CN103127490B - Medicinal composition for treating vulvovaginal candidiasis - Google Patents
Medicinal composition for treating vulvovaginal candidiasis Download PDFInfo
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- CN103127490B CN103127490B CN201310080636.7A CN201310080636A CN103127490B CN 103127490 B CN103127490 B CN 103127490B CN 201310080636 A CN201310080636 A CN 201310080636A CN 103127490 B CN103127490 B CN 103127490B
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- Prior art keywords
- peptide
- laipu
- pharmaceutically acceptable
- vulvovaginal candidiasis
- candida albicans
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- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 title claims abstract description 31
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- 238000011282 treatment Methods 0.000 claims description 20
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention discloses a medicinal composition for treating vulvovaginal candidiasis. The composition comprises 0.02 to 0.5 weight percent of Silaipufa peptide or pharmaceutically acceptable salt or ester, and pharmaceutically acceptable excipient and/or carrier. The invention also provides application of the Silaipufa peptide or pharmaceutically acceptable salt or ester in preparation of a medicament for treating the vulvovaginal candidiasis. The Silaipufa peptide can effectively inhibit the activity of candida albicans in vivo and in vitro, is used for local delivery of vulva, can effectively treat the vulvovaginal candidiasis, does not have side effect, and has a broad application prospect.
Description
Technical field
The present invention relates to pharmaceutical art, particularly a kind of pharmaceutical composition for the treatment of vulvovaginal candidiasis.
Background technology
Vulvovaginal candidiasis (Vulvovaginal candidiasis, VVC) is pudendum, the colpitis that candidiasis infringement pudendum and/or vaginal mucosa cell cause.It is the common vaginal inflammation being only second to bacterial vaginitis, be called colpitis mycotica, monilial vaginitis etc. in the past, its cause of disease is the yeast in fungus, wherein based on Candida albicans (Candida albicans), account for 80% ~ 90%, non-white candidiasis such as Candida glabrata (C.torulopsisglabrata), Oidium tropicale (C.tropicalis), Candida parapsilosis (C.parapsilosis) etc. occupy the minority.The symptom that this disease shows is relatively serious, and sickness rate is high and very easily recur after treatment.According to statistics, have the women of 75% they in life to I haven't seen you for ages infect a VVC, have the women of 40% ~ 50% even can infect twice or more, the women of about 5% is diagnosed as recurrent or chronic VVC.Annual doctor can run into 5,000,000 ~ 10,000,000 this type of patient.The probability that some factor can make women suffer from VVC increases, as pregnancy period, diabetes and the antimicrobial drug using some common and contraceptive.The VVC patient made a definite diagnosis first carries out Canonical management, has extremely important effect to its recurrence of minimizing, but still lack efficiently at present, the medicine of low toxicity and method.
The VVC patient of 80% ~ 90% uses imidazoles to treat, it can relief of symptoms prevent the concurrent of inflammation, but about there is the patient of 7% with side effect such as pruritus of vagina, calcination and stimulations, most genus local anaphylaxis, these side effect can cause redness, hypertrophy, rubella and external genital laceration, and the systematic influence having some rare, comprise frequent micturition, cramp, dysmenorrhea, paraesthesia, headache, heating and fear of cold; Oral Treatment With Ketoconazole VVC, brings potential system toxicity to patient.The triazole type medicine such as fluconazol, itraconazole is the oidiomycotic common drug of clinical treatment.But the life-time service of this type of medicine causes persister extensively to occur.41 national multicenter study find, Candida albicans has risen to 1.4% in 2007 from 0.9% in 2000 to the persister of fluconazol.Wroblewska etc. from being separated 851 strain Candida albicans clinically, wherein 37.2% pair of fluconazole resistant, 47.6% pair of itraconazole drug resistance.Candida albicans has become clinical stubborn problem to the drug resistance of azole drug.
Triazole antifungal agent may kill organism, but it is bad for some Candida albicans and non-white candida infection treatment effect, clinical failed probability is larger, medicine as fluconazol, for treatment and effectively suppress Candida albicans and Candida albicans microbial colpitis effect not too obvious.Therefore, seek a kind of antibacterial new drug for drug resistance Candida albicans strain, for the treatment of VVC, there is important clinical meaning.
Summary of the invention
The technical problem to be solved in the present invention is for providing a kind of pharmaceutical composition for the treatment of vulvovaginal candidiasis.
Particularly, the pharmaceutical composition for the treatment of vulvovaginal candidiasis provided by the present invention, comprises compound shown in formula I or its pharmaceutically acceptable salt or ester, and pharmaceutically acceptable excipient and/or carrier; Described formula I or its pharmaceutically acceptable salt or the weight percentage of ester in pharmaceutical composition are 0.02% ~ 0.5%;
Formula I.
Shown in above-mentioned formula I, compound cuts down peptide also known as Si Laipu, and its chemical name is: (acetyl-cysteine-11-13 ALPHA-MSH-amino)
2, being two dimers having bioactive short peptide chain and be linked to be by disulfide bond, is a kind of antibacterial pair of peptide.
Preferably, described formula I or its pharmaceutically acceptable salt or the weight percentage of ester in pharmaceutical composition are 0.05% ~ 0.1%.
Preferably, be 1 ~ 5mg containing the amount of compound shown in formula I or its pharmaceutically acceptable salt or ester in each preparation unit of described pharmaceutical composition.
Present invention also offers a kind of suppository of aforementioned pharmaceutical compositions, the preparation of 100 weight portions comprises the ethyl hydroxybenzoate of the formula I of 0.05 weight portion, the gelatin of 15 weight portions, the glycerol of 60 weight portions, the PEG400 of 12.5 weight portions and 0.05 weight portion, and the pH value of described preparation is 4.3 ± 0.1.
Present invention also offers compound shown in formula I or its pharmaceutically acceptable salt or ester for the preparation of the application in treatment vulvovaginal candidiasis medicine.Inventor demonstrates the therapeutical effect of compound shown in formula I for vulvovaginal candidiasis by extracorporeal bacteria inhibitor test, rat candida albicans vaginitis model test and random contrast clinical trial, result shows: formula I obviously can reduce the ability that Candida albicans forms bacterium colony, can effectively suppress Candida albicans to grow in vitro; Formula I has significant antibacterial action for rat candida albicans vaginitis, and has good Tissue-protective effect; Random contrast clinical trial result shows, and the vaginal suppository of contained I can effective Killing Candida Albicans, the clinical symptoms of alleviation vulvovaginal candidiasis and having no side effect.
In above-mentioned application, described medicine is using topical preparations.
Particularly, described medicine is suppository, gel, ointment, tablet, capsule or spray.
The present invention finds, formula I all effectively can suppress the activity of Candida albicans in vivo and in vitro, for vulvovaginal topical, effectively can treat the disease of vulvovaginal candidiasis, have no side effect, have good potential applicability in clinical practice.
Detailed description of the invention
The invention discloses a kind of pharmaceutical composition, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Application of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
In order to make those skilled in the art understand technical scheme of the present invention better, below in conjunction with specific embodiment, the present invention is described in further detail.
The suppository preparation of embodiment 1 pharmaceutical composition of the present invention
The vaginal suppository prescription of (1) 100 piece of pharmaceutical composition of the present invention:
| Composition | Consumption |
| Si Laipu cuts down peptide | 0.20g |
| Gelatin | 60g |
| Glycerol | 240g |
| PEG400 | 50g |
| Ethyl hydroxybenzoate | 0.20g |
| NaOH | Adjust pH to 4.3 ± 0.1 |
| Purified water | About 50ml, adds to 400g |
(2) preparation process
Get recipe quantity gelatin to add appropriate purified water infiltration is expanded, add glycerol, PEG400 and ethyl hydroxybenzoate, stir; The Si Laipu getting recipe quantity cuts down peptide, adds appropriate purified water and dissolves and be mixed with Si Laipu and cut down peptide solution, this solution is added aforementioned substrate, fully stirs mixing in 5 minutes; Drip 1mol/LNaOH solution, limit edged stirs, and regulates pH to 4.3 ± 0.1.Supply purified water to recipe quantity, stir at least 5 minutes.Mixing is placed in calorstat, and 70 DEG C of constant temperature deaerations 2 hours, are poured into after taking-up and scribble in the vaginal suppository mould of liquid Paraffin in advance, and after to be solidified, the demoulding, packaging, to obtain final product.Prepare 100 pieces of Si Laipu altogether and cut down peptide vaginal suppository, every piece heavy 4g, every piece is cut down peptide 2mg containing Si Laipu.
Embodiment 2 takes charge of the general extracorporeal bacteria inhibitor test cutting down peptide
(1) test objective
The Si Laipu investigating variable concentrations cuts down the suppression degree of peptide to albicans growth.
(2) test method
Cultivate 24 hours in picking bacterial strain to 100ml fungi culture medium; Pipette 0.5ml bacterium liquid in fluid medium, add four kinds of concentration (10 respectively
-8, 10
-7, 10
-6, 10
-5mol/L, be equivalent to 0.01,0.1,1.0,10.0mg/ml) Si Laipu cut down peptide solution 1.0ml, another increment product add bacterium liquid culture medium as blank; Cultivate 2 hours, cultivation temperature is 28 DEG C.By the concentration that the bacterium liquid of cultivation after 2 hours is extremely suitable for 0.9% normal saline dilution; Getting diluent 1.0ml is coated on agar plate, observes clump count, calculates bacteriostasis rate.
(3) result of the test
As shown in table 1.
Table 1, variable concentrations Si Laipu cut down the In Vitro Bacteriostasis rate of peptide
| Si Laipu cuts down peptide concentration | 10 -5mol/L | 10 -6mol/L | 10 -7mol/L | 10 -8mol/L |
| Bacteriostasis rate | 89.6% | 78.5% | 56.8% | 20.0% |
Table 1 result shows, Si Laipu cuts down Toplink obviously to be reduced Candida albicans and form the ability of bacterium colony, can effectively suppress Candida albicans to grow in vitro, and cuts down increasing of peptide concentration along with Si Laipu, and its bacteriostasis strengthens.
Embodiment 3 takes charge of the general pharmacodynamics test cutting down peptide treatment rat candida albicans vaginitis
(1) test objective
Division of Research carrys out the general peptide that cuts down to the colpitic therapeutical effect of rats complicated Candida albicans.
(2) test method
A, rat candida albicans vaginitis model building:
I. modeling rats with bilateral oophorectomize: it is some to get the non-copulation of body weight 80 ~ 100g sexual maturity female Sexual health Wistar rat, and 7% chloral hydrate intraperitoneal anesthesia (0.5ml/100g), extracts bilateral ovaries under aseptic condition.Postoperative muscle injection penicillin 100,000 U/ only, once a day, for three days on end, infect by control.
Ii. manufacture false rutting period, cause immunologic hypofunction: within postoperative 7th day, start gavage and give estradiol valerate, every day 800 μ g/100g, continuous 4 days.
Iii. course of infection: read bacterial cell (clinical separation vaginosis bacterial strain SA-40) MH broth bouillon in vain with the jolting of 200rpm speed, cultivate 5 hours for 30 DEG C.Growing number UV spectrophotometer measuring.Before to animal inoculation, with normal saline dilution to 4 × 10
7individual/100 μ l, 50 μ l/ only inoculate.Modeling rat gets position upside down, and bacterium liquid is injected intravaginal, and original position stops 1 ~ 2min, prevents bacterium hydrorrhea from going out.After infecting, the next day of modeling animal, gavage gives estradiol valerate (1200 μ g/100g) once, to keep false rutting period and general immunity hypofunction state, increases Candida albicans in intravaginal susceptibility.
Infect (Post operation the 15th day) after 4 days, visible modeling rat pudendum redness (not necessarily), accompany a small amount of white secretions, dip secretions with aseptic cotton carrier, be applied to sabouraud culture medium surface, cultivate 24 hours for 30 DEG C, the white colony that perusal is differed in size as seen, the visible pseudohypha of secretions microscopy and in groups spore, rat of getting all is positive, modeling success.
B, drug treatment:
12 candida albicans vaginitis rats are divided into three groups: positive control (miconazole ointment; There is provided unit: first sign pharmacy; Specification: 15mg/20g/ manages) group 4, Si Laipu cuts down peptide gel (by the self-control of this area conventional method, the weight percentage that Si Laipu cuts down peptide is 0.1%) group 4, normal saline group 4.Positive control medicine is identical with the amount of substance of Experimental agents, and the dosage of positive drug is the dosage that 25 μ g/100g, Si Laipu cut down peptide is 50 μ g/100g, and only, morning every day, afternoon are respectively administered once normal saline 50 μ l/.The next day that period continuing, gavage gives estradiol valerate (1200 μ g/100g) once, the next day get vaginal secretion coated plate cultivate, totally three times, later stage, got every three days vaginal secretion coated plate cultivate, twice totally.
C, pathology detect:
Pathogenic examination: get rat vagina secretions and check.
Histopathologic examination: take vagina tissue to put neutral formalin after sacrifice of animal immediately, carry out organization embedding, section, dyeing.
(3) result of the test
A, rat vagina liquid mycotic culture result: three components is not before administration, within after administration 2 days, 4 days, 8 days, 12 days, get vaginal secretion, inject 100 μ l normal saline lavations, often pipe irrigating solution gets 5 μ l, by normal saline dilution to 100 μ l inoculated and cultured, vaginal secretion cultivates data and photo display, and after saline therapy, clump count does not significantly reduce; Compare with normal saline group, cut down after peptide treats 12 days through daktarin and Si Laipu, Candida albicans clump count all significantly reduces, and wherein Si Laipu cuts down peptide group curative effect and is better than daktarin group; Show: Si Laipu cuts down the effect that peptide has more significant anti-candida albicans, and antibacterial action is better than daktarin.
B, rat examination of vulva: the vulvar sample that often group gets two animals carries out visual examination, and result shows: red and swollen, due to intestine erosion and ulcer phenomenon appears in daktarin group, and Si Laipu cuts down peptide group and normal saline group xerosis vulae, does not occur red and swollen grade for abnormal phenomena; Show: Si Laipu cuts down peptide does not have apparent side effect.
C, section statining result: after connecing bacterium last day, get rat vagina tissue and immerse in neutral formalin, carries out cutting into slices and HE, PAS dyeing after 24 hours.HE coloration result shows: the immuning cell number that equimolar amounts Si Laipu cuts down peptide group is obviously less than daktarin group, and prompting Si Laipu cuts down peptide has good antiinflammatory action to vaginitis, and is better than positive control drug daktarin.PAS coloration result shows: Si Laipu cuts down peptide group and daktarin group is showed no obvious mycelia, has no tissue injury's phenomenons such as obvious vaginal mucosa or epithelium ulcer, shows that Si Laipu cuts down peptide and daktarin all has good Tissue-protective effect to vaginitis.
To sum up result, Si Laipu cuts down peptide and has significant antibacterial and anti-inflammation functions for rat candida albicans vaginitis, and its effect is better than existing medicine daktarin, and has no apparent side effect.
Embodiment 4 takes charge of the general random contrast clinical trial cutting down peptide treatment vulvovaginal candidiasis
(1) test objective
By random contrast clinical trial, compare Si Laipu and cut down the vagina local application of peptide vaginal suppository (being prepared by embodiment 1) and miconazole suppository to the therapeutic effect of vulvovaginal candidiasis (VVC).
(2) testing program
MethodsThe cases enrolled 33 example, have VVC symptom, comprise the clinical manifestations such as pruritus, burn feeling or secretions, the secretions obtained above fornix vagina with cotton swab carries out microscopy has pseudohypha to exist.33 routine patients are divided into two groups at random: test group 23 people, use the Si Laipu prepared by embodiment 1 to cut down peptide vaginal suppository; Matched group 10 people, uses the miconazole suppository that specification is 200mg.Before sleeping every day once, continuous use one week.The prohibitive life of treatments period, must not use other intravaginal drug process, comprise vaginal contraception device, vaginadouche.The final stage for the treatment of, namely the 7th day, patient got back to clinic and continues to accept observation, vaginal secretions cultivation and CBC(complete blood count) and hepatic and renal function detection.The side effect that inquiry patient is relevant with medicine.
(3) result of the test
Si Laipu cuts down in 23 patients of peptide vaginal suppository treatment, 13 patient pseudohyphas are for negative and symptom is controlled (accounting for 56.5%) completely, 7 patient symptoms improve (accounting for 30.4%), 2 patient pseudohyphas aobvious negative (accounting for 8.7%), vaginal wall corrosion improves, clinical symptoms is controlled, 1 patient pseudohypha aobvious positive (accounting for 4.3%), and vaginal wall corrosion is controlled; The control rate of its pseudohypha reaches 95.7%, and symptom controls and improvement rate reaches 100%.
Matched group is with miconazole treatment 10 patients, and 5 patient pseudohyphas are negative and symptom obtains controlling (accounting for 50%), and 2 patient symptoms improve (accounting for 20%), and all the other 3 patient symptoms do not disappear and pseudohypha is positive (accounting for 30%) completely; Its pseudohypha control rate only about 70%, symptom controls and improvement rate is 70%.
The above results shows: Si Laipu cuts down peptide vaginal suppository can make the symptoms such as the pruritus of VVC patient, erythema, burn into burning sensation all improve, and compared with miconazole vaginal suppository, it is more effective in treatment vulvovaginal candidiasis that Si Laipu cuts down peptide vaginal suppository; Show: Si Laipu cuts down peptide vaginal suppository can effective Killing Candida Albicans, alleviates VVC clinical symptoms and has no side effect.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (3)
1. be used for the treatment of a pharmaceutical composition for vulvovaginal candidiasis, it is characterized in that, comprise compound shown in formula I or its pharmaceutically acceptable salt or ester, and pharmaceutically acceptable excipient and/or carrier; Described formula I or its pharmaceutically acceptable salt or the weight percentage of ester in pharmaceutical composition are 0.05% ~ 0.1%;
Formula I.
2. pharmaceutical composition as claimed in claim 1, is characterized in that, the amount containing compound or its pharmaceutically acceptable salt or ester shown in formula I in each preparation unit is 1 ~ 5mg.
3. the suppository of a pharmaceutical composition as claimed in claim 1, it is characterized in that, the preparation of 100 weight portions comprises the ethyl hydroxybenzoate of the formula I of 0.05 weight portion, the gelatin of 15 weight portions, the glycerol of 60 weight portions, the PEG400 of 12.5 weight portions and 0.05 weight portion, and the pH value of described preparation is 4.3 ± 0.1.
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| CN112451654A (en) * | 2020-12-10 | 2021-03-09 | 兆科药业（广州）有限公司 | New use of selepravastatin |
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| CN1839983A (en) * | 2006-01-23 | 2006-10-04 | 贵阳新天药业股份有限公司 | Ointment for treating female genital system inflammation and its preparing process |
| CN1853683A (en) * | 2005-04-20 | 2006-11-01 | 深圳市东广医药科技开发有限公司 | Medicine for treating colpitis and preparation thereof |
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| CN1853683A (en) * | 2005-04-20 | 2006-11-01 | 深圳市东广医药科技开发有限公司 | Medicine for treating colpitis and preparation thereof |
| CN1839983A (en) * | 2006-01-23 | 2006-10-04 | 贵阳新天药业股份有限公司 | Ointment for treating female genital system inflammation and its preparing process |
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