CN100394919C - Medicinal composition for treating vagina disease - Google Patents
Medicinal composition for treating vagina disease Download PDFInfo
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- CN100394919C CN100394919C CNB2006100578676A CN200610057867A CN100394919C CN 100394919 C CN100394919 C CN 100394919C CN B2006100578676 A CNB2006100578676 A CN B2006100578676A CN 200610057867 A CN200610057867 A CN 200610057867A CN 100394919 C CN100394919 C CN 100394919C
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- nifuratel
- nysfungin
- promestriene
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- pharmaceutical composition
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a medicinal composition for treating vagina diseases. The medicinal composition contains promestriene, nifuratel and nysfungin as active ingredients, wherein the daily dosage of the nifuratel is from at least 0.1g to at most 0.5g, is preferably from at least 0.2g to at most 0.4g, and is optimally 0.3g; the daily dosage of the nysfungin is from at least 50 thousand IU to at most 200 thousand IU, is preferably from at least 100 thousand IU to at most 200 thousand IU, and is optimally 150 thousand IU; the daily dosage of the promestriene is from at least 5 mg to at most 10 mg, is preferably from at least 6 mg to at most 8 mg, and is optimally 8 mg. The medicinal composition can optionally contain pharmaceutical acceptable carriers. The medicinal composition of the present invention can be prepared into preparations suitable for vaginal administration, such as suppositories, capsules, tablets, creams, lotions, etc.
Description
Invention field
The present invention relates to a kind of pharmaceutical composition, be specifically related to be used for the treatment of the pharmaceutical composition of vagina, its with nifuratel, nysfungin and promestriene as active component.
Background technology
The gynaecologic vaginal disease is women's commonly encountered diseases and a frequently-occurring disease, and trichomonal vaginitis, bacterial vaginosis and vulvovaginal candidiasis are comparatively typical gynaecologic vaginal diseases, and its sickness rate rises year by year.Clinically can be of a great variety for the medicine that vagina is selected for use, but from therapeutic effect and drug resistance aspect, the relevant preparation of nifuratel is reasonable selection, the preparation of at present domestic relevant nifuratel is mainly the oral tablet of nifuratel, but the side effect of nifuratel oral tablet is bigger, untoward reaction is more, and effect is poor relatively, and bioavailability is low.
Have the compound preparation that contains nifuratel and nysfungin at present, as ordinary suppository, effervescent tablet and soft capsule etc.Nifuratel-nysfungin is by suppressing the pyruvate dehydrogenase system of pathogen, the blocking-up tricarboxylic acid cycle has inhibition or killing action to fungus, antibacterial and protozoon, can promote the growth and breeding of vagina lactobacillus, keep the microecology in vaginas balance, recurrence has important effect for prevention of inflammation.This compound preparation adopts the approach of vagina administration, though the side effect of having avoided oral administration to produce effectively, but still there is a untoward reaction, clinical mainly show as occur that slight pudendum is scorching hot, vaginal dryness and feeling sick, and have still that bioavailability of medicament is low, drug absorption is lower, drug action is of short duration, not steadily, need the characteristics of multiple dosing.
Promestriene promotes the differentiation and the maturation of vagina epithelium mucomembranous cell by the performance estrogen function, has effect synthetic and the secretion glycogen simultaneously, and can promote DoderleinShi bacillus (vagina bacillus acidophilus's) regeneration, and produce lactic acid, stimulate to change intravaginal sour environment.Promestriene is widely used clinically, is mainly emulsifiable paste, soft capsule, suppository, in order to the treatment vulvovaginal disease, as contracting property of flaccidity vaginitis, outer impotence contract, vaginal orifice atrophy etc., also can be used for seborrheic dermatitis.
Still nifuratel, nysfungin and promestriene are not united at present report or the corresponding techniques enlightenment of using the treatment vagina.
Summary of the invention
The inventor finds first: promestriene is except the effect of the anti-inflammatory of bringing into play self, the more important thing is that promestriene improves patient's self immunity, excite the repair function of patient's body self, and this function can reduce the untoward reaction of nifuratel-nysfungin, quicken patient's self rehabilitation simultaneously, show as the transference cure of untoward reaction, therapeutic effect improves, and shorten the course of treatment of rehabilitation.
The inventor is on the basis of nifuratel-nysfungin preparation, and the research through a large amount of adds promestriene in active constituents of medicine, eliminated above-mentioned untoward reaction effectively, makes the drug action of medicine lasting and steady.
Therefore, the purpose of this invention is to provide a kind of pharmaceutical composition that comprises promestriene, nifuratel and nysfungin, be used for the treatment of the gynaecologic vaginal disease, thereby select for doctor and patient provides a kind of better medication.
In one aspect, the invention provides a kind of pharmaceutical composition that is used for the treatment of vagina, it contains promestriene, nifuratel and nysfungin as active component, daily dose≤the 0.5g of 0.1g≤nifuratel wherein, preferably, 0.2g the daily dose≤0.4g of≤nifuratel, most preferably the daily dose of nifuratel is 0.3g; The daily dose of 50,000 IU≤nysfungin≤200,000 IU, preferably, the daily dose of 100,000 IU≤nysfungin≤200,000 IU, the daily dose of most preferred nysfungin are 150,000 IU; The daily dose of 5mg≤promestriene is≤10mg, and preferably the daily dose of 6mg≤promestriene is≤8mg, and most preferably the daily dose of promestriene is 8mg.
Pharmaceutical composition of the present invention is also chosen wantonly and is contained pharmaceutically acceptable carrier.
In a further preferred embodiment, pharmaceutical composition of the present invention also contains the clathrate material of main part.Described clathrate material of main part is cyclodextrin and/or its derivant, is selected from beta-schardinger dextrin-(β-CD), methyl beta-schardinger dextrin-(M-β-CD), hydroxypropyl (HP-β-CD), ethoxy beta-schardinger dextrin-(HE-β-CD), cyclodextrin polymer, ethyl beta-schardinger dextrin-(E-β-CD) and branching cyclodextrin.
Active component, promptly the mixture of promestriene, nifuratel and nysfungin and cyclodextrin and/or its derivant are mixed and made into clathrate according to 3: 1～1: 1, preferred 2: 1 weight ratio.
Pharmaceutical composition of the present invention can be prepared into the dosage form of intravaginal administration, including, but not limited to suppository, capsule, tablet, emulsifiable paste and washing liquid.
The vagina that pharmaceutical composition of the present invention is used for the treatment of is including, but not limited to bacterial vaginitis, trichomonal vaginitis, candidal vulvovaginitis and vagina mixed infection, vagina administration, once a day.
Specific embodiments
Below specify various aspects of the present invention and feature by preferred embodiment.It should be appreciated by those skilled in the art that these embodiment just are used for illustration purpose, and do not limit the scope of the invention.Protection scope of the present invention only is subjected to the restriction of claims.Under the condition that does not deviate from claims scope.Those skilled in the art can carry out various modifications and improvement to various aspects of the present invention, and these modifications and improvement also belong to protection scope of the present invention.For instance; though in the embodiment of the invention pharmaceutical composition of the present invention is made suppository; but those skilled in the art is after reading present specification; to be easy to prepare other forms of pharmaceutical compositions of the present invention such as capsule, tablet, emulsifiable paste, washing liquid, so these dosage forms are positioned within protection scope of the present invention according to description of the invention.
In addition, unless it should be noted that and specialize, below among the embodiment used various materials and reagent all be material and reagent commonly used in this area, can obtain by conventional commercial sources; Method therefor is and well known to a person skilled in the art conventional method.
Embodiment 1-prescription 1
Nifuratel with 30g, the nysfungin of 3g (tiring of 1mg is equivalent to 5000 nysfungin units), 0.8g the promestriene mix homogeneously, then mixture is mixed to mill as inclusion agents with the beta-schardinger dextrin-of 17.9g and make beta-CD inclusion, then clathrate and 163.5g are melted under 60-80 ℃ of water-bath and refrigerative a little semi-synthetic fatty acid ester is milled and mixed, when treating that temperature is reduced to 40 ℃, be poured in the bolt mould that scribbles paraffin oil, scrape off redundance after the cooling, take out molding suppository, packing is promptly made 100 of controlled-releasing vaginal suppositorys, makes every to contain nifuratel 0.3g, nysfungin 150,000 IU and promestriene 8mg.
Embodiment 2-prescription 2
Nifuratel with 50g, the nysfungin of 3g (tiring of 1mg is equivalent to 5000 nysfungin units), 0.8g the promestriene mix homogeneously, then mixture is mixed to mill as inclusion agents with the beta-schardinger dextrin-of 26.9g and make compound beta-CD inclusion, then clathrate and 246g are melted under 60-80 ℃ of water-bath and refrigerative a little semi-synthetic fatty acid ester is milled and mixed, when treating that temperature is reduced to 40 ℃, be poured in the bolt mould that scribbles paraffin oil, scrape off redundance after the cooling, take out molding suppository, packing is promptly made 100 of controlled-releasing vaginal suppositorys, makes every to contain nifuratel 0.5g, nysfungin 150,000 IU and promestriene 8mg.
Embodiment 3-prescription 3
Nifuratel with 30g, the nysfungin of 4g (tiring of 1mg is equivalent to 5000 nysfungin units), the promestriene mix homogeneously of 1g, then mixture is mixed to mill as inclusion agents with the beta-schardinger dextrin-of 17.5g and make compound beta-CD inclusion, then clathrate and 230g are melted under 60-80 ℃ of water-bath and refrigerative a little semi-synthetic fatty acid ester is milled and mixed, when treating that temperature is reduced to 40 ℃, be poured in the bolt mould that scribbles paraffin oil, scrape off redundance after the cooling, take out molding suppository, packing is promptly made 100 of controlled-releasing vaginal suppositorys, makes every to contain nifuratel 0.3g, nysfungin 200,000 IU and promestriene 10mg.
Embodiment 4-prescription 4
Nifuratel with 50g, the nysfungin of 4g (tiring of 1mg is equivalent to 5000 nysfungin units), the promestriene mix homogeneously of 1g, then mixture is mixed to mill as inclusion agents with the beta-schardinger dextrin-of 19g and make compound beta-CD inclusion, then clathrate and 222g are melted under 60-80 ℃ of water-bath and refrigerative a little semi-synthetic fatty acid ester is milled and mixed, when treating that temperature is reduced to 40 ℃, be poured in the bolt mould that scribbles paraffin oil, scrape off redundance after the cooling, take out molding suppository, packing is promptly made 100 of controlled-releasing vaginal suppositorys, makes every to contain nifuratel 0.5g, nysfungin 200,000 IU and promestriene 10mg.
Semi-synthetic fatty acid ester among the above embodiment all can replace with other excipient commonly used in semi-synthetic cocos nucifera oil fat or the pharmaceutical technology.The fat-soluble substrate of the general selection of excipient, its fusion temperature is preferably between 37-40 ℃.
Ultraviolet spectra is identified and the X-diffraction analysis is identified and all shown after medicinal mixture and beta-schardinger dextrin-are milled and formed clathrate; The differential scanning calorimetry has also confirmed the formation of clathrate: under the melting temperature of nifuratel, spike disappears in the clathrate, and this peak of physical mixed still exists.
Embodiment 5: local excitation and anxious poison research
Be subjected to the reagent thing: the preparation method by ordinary suppository is directly made common suppository, contains nifuratel 0.5g, nysfungin 200,000 IU and promestriene 8mg in making every;
The positive control medicine: the preparation method by ordinary suppository is directly made common suppository, only contains nifuratel 0.5g and nysfungin 200,000 IU in making every;
The negative control medicine: press the preparation method of ordinary suppository, preparation does not contain the substrate figuration suppository of medicine;
Adopting rabbit is local excitation and the anxious poison test that laboratory animal is carried out three kinds of suppositorys.
To being subjected to three dosage of examination group design, be respectively high dose group, dosage is equivalent to 20 times of human body consumption; Middle dosage group, dosage is equivalent to 10 times of human body consumption; Low dose group, dosage are equivalent to 3.8 times of human body consumption;
One group of positive controls, dosage are equivalent to 10 times of human body consumption.
Usage: used dosage is every day twice, but total dosage is no more than above-mentioned requirements, and medicine is filled in the animal intravaginal; Observed 7 days.Leading indicator: the activity of animal, feed, defecation, fur, the vagina outward appearance, it is no abnormal etc. to have or not edema, hyperemia, ulceration and secretions to have.
Sacrificed by exsanguination rabbit after the last administration.1. dissect pelvic cavity perusal reproductive system and the surrounding tissue organ has or not abnormal phenomenas such as edema, hyperemia, erosion; 2. dissect ANOMALOUS VARIATIONS such as vagina perusal vaginal walls color, edema, hyperemia, erosion, ulcer; 3. win part animal vagina and carry out pathological section, and observe, take a picture.
Experimental result:
1. general reaction: administration and viewing duration are subjected to examination group and positive controls, negative control group animal activity, feed, defecation, fur etc. all no abnormal, body weight, breathing, heart rate, Non Apparent Abnormality.
2. vagina is dissected perusal: be subjected to examination group, negative control group not to have abnormal phenomenas such as hyperemia, swelling and surrounding tissue adhesion, and positive controls has slight red and swollen phenomenon.
3. vagina pathology structure observation: select the animal subject vagina to do the pathology section at random, carry out histological examination, the result does not have pathology and changes.
Observe to find, contain promestriene be subjected to reagent thing group without any abnormal phenomena; And untoward reaction has appearred in the control drug group that does not contain promestriene; But two groups pathology are all no abnormal.Description of test, the adding of promestriene have the effect that alleviates nifuratel and nysfungin untoward reaction.
Embodiment 6: the long term toxicity research of the local application of compound preparation
Be subjected to the reagent thing: with embodiment 5
Method: according to the design of above-mentioned three dosage groups that are subjected to the examination group, adopt rat to experimentize, make high, medium and low dosage group be equivalent to 40,20,10 times of amounts of human body administration respectively, three dosage are administered once every day, observed 30 days repeated experiments three times continuously.
The result shows that animal whole body and vagina part there is no toxic reaction and local irritation; Pathological change is not seen in section film-making microscopic examination yet, shows that three dosage group medicines all do not have pathogenic effects to each layer of vagina, and long-term prescription is very safe.
Embodiment 7: clinical research
Carry out the clinical trial of 192 examples in Beijing San Jia hospital, wherein matched group is one group, one group of test group, every group of each 96 routine patient, every group is divided trichomonal vaginitis group, bacterial vaginitis group, vulvovaginal candidiasis group again, each 32 example of every group, and the patient satisfies the requirement of clinical research; Before test group each group therapy corresponding with matched group aspect symptom, sign and lab testing equal no difference of science of statistics, during the treatment and treatment back is all with symptom, sign and the lab testing index as judgement.Efficacy determination is as follows:
Cure: symptom complete obiteration, lab testing feminine gender.
Effectively: the symptom complete obiteration, but the lab testing positive or symptom are obviously alleviated the lab testing feminine gender.
Invalid: symptom does not have improvement, the lab testing positive.
Trial drug is according to the compound controlled release suppository of embodiment 1 preparation, comprises promestriene 8mg, nifuratel 300mg and nysfungin 150000IU as effective ingredient.With finger medicine is sent into the vagina deep by the experimenter before sleeping evening, take measures, prevent medicine liquid leakage, once a day, continuous six days is a course of treatment.
Control drug is nifuratel/nysfungin suppository, comprises nifuratel 500mg and nysfungin 200000IU as effective ingredient.With finger medicine is sent into the vagina deep by the experimenter before sleeping evening, take measures, prevent medicine liquid leakage, once a day, continuous six days is a course of treatment.
The clinical efficacy of test group and matched group, total effects are analyzed with Ridit and are compared.Carry out statistical analysis with SAS6.12 software.Trichomonal vaginitis research (test group 32 examples, matched group 32 examples) the results are shown in following table 1.
Table 1
As can be seen from Table 1, totally 32 examples of test group recovery from illness+effectively, total effective rate 100%, totally 29 examples of matched group recovery from illness+effectively, total effective rate is that significant difference (p＜0.05) is arranged between 90.6%, two group;
Bacterial vaginitis research (test group 32 examples, matched group 32 examples) the results are shown in following table 2.
Table 2
As can be seen from Table 2, totally 31 examples of test group recovery from illness+effectively, total effective rate 96.9%, totally 31 examples of matched group recovery from illness+effectively, total effective rate is no difference of science of statistics between 96.6%, two group (p＞0.05); But on cure rate, difference is apparent in view, and test group is significantly better than matched group;
Vulvovaginal candidiasis research (test group 32 examples, matched group 32 examples) the results are shown in following table 3.
Table 3
As can be seen from Table 3, totally 31 examples of test group recovery from illness+effectively, total effective rate 96.9%, totally 29 examples of matched group recovery from illness+effectively, total effective rate is that significant difference (p＜0.05) is arranged between 90.6%, two group; On cure rate, test group is significantly better than matched group, significant difference on the statistics.
Following table 4 is the comparison of test group and matched group untoward reaction.
Table 4
The stronger confirmation in untoward reaction of test group and matched group zooperal result, illustrate that promestriene obviously reduces the side effect that nifuratel produces.
Claims (5)
1. the pharmaceutical composition that is used for the treatment of vagina, wherein active component is nifuratel, nysfungin and promestriene.
2. the described pharmaceutical composition of claim 1, it also contains the clathrate material of main part.
3. the described pharmaceutical composition of claim 2, wherein said clathrate material of main part is cyclodextrin and/or its derivant, is selected from beta-schardinger dextrin-, methyl beta-schardinger dextrin-, hydroxypropyl, ethoxy beta-schardinger dextrin-, cyclodextrin polymer, ethyl beta-schardinger dextrin-and branching cyclodextrin.
4. each described pharmaceutical composition of claim 1-3, it is prepared into the dosage form of intravaginal administration.
5. the described pharmaceutical composition of claim 4, the dosage form of wherein said intravaginal administration is suppository, capsule, tablet, emulsifiable paste or washing liquid.
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| CN102579473B (en) * | 2012-01-17 | 2013-09-04 | 程雪翔 | Nifuratel-nysfungin gel and preparation method thereof |
| CN102813938A (en) * | 2012-09-14 | 2012-12-12 | 扬州大学 | Llex A-cyclodextrin polymer medicine composition for preventing and curing atherosclerosis and preparation method thereof |
| CN104434942A (en) * | 2014-11-19 | 2015-03-25 | 江苏悦兴药业有限公司 | Nifuratel nysfungin vaginal soft capsule and preparation process thereof |
| CN112972418B (en) * | 2021-05-18 | 2021-08-27 | 北京金城泰尔制药有限公司 | Nifuratel nysfungin vaginal soft capsule and preparation method thereof |
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| WO2003043612A1 (en) * | 2001-11-21 | 2003-05-30 | Besins International Belgique | Micronized film-forming powder comprising an active substance |
| WO2004096259A1 (en) * | 2003-04-30 | 2004-11-11 | Debiopharm S.A. | Methods and compositions using gonadotropin hormone releasing hormone |
| WO2005014047A1 (en) * | 2003-08-08 | 2005-02-17 | Mipharm S.P.A. | Bioadhesive gel based on hydroxyethylcellulose |
| CN1600315A (en) * | 2003-09-22 | 2005-03-30 | 陈云芳 | Soft capsule combination of Cloquinate/Promestriene in use for vagina |
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| WO2003043612A1 (en) * | 2001-11-21 | 2003-05-30 | Besins International Belgique | Micronized film-forming powder comprising an active substance |
| WO2004096259A1 (en) * | 2003-04-30 | 2004-11-11 | Debiopharm S.A. | Methods and compositions using gonadotropin hormone releasing hormone |
| WO2005014047A1 (en) * | 2003-08-08 | 2005-02-17 | Mipharm S.P.A. | Bioadhesive gel based on hydroxyethylcellulose |
| CN1600315A (en) * | 2003-09-22 | 2005-03-30 | 陈云芳 | Soft capsule combination of Cloquinate/Promestriene in use for vagina |
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