CN101703504B - Medicinal composition for vagina - Google Patents
Medicinal composition for vagina Download PDFInfo
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- CN101703504B CN101703504B CN2009102227517A CN200910222751A CN101703504B CN 101703504 B CN101703504 B CN 101703504B CN 2009102227517 A CN2009102227517 A CN 2009102227517A CN 200910222751 A CN200910222751 A CN 200910222751A CN 101703504 B CN101703504 B CN 101703504B
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Abstract
The invention relates to a medicinal composition for vagina. The composition comprises butoconazole nitrate, poloxamer, hydroxypropyl methylcellulose, Carbomer and other additives. The composition has the characteristics of good vagina mucosa adhesion and long-acting slow release, and in vivo and in vitro experiment results prove that the composition can continuously release the medicament for more than 72 hours.
Description
Technical field
The present invention relates to technical field of medicine, but be specifically related to a kind of medicinal composition for vagina.
Background technology
Gynecological inflammation is women's a commonly encountered diseases, adult female's infection in various degree in the whole world about 87% gynecological inflammation, clinical common gynecologic inflammation has vaginitis, cervicitis, pelvic inflammatory disease, endometritis etc., and wherein the vaginitis sickness rate is the highest, accounts for 1/3rd of gynecological inflammation.Vaginitis mainly is divided into colpitis mycotica, bacterial vaginitis, trichomonal vaginitis, and wherein bacterial vaginitis and colpitis mycotica sickness rate are higher, and along with growth in the living standard, the trichomonal vaginitis sickness rate reduces greatly.Colpitis mycotica mainly causes by candidiasis, therefore is monilial vaginitis again, and vulvovaginal candidiasis was taking place nearly according to statistics 50%～60% women in life, wherein 85%～95%, cause by Candida albicans.If vulvovaginal candidiasis can not get in time treating completely, be easy to recurrence, develop into RVVC, make patients ' life quality be subjected to very big influence, also be the very big difficulty of disease treatment manufacturing simultaneously.
The medicine of the vulvovaginal candidiasis of China's treatment at present is less relatively, and needs the long-term prescription of repeated multiple times, brings very big inconvenience to the patient, often just discontinues medication symptom is eased after, treats not thoroughly, causes recurring.At present, the treatment of vulvovaginal candidiasis mainly is to adopt antimicrobial medicine, and majority is imidazoles, as miconazole nitrate, clotrimazole, fluconazol etc., a small amount of antibiotic arranged in addition, and medication comprises oral and two kinds of vagina topicals.
Adopt the oral administration mode, though it is convenient, but because medicine all has distribution in blood and each tissue, simultaneously also constantly by metabolism with drain, cause local drug concentration low, therefore will reach effective treatment concentration, required oral drugs dosage is big, and causes the untoward reaction and the toxic and side effects of system easily.
For these reasons, the vagina topical is adopted in the treatment of vulvovaginal candidiasis disease at present more, vagina local drug concentration height after the medication, only need very low dose ofly can reach valid density, test simultaneously shows that these medicines are absorbed into blood volume seldom through vaginal mucosa, reducing adverse reaction rate greatly, is treatment vulvovaginal candidiasis disease therapeutic modality preferably.
The dosage form that is used for vagina administration at present mainly contains ointment, emulsifiable paste, gel, suppository, vaginal tablet, effervescent tablet, vaginal capsule, soft capsule etc., and mainly there is following problem in these general formulations:
1) leaks easily.After the ordinary preparation medication, under vaginal secretions and excremental effect, be easy to leak out, make drug loss on the one hand, can not guarantee curative effect, on the other hand, owing to leak easily, require patient's preceding administration of sleeping at night, adopt the position that couches after the administration, bring very big inconvenience to the patient, reduce the compliance of patient's medication.
2) the medication number of times is frequent.Owing to have leakage, the fast problem of drug release, medicine is short in intravaginal action time, and curative effect is low, therefore in most cases needs medication every day once, continuous use 7～10 days, and administration number of times is frequent.Frequently repeatedly medication causes patient's medication poor compliance, have in addition can not guarantee to finish the whole course of treatment, affect the treatment.
Nitric acid butoconazole is a latest generation imidazoles antifungal drug, be mainly used in the treatment vulvovaginal candidiasis, external existing Nitric acid butoconazole vaginal cream listing, having significant clinical efficacy and good safety, is the choice drug that the treatment vulvovaginal candidiasis is recommended by U.S. CDC.
Summary of the invention
The invention provides a kind of medicinal composition for vagina with treatment vulvovaginal candidiasis of good biological mucosa adhesiveness, good slow release performance, good stable.
The present invention utilizes molecule inclusion technology, vaginal adhesion technology, slow release method, and the eutherapeutic Nitric acid butoconazole of known treatment vulvovaginal candidiasis is made the slow release heat-sensitive gel, reduces the medication number of times, makes things convenient for patient's medication; Reduce and leak, improve patient's medication compliance; This gel has good stable.
Technical scheme of the present invention is as follows:
The medicinal composition for vagina of treatment vulvovaginal candidiasis of the present invention, components in weight percent is as follows:
Nitric acid butoconazole 1%～10%, poloxamer 407 12%～25%, hypromellose 0.2%～4%, carbomer 0.05%～10%, other additives 0.001%～40%, water or buffer surplus.
Described compositions feature is that phase transition temperature is no more than 36 ℃, preferred 10 ℃～36 ℃, continues to discharge Nitric acid butoconazole and be not less than 72h in medium.
Above-mentioned buffer is selected from one or more in phosphate buffer, acetate buffer, citrate buffer or the phthalate buffer.
Above-mentioned other additives are selected from one or more in antiseptic, pH regulator agent, dissolution accelerator, aromatic, the chelating agent.
Antiseptic in above-mentioned other additives is selected from one or several in the salt of salt, benzoic acid or benzoic salt, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, benzyl alcohol, chlorobutanol, chlorhexidine or chlorhexidine of sorbic acid or sorbic acid.
PH regulator agent in above-mentioned other additives is selected from one or more in hydrochloric acid, phosphoric acid, lactic acid, sodium lactate, vitamin C, sorbic acid, citric acid, sodium hydroxide, sodium phosphate, disodium-hydrogen or the sodium dihydrogen phosphate.
Dissolution accelerator in above-mentioned other additives is selected from one or more in Polyethylene Glycol, cyclodextrin derivative, propylene glycol, glycerol, tween or the ethanol.
Aromatic in above-mentioned other additives is selected from one or more in Oleum menthae, Fructus Citri tangerinae essence, honey peach essence, apple essence, flavoring banana essence or the flavoring pineapple essence.
Chelating agent in above-mentioned other additives is selected from a kind of in disodium edetate, the sodium calcium edetate or their combination.
The pharmaceutical composition of treatment vulvovaginal candidiasis of the present invention, the preferred weight percent component is as follows:
Nitric acid butoconazole 1%～10%
Carbomer 0.05%～0.5%
Hypromellose 0.2%～4%
Poloxamer 407 12%～25%
Polyethylene Glycol 1%～20%
Glycerol 1%～20%
Methyl hydroxybenzoate 0.01%～0.26%
Propylparaben 0.01%～0.26%
Disodium edetate 0.001%～0.2%
Water or buffer surplus.
The pharmaceutical composition of treatment vulvovaginal candidiasis of the present invention, the preferred weight percent component is as follows:
Nitric acid butoconazole 1%～10%
Carbomer 0.05%～0.5%
Hypromellose 0.2%～4%
Poloxamer 407 12%～20%
HYDROXYPROPYL BETA-CYCLODEXTRIN 5%～40%
Methyl hydroxybenzoate 0.01%～0.26%
Propylparaben 0.01%～0.26%
Disodium edetate 0.001%～0.2%
Water or buffer surplus.
The pharmaceutical composition of treatment vulvovaginal candidiasis of the present invention, the preferred weight percent component is as follows::
Nitric acid butoconazole 1%～10%
Carbomer 0.05%～0.5%
Hypromellose 0.2%～4%
Poloxamer 407 12%～20%
HYDROXYPROPYL BETA-CYCLODEXTRIN 5%～40%
Propylene glycol 1%～10%
Methyl hydroxybenzoate 0.01%～0.26%
Propylparaben 0.01%～0.26%
Disodium edetate 0.001%～0.2%
Water or buffer surplus.
The pharmaceutical composition of treatment vulvovaginal candidiasis of the present invention has the following advantages:
1) said composition has good mobility, helps compositions after the use the sprawling of vaginal mucosa, and is beneficial to disease treatment;
2) said composition has remarkable thermal sensitivity and special bioadhesive, change immobilising semi-solid state after the use rapidly into and stick to the vaginal mucosa surface, keep the long time, reduce the leakage of medicine, prolong drug and vaginal mucosa time of contact, guarantee curative effect;
3) said composition has specific sustained release performance, more than the big 72h of sustained release drug, can reduce the medication number of times and make things convenient for patient's medication.
Description of drawings
Fig. 1 is a release in vitro degree result of the test, and Fig. 2 is an experimental result in the animal body.
The specific embodiment
Below in conjunction with embodiment the present invention is done detailed elaboration, but be not limited to the embodiment of these concrete records.The each component consumption all is weight percentage.
Embodiment 1. components of pharmaceutical composition are as follows:
Nitric acid butoconazole 2%
Polyethylene Glycol 16%
Glycerol 8%
Poloxamer 407 22%
Hypromellose K15M 1%
Acritamer 940 0.2%
Methyl hydroxybenzoate 0.1%
Propylparaben 0.1%
Water surplus
Preparation method:
1, get methyl hydroxybenzoate and propylparaben, add water and continue stirring and dissolving, add carbomer simultaneously in stirring, the dissolving back adds hypromellose and poloxamer, places under 4 ℃ of conditions, makes abundant swelling, as gel-type vehicle;
2, get Nitric acid butoconazole and add in Polyethylene Glycol and the glycerol, stir 2h, as containing medicinal liquid;
3, stirring simultaneously, will contain medicinal liquid and add in the gel-type vehicle, mix homogeneously, regulating pH with 0.1mol/l NaOH solution and 0.1mol/l HCl solution in case of necessity is 3～7, be sub-packed in the vaginal administration device, every of 5g, promptly.
Embodiment 2. components of pharmaceutical composition are as follows:
Nitric acid butoconazole 2%
HYDROXYPROPYL BETA-CYCLODEXTRIN 32%
Poloxamer 407 15.5%
Hypromellose K100M 0.6%
Carbomer 974 0.1%
Methyl hydroxybenzoate 0.12%
Propylparaben 0.06%
Water surplus
Preparation method:
Get carbomer, add water and continue stirring and dissolving, add Nitric acid butoconazole, HYDROXYPROPYL BETA-CYCLODEXTRIN, methyl hydroxybenzoate, propylparaben, add poloxamer, hypromellose simultaneously stirring, under 4 ℃ of conditions, to place, treat abundant swelling after, NaOH solution and 0.1mol/l HCl solution adjusting pH with 0.1mol/l is 4～6 in case of necessity, be sub-packed in the vaginal administration device, every of 5g, promptly.
Embodiment 3. components of pharmaceutical composition are as follows:
Nitric acid butoconazole 2%
HYDROXYPROPYL BETA-CYCLODEXTRIN 25%
Poloxamer 407 18%
Hypromellose K100M 0.3%
Carbomer 980 0.1
Propylene glycol 5%
Methyl hydroxybenzoate 0.1%
Propylparaben 0.5%
Water surplus
Preparation method:
Get Nitric acid butoconazole, HYDROXYPROPYL BETA-CYCLODEXTRIN, methyl hydroxybenzoate, propylparaben, add water and propylene glycol mixing and continue stirring and dissolving, add carbomer, poloxamer, hypromellose simultaneously in stirring, under 4 ℃ of conditions, place, after treating abundant swelling, NaOH solution and the 0.1mol/l HCl solution adjusting pH with 0.1mol/l is 3～7 in case of necessity, is sub-packed in the vaginal administration device, every of 5g, promptly.
Embodiment 4. components of pharmaceutical composition are as follows:
Nitric acid butoconazole 2%
HYDROXYPROPYL BETA-CYCLODEXTRIN 30%
Poloxamer 407 15%
Hypromellose K100M 0.3%
Carbomer 974 0.2%
Methyl hydroxybenzoate 0.08%
Propylparaben 0.08%
Disodium edetate 0.005%
Water surplus
Preparation method:
Get Nitric acid butoconazole, HYDROXYPROPYL BETA-CYCLODEXTRIN, methyl hydroxybenzoate, propylparaben, disodium edetate, add water and continue stirring and dissolving, add carbomer, poloxamer, hypromellose simultaneously in stirring, under 4 ℃ of conditions, place, after treating abundant swelling, NaOH solution and the 0.1mol/l HCl solution adjusting pH with 0.1mol/l is 3～7 in case of necessity, is sub-packed in the vaginal administration device, every of 5g, promptly.
The outer release test of embodiment 5. compositions
For estimating the slow release effect of compositions, carry out the test of release in vitro degree, and compare with the Nitric acid butoconazole emulsifiable paste.Test method is as follows:
Get embodiment 2, embodiment 4 compositionss and Nitric acid butoconazole emulsifiable paste 5g, place to discharge the pond, the microporous filter membrane that can cover 0.45 micron in case of necessity on the release pond is fixed.Adopt two appendix XD of Chinese Pharmacopoeia version in 2005 drug release determination method, second subtraction unit to measure, release medium is phosphate buffer 500ml, temperature is 37 ℃ ± 0.5 ℃, rotating speed is 50r/min, certain hour sampling at interval, and additional equality of temperature adopts HPLC method mensuration with the volume release medium, the calculating total release percentage.
The result shows that different pharmaceutical composition drug release rates is slow, and sustained release drug reaches more than the 72h, have significant sustained release performance, and the Nitric acid butoconazole emulsifiable paste only can continue release 48h.The release experimental result is seen Fig. 1.
The sustained release profile in vivo test of embodiment 6. compositionss and delay test
For estimating the sustained release profile in vivo test and the delay situation of compositions, adopt rabbit to test.Test method is as follows:
Get 6 of Female rabbits, adopt three trial design, give the pharmaceutical composition or the Nitric acid butoconazole emulsifiable paste 1g of embodiment 2, embodiment 4 preparations respectively, behind the vagina administration, get vaginal secretion, adopt the HPLC method to measure vaginal secretion Chinese medicine concentration respectively at certain hour.The result shows compositions of the present invention after 72h, vaginal secretion Chinese medicine concentration still much larger than Nitric acid butoconazole to the oidiomycetic MIC of white (about 10 μ g/ml), and the Nitric acid butoconazole emulsifiable paste has detected when 48h less than medicine, the results are shown in Figure 2.
Claims (7)
1. medicinal composition for vagina for the treatment of vulvovaginal candidiasis is characterized in that components in weight percent is as follows:
Nitric acid butoconazole 1%～10%, poloxamer 407 12%～25%, hypromellose 0.2%～4%, carbomer 0.05%～2%, other additives 0.001%～40%, water or buffer surplus;
Described other additives are selected from one or more in antiseptic, pH regulator agent, dissolution accelerator, aromatic, the chelating agent;
10 ℃～36 ℃ of described compositions phase transition temperatures continue to discharge Nitric acid butoconazole and are not less than 72h in medium.
2. medicinal composition for vagina as claimed in claim 1 is characterized in that described buffer is selected from one or more in phosphate buffer, acetate buffer, citrate buffer or the phthalate buffer.
3. medicinal composition for vagina as claimed in claim 1, it is characterized in that described antiseptic is selected from one or several in the salt of salt, benzoic acid or benzoic salt, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, benzyl alcohol, chlorobutanol, chlorhexidine or chlorhexidine of sorbic acid or sorbic acid.
4. medicinal composition for vagina as claimed in claim 1, it is characterized in that described pH regulator agent is selected from one or more in hydrochloric acid, phosphoric acid, lactic acid, sodium lactate, vitamin C, sorbic acid, citric acid, sodium hydroxide, sodium phosphate, disodium-hydrogen or the sodium dihydrogen phosphate.
5. medicinal composition for vagina as claimed in claim 1 is characterized in that described dissolution accelerator is selected from one or more in Polyethylene Glycol, HYDROXYPROPYL BETA-CYCLODEXTRIN, propylene glycol, glycerol, tween or the ethanol.
6. medicinal composition for vagina as claimed in claim 1 is characterized in that, described aromatic is selected from one or more in Oleum menthae, Fructus Citri tangerinae essence, honey peach essence, apple essence, flavoring banana essence or the flavoring pineapple essence.
7. medicinal composition for vagina as claimed in claim 1 is characterized in that, described chelating agent is selected from a kind of in disodium edetate, the sodium calcium edetate or their combination.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102227517A CN101703504B (en) | 2009-07-08 | 2009-11-14 | Medicinal composition for vagina |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910016299.9 | 2009-07-08 | ||
| CN200910016299 | 2009-07-08 | ||
| CN2009102227517A CN101703504B (en) | 2009-07-08 | 2009-11-14 | Medicinal composition for vagina |
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| CN101703504A CN101703504A (en) | 2010-05-12 |
| CN101703504B true CN101703504B (en) | 2011-07-20 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872026A (en) * | 2005-05-30 | 2006-12-06 | 张东军 | New medicinal preparation for vagina |
| CN101185650A (en) * | 2006-11-27 | 2008-05-28 | 中国医学科学院医药生物技术研究所 | Penciclovir ophthalmic temperature sensitivity in situ gel preparation and preparation method thereof |
| CN101224204A (en) * | 2007-12-21 | 2008-07-23 | 武汉药谷科技开发有限公司 | Butoconazole nitrate soft capsule for vagina and preparing method thereof |
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2009
- 2009-11-14 CN CN2009102227517A patent/CN101703504B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872026A (en) * | 2005-05-30 | 2006-12-06 | 张东军 | New medicinal preparation for vagina |
| CN101185650A (en) * | 2006-11-27 | 2008-05-28 | 中国医学科学院医药生物技术研究所 | Penciclovir ophthalmic temperature sensitivity in situ gel preparation and preparation method thereof |
| CN101224204A (en) * | 2007-12-21 | 2008-07-23 | 武汉药谷科技开发有限公司 | Butoconazole nitrate soft capsule for vagina and preparing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 邓树梅 等.智能化凝胶控释黏膜给药系统应用研究进展(1).《中国医药技术经济与管理》.2008,第2卷(第8期),52-59. * |
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| CN101703504A (en) | 2010-05-12 |
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Owner name: JIANGXI ANGTAI PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: JINAN PROFOUND PHARMACEUTICAL TECHNOLOGY DEVELOPMENT CO., LTD. Effective date: 20150612 |
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Effective date of registration: 20150612 Address after: 332300 Jiangxi Province, Wuning Industrial Park, anthee Road No. 1 Patentee after: JIANGXI ANGTAI PHARMACEUTICAL CO., LTD. Address before: 250100 building 3, Pioneer Park, 26 Huayang Road, hi tech Zone, Shandong, Ji'nan Patentee before: Jinan Profound Pharmaceutical Technology Development Co., Ltd. |