps are as follows for the preparation method of sour sodium-acetate buffer solution：Anhydrous sodium acetate is taken to be dissolved in a small amount of purified water, mixed with glacial acetic acidAfter conjunction, adds purified water to be diluted to 1L and obtain Acetate-acetate buffer solution；The concentration of the anhydrous sodium acetate is preferably 83g/L；InstituteThe concentration for stating glacial acetic acid is preferably 60mL/L；The pH of the Acetate-acetate buffer solution ranging from 3.2~6.0.
The pH of pharmaceutical composition can also be adjusted using pH adjusting agent in the specific implementation process of the present invention, it is excellentThe pH adjusting agent of choosing is one or more of in sodium hydroxide, hydrochloric acid, boric acid, citric acid, tartaric acid and sodium acetate.
In the present invention, the dosage form of the pharmaceutical composition of the treatment senile vahinitis is ointment, capsule, gelAgent, powder, effervescent tablet, suppository or solution.
The present invention provides the pharmaceutical compositions of the treatment senile vahinitis described in said program to prepare treatment old ageApplication in the drug of property vaginitis.
The temperature sensitive slow-releasing gel used of senile vahinitis drug is treated the present invention provides a kind of, includes following per 1000mLRaw material：50~200g of nitroimidazoles medicine, 10~50g of quinolone drugs, 0.1~0.8g of estrogen drugs, sugared cortex0.5~2g of hormone medicine, 50~200g of glucose, 100~300g of PLURONICS F87,100~400g of poloxamer188,The pH of 30~60g of sodium carboxymethylcellulose, 5~15g of moisturizer, 1.5~2.5g of preservative, 500~900mL of purified water and surplusBuffer solution, pH value are 3.5~4.8；Preferably, in terms of 1000mL, including following raw material：90~150g of nitroimidazoles medicine,20~40g of quinolone drugs, 0.2~0.6g of estrogen drugs, 1~1.5g of glucocorticoid medicine, glucose 90~150g, 150~250g of PLURONICS F87,200~300g of poloxamer188,40~50g of sodium carboxymethylcellulose, moisturizerThe pH buffer solutions of 8~12g, 1.8~2.2g of preservative, 600~800mL of purified water and surplus, pH value are 3.8~4.5；More preferably, in terms of 1000mL, including following raw material：Nitroimidazoles medicine 100g, quinolone drugs 30g, estrogen drugs0.5g, glucocorticoid medicine 1.2g, glucose 100g, PLURONICS F87 200g, poloxamer188 250g, carboxymethyl are fineThe pH buffer solutions of the plain sodium 45g of dimension, moisturizer 10g, preservative 2g, purified water 700mL and surplus, pH value 4.2.In the present inventionIn, the purified water is preferably deionized purified water.
The present invention provides the temperature sensitive slow-releasing gel used preparations of the treatment senile vahinitis drug described in said programMethod takes sodium carboxymethylcellulose to mix swelling with purified water in the present invention, stands, obtains component A；The present invention is to swellingTemperature and time be not particularly limited, sodium carboxymethylcellulose of being subject to is sufficiently humidified so as to and evenly dispersed in purified water.
In the present invention, the component A obtained in PLURONICS F87, poloxamer188 and above-mentioned steps is stirred,Obtain component B；The temperature being stirred is 0~4 DEG C, preferably 1~3 DEG C.The present invention does not have the time being stirredSpecifically limited, component of being subject to is uniformly mixed；The present invention is not particularly limited to stating the stir speed (S.S.) being stirred, mixed with componentIt closes uniformly and does not generate subject to a large amount of bubbles.
In the present invention, by nitroimidazoles medicine, quinolone drugs, estrogen drugs, glucocorticoids medicineAfter the component B obtained in object, glucose, moisturizer, preservative and above-mentioned steps is stirred, pH buffer solutions are added, are adjustedEmbedding after pH obtains temperature sensitive slow-releasing gel used；The temperature being stirred is 0~4 DEG C, preferably 1~3 DEG C.The present invention coupleThe time being stirred is not particularly limited, and component of being subject to is uniformly mixed；The present invention does not have to stating the stir speed (S.S.) being stirredHave it is specifically limited, component of being subject to be uniformly mixed and do not generate a large amount of bubbles.In the present invention, the mode of the embedding is conventional medicineAgent embedding mode；The temperature sensitive slow-releasing gel used specification is preferably 10g/10mL.
The temperature sensitive slow-releasing gel used storage temperature for the treatment of senile vahinitis drug of the present invention is preferably 0~4 DEG C.
With reference to embodiment to it is provided by the invention it is a kind of treat the temperature sensitive slow-releasing gel used of senile vahinitis and systemPreparation Method is described in detail, but they cannot be interpreted as limiting the scope of the present invention.
Embodiment 1 is temperature sensitive slow-releasing gel used to be made of following drug：
Steps are as follows for the temperature sensitive slow-releasing gel used preparation method：Sodium carboxymethylcellulose is dispersed in appropriate purifying firstIt in water, stands, after it is fully swollen, in the case where 0~4 DEG C is stirred continuously, it is added in PLURONICS F87 and poloxamer188In；Then recipe quantity drug, moisturizer, preservative are sequentially added, is stirred continuously, is uniformly mixed, adjust pH to 3.5~4.8Afterwards, embedding, 0~4 DEG C of preservation.
Embodiment 2 is temperature sensitive slow-releasing gel used to be made of following drug：
The preparation method is the same as that of Example 1.
Embodiment 3 is temperature sensitive slow-releasing gel used to be made of following drug：
The preparation method is the same as that of Example 1.
Embodiment 4 is temperature sensitive slow-releasing gel used to be made of following drug：
The preparation method is the same as that of Example 1.
Embodiment 5 is temperature sensitive slow-releasing gel used to be made of following drug：
The preparation method is the same as that of Example 1.
Embodiment 6 is temperature sensitive slow-releasing gel used to be made of following drug：
The preparation method is the same as that of Example 1.
7 clinical test of embodiment：
The present invention has certain curative effect for senile vahinitis, and to observe the Clinical efficacy of this preparation, the present invention providesTo making a definite diagnosis the clinical test results of senile vaginitis patients treatment.
1) general information：50~65 years old out-patients 100.
2) clinical symptoms：Cardinal symptom increases for vaginal fluid and pruritus vulvue, burning heat sensation.Inspection is shown in vagina in old ageIt sexually revises, epithelial atrophy, pleat disappears, and smooth muscle layer is thinning, and vagina contraction power reduces etc..Vaginal mucosa hyperemia is shown as, is stickedFilm petechial hemorrhage or sheet bleeding, are shown in superficial ulcer sometimes.
3) dosage regimen：
Treatment group：Vagina gives the preparation of the embodiment of the present invention 6,10g/ times, 1 time every night, 7 days as one therapeutic course；
Control group：Vagina gives metronidazole,clotrimazole and chlorhexidine acetate suppositories, one time 1 piece, 1 time every night, 7 days as one therapeutic course.
4) treatment results：
Temperature sensitive sustained-release gel in 1 present invention of table treats senile vahinitis test result with metronidazole,clotrimazole and chlorhexidine acetate suppositories
By the experimental result of table 1 it is found that the present invention's is temperature sensitive slow-releasing gel used compared with metronidazole,clotrimazole and chlorhexidine acetate suppositories, therapeutic effect is moreIt is good, total effective rate higher, it is seen then that of the invention temperature sensitive slow-releasing gel used to realize good control for treating senile vahinitisTherapeutic effect.
As seen from the above embodiment, the present invention provides a kind of temperature sensitive sustained-release gels for treating senile vahinitis drugAgent, not only convenient drug administration, number are few for treating senile vahinitis for the gelling agent, and compared with the prior art in polybenzobisoxazoleSafe bolt therapeutic effect is more preferable, efficient higher, it is seen then that treatment senile vahinitis drug of the invention it is temperature sensitive slow-releasing gel usedWith good therapeutic effect.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the artFor member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answeredIt is considered as protection scope of the present invention.