CN105796520A - Slow release butoconazole nitrate directly compressed tablet and preparation method thereof - Google Patents
Slow release butoconazole nitrate directly compressed tablet and preparation method thereof Download PDFInfo
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- CN105796520A CN105796520A CN201410849034.8A CN201410849034A CN105796520A CN 105796520 A CN105796520 A CN 105796520A CN 201410849034 A CN201410849034 A CN 201410849034A CN 105796520 A CN105796520 A CN 105796520A
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- Prior art keywords
- nitric acid
- vertical compression
- acid butoconazole
- butoconazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- ZHPWRQIPPNZNML-UHFFFAOYSA-N butoconazole nitrate Chemical compound O[N+]([O-])=O.C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 ZHPWRQIPPNZNML-UHFFFAOYSA-N 0.000 title abstract description 7
- 229960002120 butoconazole nitrate Drugs 0.000 title abstract description 7
- 239000007891 compressed tablet Substances 0.000 title abstract 3
- 239000000463 material Substances 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000000314 lubricant Substances 0.000 claims abstract description 15
- 239000003085 diluting agent Substances 0.000 claims abstract description 13
- 239000012052 hydrophilic carrier Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000011248 coating agent Substances 0.000 claims abstract description 9
- 238000000576 coating method Methods 0.000 claims abstract description 9
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 claims description 84
- 229960005074 butoconazole Drugs 0.000 claims description 80
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 78
- 229910017604 nitric acid Inorganic materials 0.000 claims description 78
- 238000007906 compression Methods 0.000 claims description 66
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- 238000000034 method Methods 0.000 claims description 20
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- 239000008101 lactose Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
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- 229960001631 carbomer Drugs 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 5
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
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- 150000002460 imidazoles Chemical class 0.000 description 7
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
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- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a slow release butoconazole nitrate directly compressed tablet and a preparation method thereof and belongs to the technical field of medicines. The slow release butoconazole nitrate directly compressed tablet comprises a, an active component butoconazole nitrate, b, a single or compound directly compressed slow release material and c, a hydrophilic carrier material. The preparation method comprises blending the butoconazole nitrate and the hydrophilic carrier material, grinding the mixture, sieving the mixture, blending the mixture, the single or compound directly compressed slow release material, any pharmaceutically acceptable diluents and a flow aid, adding a lubricant into the mixture, carrying out mixing and direct tabletting and carrying out coating or not.
Description
Technical field
The present invention relates to a kind of spacetabs type Nitric acid butoconazole vertical compression tablet and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Gynecological inflammation is the commonly encountered diseases of women, and vaginitis sickness rate accounts for 1/3rd of gynecological inflammation.The reason causing colpitic high incidence includes: abuse of antibiotics, corticosteroid, oral contraceptive, endocrine disturbance etc..Candidal vulvovaginitis is very general in women, and in vagina, accounting reaches 30-45%.Wherein, Candida albicans the vaginitis caused occupies the overwhelming majority.
China is mainly imidazoles antifungal drug for the treatment of beads bacterial type vulvovaginitis, imidazoles antibacterials usually rely on suppression Cytochrome P450 14 α-demethylase to lanosterol to the conversion of ergosterol, thus changing the composition of fungal cell's membrane lipid.The change of this structure causes the change of cell permeability, finally causes fungus dead.
Nitric acid butoconazole is a kind of imdazole derivatives with antifungal activity, and it is primarily adapted for use in treatment candidal vulvovaginitis.Its infection being proved to clinically Candida albicans is caused is effective.Nitric acid butoconazole mechanism of action in antifongin is similar with other imidazoles antibacterials by inference, is by suppressing steroid synthesis to cause that fungus is dead.Gram positive bacteria is had antibacterial activity by Nitric acid butoconazole, and gram negative bacteria is inactive, and aspergillus fungi and candidiasis antibacterial activity is good.Candidiasis, trichophyta, microspore bacterium and epidermophyton had resistant function by vitro tests.The vaginal infection height clinically Candida albicans, Oidium tropicale etc. caused is effective.External a large amount of clinical trial and clinical practice data show, Nitric acid butoconazole has good safety and effectiveness.
The chemistry of Nitric acid butoconazole is called: (±)-1-[4-(p-chlorphenyl)-2 [(-2,6-Dichlorobenzene base) sulfenyl] butyl] imidazoles] nitrate, structural formula is as follows:
Nitric acid butoconazole is developed by Syntex company of the U.S., and discloses, in 1978, the general formula compound patent including Nitric acid butoconazole in US Patent No. 4078071.The said firm discloses the compound patent of butoconazole in the British patent GB1567431 that 1980 authorize.1985 by Hoffmann-LaRoche company first in U.S.'s list marketing, dosage form is vaginal cream and vaginal suppository.1997, U.S. FDA ratified the vaginal emulsifiable paste listing that KV drugmaker adopts slow release method to prepare, and its commodity are calledOne course for the treatment of has only to medication once.
One course for the treatment of has only to medication vagina slowly-releasing preparation once compared with vagina ordinary preparation, and advantage is apparent from.Ordinary preparation needs multiple dosing in one course for the treatment of, is generally 3-5 days even 7 days, and most drug patient's compliance is low, there is leakage and uses, changes voluntarily the possibility of therapeutic regimen；Further, ordinary preparation easily leaks, and causes drug dose to lose, and drug effect can not get ensureing.And slow releasing preparation can maintain the active drug concentration of relative constancy for a long time, make human body obtain smoothly effectively medicine concentration, it is ensured that the therapeutic effect of medicine, make curative effect-dosage optimization；Simultaneously, dosage and the times for spraying of slow releasing preparation substantially reduce, slowly, uniformly, local drug concentration is high, long action time for drug release, vaginal mucosa is stimulated little, leakage rate is few, not pollution clothes, not only increases curative effect, and reduce the phenomenon of patient's leakage medicine, improve patient medication compliance.Therefore, exploitation vulvovaginitis topical sustained release preparation is have very practical and important meaning.
The Nitric acid butoconazole slow release emulsifiable paste of KV drugmaker exploitation, its correlation technique is mentioned in the United States Patent (USP) that the said firm applies for.US Patent No. 5266329 discloses a kind of vagina slowly-releasing administration system, this slow release emulsifiable paste comprises the oil phase (foreign minister) and the aqueous phase (interior phase) containing ingredient with bioadhesive, and the ratio of wherein aqueous phase accounts for more than 70%, this system containing the imidazoles including butoconazole can at least reduce treatment time or dosage 25%.Another US Patent No. 5055303 of the said firm discloses a controlled-release administrating system with biological viscosity comprising water, glycerol, active medicine, reduces the spilling of Nitric acid butoconazole emulsifiable paste, the practicality that improve.It is well known, however, that ointment is all Unstable Systems on thermodynamics and kinetics, effect duration is short, is generally only about 2 years；Further, ointment is semi-solid preparation, need to can be applied in affected part through administrator, adds drug cost and uses difficulty.
US Patent No. 6916485 discloses a kind of tablet for administration system with biological viscosity.This system is with the imidazoles antifungal drugs such as Nitric acid butoconazole and polyenoid for main component, also include more than 20% native protein, the hydrophilic polymer of 10-20%, compressible excipients (as, corn starch), 4-10% for improve local efficacy alkali metal alkyl sulfate (as, sodium lauryl sulphate or sulfosuccinic diethyl phthalate) and 0.1-1% one hydration sugar (e.g., lactose monohydrate or a water sucrose).It is said that this drug-supplying system at the active component dissolution of 8 hours more than 70%, but this drug-supplying system is more suitable for oral administration.
Patent CN101721353 discloses a kind of medicine thermal sensitive gel comprising Nitric acid butoconazole, poloxamer, hypromellose, carbomer and aqueous carrier etc..Said preparation, in vitro in flow-like, enters internal rear effected by a temperature increase in semi-solid state, solves the shortcoming that tradition emulsifiable paste easily overflows.But just because of its thermal sensitivity, the relative tablet of requirement on producing, transport and storing is more strict, and cost is also relatively higher.Patent is referred to this gel within 1 year without substantially layering, there is certain stability.But be subject to the physics of gel itself and the restriction of chemical property, relative to tablet described in this patent, its stability estimates that the shelf-life of more than 3 years is then substantially on the low side.Further, gel, as semi-solid preparation, also needs to be applied in affected part through administrator, adds drug cost and uses difficulty.
US Patent No. 6423307 discloses the sustained-release gel that complex is main component of a kind of imidazoles including Nitric acid butoconazole and polycarbophil.The preparation of this complex relies on and medicine and polycarbophil is dissolved in identical solvent, by distilling, prepares solid-state complex finished product.Again this complex is dissolved in the pharmaceutical carriers such as propylene glycol, makes gel.According to patent description, this imidazoles-polycarbophil complex has better mucoadhesive relative to medicine itself, can delay the release of medicine significantly, and have good curative effect in living animal.Chinese patent CN101698101 discloses a kind of by Nitric acid butoconazole, HYDROXYPROPYL BETA-CYCLODEXTRIN, poloxamer, hypromellose, methyl hydroxybenzoate, propylparaben, her ground acid disodium and gel of form of water, and this patent states has and reduces medicine and reveal and certain sustained release performance.But, as semi-solid preparation, there is the problem identical with ointment in gel.
In summary, prior art and listed Nitric acid butoconazole slow releasing preparation, it mostly is the semi-solid preparation such as ointment, gel, shelf-life is shorter, need to can be applied in affected part through administrator, market is badly in need of the Nitric acid butoconazole slow-release solid preparation that the shelf-life is longer, it is more convenient to use and good effect, safety are high, with low cost.
Although the embodiment 2 of Chinese patent CN101698101 discloses prescription and consists of Nitric acid butoconazole, hypromellose, carbomer, Polyethylene Glycol, preparation method is supplementary material mixing, add 80% alcoholic solution and make soft material, granulate, dry to obtain dry granule, granulate, add fluidizer and lubricant, mixing, tabletting, obtain butoconazole nitrate vaginal sheet.But what this butoconazole nitrate vaginal sheet adopted is traditional wet granulation technology.We are it have to be observed that the defect of wet granulation: product quality aspect, owing to wet granulation technology is complicated, long flow path, affected greatly by material and operative, cause repeatability between criticizing poor, and in wet-granulation process, the introducing of wet heat condition may result in unstable product quality；Energy-conserving and environment-protective aspect, owing to wet granulation energy consumption is high, Material Cost and human cost are high, production efficiency is on the low side, yield rate is on the low side, and the high viscosity adjuvant such as the hydroxypropyl methylcellulose used for slow controlled release purpose, brings very big difficulty to clearing out a gathering place of formulating plant.
And direct powder compression technical matters production equipment simple, required is few, energy-and time-economizing, production cost is low and efficiency is high, constant product quality, batch between favorable reproducibility, compared with other tablet manufacturing techniques, there is obvious advantage, it has also become trend that preparation industry is following and focus.Having the oral solid formulation more than 40% in developed country according to statistics is adopt technique of direct powder compression to prepare production.
There is no the report of Nitric acid butoconazole sustained-release preparation direct powder compression at present, if its reason and technical bottleneck that may be present are that active component Nitric acid butoconazole makes slow releasing preparation, its drug content is higher, and poor fluidity after crude drug pulverizing, use existing adjuvant and technical matters, it is impossible to realize direct powder compression.
Therefore, for the consideration to Product Safety, effectiveness, repeatability and each side such as economy and energy-conserving and environment-protective, need a kind of spacetabs type Nitric acid butoconazole vertical compression tablet of exploitation and preparation method thereof badly.
Summary of the invention
By research deep for a long time, present inventor have been surprisingly found that and can prepare spacetabs type Nitric acid butoconazole tablet by the method for powder vertical compression.
Therefore, provide a kind of spacetabs type Nitric acid butoconazole vertical compression tablet in one aspect of the invention, comprise:
A. active component Nitric acid butoconazole；
B. unitary type or compound vertical compression slow-release material；With
C. hydrophilic carrier material.
In the embodiment that this law is bright, described unitary type vertical compression slow-release material is selected from vertical compression type HPMC, vertical compression type ethyl cellulose, Glyceryl Behenate, carbomer or its mixture, and compound vertical compression slow-release material is HPMC and the spray drying complex of lactose composition.
In another embodiment that this law is bright, the weight ratio of described unitary type or compound vertical compression slow-release material and active component Nitric acid butoconazole is 10:1 to 1:3, it is preferred to 6:1 to 1:2.
In another embodiment of the invention, described hydrophilic carrier material is selected from Pu Luoshamu, mannitol, PVP, PEG or its mixture, and its weight ratio with active component Nitric acid butoconazole is 8:1 to 1:4, it is preferred to 4:1 to 1:2.
In a preferred embodiment of the invention, spacetabs type Nitric acid butoconazole vertical compression tablet also comprise selected from diluent, fluidizer, lubricant pharmaceutically acceptable solid preparation molding adjuvant.Described diluent is selected from vertical compression lactose, vertical compression microcrystalline Cellulose or its mixture, and its consumption is less than the 90% of whole weight of material, it is preferable that less than the 70% of whole weight of material.Described fluidizer is micropowder silica gel, and its consumption is the 0.5% to 2.0% of whole weight of material.Described lubricant is selected from magnesium stearate, stearic acid, fixed oil, Pulvis Talci or its mixture, and consumption is the 0.5% to 2.0% of whole weight of material.
Provide a kind of method preparing above-mentioned spacetabs type Nitric acid butoconazole vertical compression tablet in another aspect of the present invention, comprise the following steps: first Nitric acid butoconazole is ground with hydrophilic carrier material mixing and sieve, mix homogeneously with unitary type or compound vertical compression slow-release material, optional pharmaceutically acceptable diluent, fluidizer again, it is eventually adding direct powder compression after lubricant mixes, optional coating or not coating.
Accompanying drawing explanation
Fig. 1 show the spacetabs type Nitric acid butoconazole vertical compression tablet vitro release result of the test of embodiment 1.
Fig. 2 show the spacetabs type Nitric acid butoconazole vertical compression tablet vitro release result of the test of embodiment 2.
Fig. 3 show the spacetabs type Nitric acid butoconazole vertical compression tablet vitro release result of the test of embodiment 3.
Fig. 4 show the spacetabs type Nitric acid butoconazole vertical compression tablet vitro release result of the test of embodiment 4.
Fig. 5 show the spacetabs type Nitric acid butoconazole vertical compression tablet vitro release result of the test of embodiment 5.
Fig. 6 show the Nitric acid butoconazole slow releasing tablet vitro release result of the test of comparative example 1.
Detailed description of the invention
Therefore, provide a kind of spacetabs type Nitric acid butoconazole vertical compression tablet in one aspect of the invention, comprise:
A. active component Nitric acid butoconazole；
B. unitary type or compound vertical compression slow-release material；With
C. hydrophilic carrier material.
In the embodiment that this law is bright, described unitary type vertical compression slow-release material is selected from vertical compression type HPMC, vertical compression type ethyl cellulose, Glyceryl Behenate, carbomer or its mixture, compound vertical compression slow-release material is HPMC and the spray drying complex of lactose composition, it is preferable that the spray drying complex of 50%HPMC-K4M and 50% α-lactose monohydrate composition.Above-mentioned vertical compression slow-release material can be made by oneself, also can buy to market, such as HPMCK4MDC (Colorcon), HPMCK100MDC (Colorcon), Compritol888ATO (Gattefosse), RetaLac (Meggle) etc..
In another embodiment that this law is bright, the weight ratio of described unitary type or compound vertical compression slow-release material and active component Nitric acid butoconazole is 10:1 to 1:3, it is preferred to 6:1 to 1:2.
In another embodiment of the invention, described hydrophilic carrier material is selected from Pu Luoshamu, mannitol, PVP, PEG or its mixture, and its weight ratio with active component Nitric acid butoconazole is 8:1 to 1:4, it is preferred to 4:1 to 1:2.
In a preferred embodiment of the invention, spacetabs type Nitric acid butoconazole vertical compression tablet also comprise selected from diluent, fluidizer, lubricant pharmaceutically acceptable solid preparation molding adjuvant.Described diluent is selected from vertical compression lactose, vertical compression microcrystalline Cellulose or its mixture, and its consumption is less than the 90% of whole weight of material, it is preferable that less than the 70% of whole weight of material.Described fluidizer is micropowder silica gel, and its consumption is the 0.5% to 2.0% of whole weight of material.Described lubricant is selected from magnesium stearate, stearic acid, fixed oil, Pulvis Talci or its mixture, and consumption is the 0.5% to 2.0% of whole weight of material.
Provide a kind of method preparing preceding claim spacetabs type Nitric acid butoconazole vertical compression tablet in another aspect of the present invention, comprise the following steps: first Nitric acid butoconazole is ground with hydrophilic carrier material mixing and sieve, mix homogeneously with unitary type or compound vertical compression slow-release material, optional pharmaceutically acceptable diluent, fluidizer again, it is eventually adding direct powder compression after lubricant mixes, optional coating or not coating.
Compared with prior art, use unitary type or compound vertical compression slow-release material and optional pharmaceutically acceptable solid preparation molding adjuvant, such as diluent, fluidizer, lubricant etc., spacetabs type Nitric acid butoconazole vertical compression tablet of fine quality is can be obtained by by technique of direct powder compression simply and efficiently, solve because of Nitric acid butoconazole poor fluidity cannot the technical barrier of direct powder compression, reduce production cost.Further, owing to powder vertical compression technique is simple, flow process is short, is affected little by material and operative, so differences between batches are little, and favorable reproducibility between batch.Meanwhile, spacetabs type Nitric acid butoconazole vertical compression tablet is solid preparation, physics and stable chemical nature, and the semi-solid preparation such as more existing ointment, gel is generally only the shelf-life of about 2 years, and effect duration is 3 to 5 years.Further, spacetabs type Nitric acid butoconazole vertical compression tablet is easy to use, it is not necessary to administrator, uses disposable hygienic fingerstall can put medicine in affected part after patient's wash clean hands；Compared with need to can being applied in the semi-solid preparations such as the ointment in affected part, gel through administrator, the spacetabs type Nitric acid butoconazole vertical compression tablet of the present invention decreases drug cost and uses difficulty.
Below in conjunction with embodiment, the present invention is further illustrated, and embodiment is only indicative content, by no means implies that the scope that it is intended to limit the present invention in any manner.
Embodiment 1
Formula (g/1000 preparation unit):
Embodiment 2
Formula (g/1000 preparation unit):
Embodiment 3
Formula (g/1000 preparation unit):
Embodiment 4
Formula (g/1000 preparation unit):
Embodiment 5
Formula (g/1000 preparation unit):
Preparation method:
First Nitric acid butoconazole is ground with hydrophilic carrier material mixing and sieve, then mix homogeneously with slow-release material, pharmaceutically acceptable diluent, fluidizer etc., be eventually adding direct powder compression after lubricant mixes, optional coating or not coating, packaging, to obtain final product.
Comparative example 1 (preparing by method described in embodiment in patent CN101698101B 2)
Formula (g/1000 preparation unit):
Preparation method:
Supplementary material sieves respectively, mixing, adds 80% alcoholic solution and makes soft material, granulates, and dries to obtain dry granule, granulate, adds Pulvis Talci (adding by granule total amount 1%) as fluidizer and lubricant, mixing, tabletting, packaging, to obtain final product.
Comparative example 2
Formula:
With comparative example 1 formula.
Preparation method:
Supplementary material sieves respectively, mixing, adds Pulvis Talci (1% adds in an amount) as fluidizer and lubricant, direct powder compression after mixing.
Result:
Due to all non-straight die mould of adjuvant used, thus the mobility extreme difference of mixed-powder, it is impossible to fill up plunger die for tabletting press, at all cannot tabletting.
Embodiment 6 vitro release is tested
Test method:
The sample of embodiment 1 to 5 and comparative example 1 is carried out vitro release test, and specific operation process is as follows.Release method: two annex XD the first method Rotating shaker of " Chinese Pharmacopoeia " version in 2010；Release medium: 1000ml NaAc_HAc buffer solution (pH4.3)；Rotating speed: 100 revs/min；Temperature: 37 DEG C；Sample time: 1,2,4,24,48,72,96,169h；Content assaying method: high performance liquid chromatography；Measure wavelength: 225nm.
Measurement result is shown in Fig. 1～Fig. 6.
Being can be seen that by Fig. 1-Fig. 6, vitro release result of the test shows: adopts technique of direct powder compression and traditional wet granulation technology gained Nitric acid butoconazole slow releasing tablet, all can obtain desirable In-vitro release curves.But, compared with traditional wet granulation technology gained Nitric acid butoconazole slow releasing tablet, adopting technique of direct powder compression gained Nitric acid butoconazole slow releasing tablet, its differences between batches are little, favorable reproducibility between batch, is therefore better than adopting traditional wet granulation technology gained Nitric acid butoconazole slow releasing tablet.
Embodiment 7 stability test
According to two annex XIXC of 2010 editions Chinese Pharmacopoeias " crude drug and pharmaceutical preparation stability test guideline ", the sample of embodiment 1 to 5 is accelerated stability (temperature 40 ± 2 DEG C, relative humidity 75% ± 5%) to investigate, stability high spot reviews project has character, has related substance, content, release.Meanwhile, the sample of commercially available Nitric acid butoconazole emulsifiable paste GYNAZOLE1 being accelerated stability (temperature 30 ± 2 DEG C, relative humidity 65% ± 5%) and investigates, stability high spot reviews project has character, has related substance, content, release.
Accelerated stability investigates result: the sample accelerated stability of embodiment 1 to 5 is investigated 12 months, character, there are related substance, content, release all in quality standard prescribed limit, sample quality is stable, it is contemplated that under the normal temperature condition of reality storage, and the shelf-life is 3 to 5 years.The sample accelerated stability of commercially available Nitric acid butoconazole emulsifiable paste GYNAZOLE1 is investigated 12 months, first 6 months character, there are related substance, content, release all in quality standard prescribed limit, to 9th month and 12nd month, character, having related substance, release beyond quality standard prescribed limit, sample stability is not so good as embodiment 1 to 5 sample.
Embodiment 8 vaginal mucosa irritation is tested
Laboratory animal: Female white rabbit.
Experiment packet: be divided into administration group and matched group.Administration group gives embodiment 1 to 5 and the sample of commercially available Nitric acid butoconazole emulsifiable paste GYNAZOLE1 respectively, and matched group gives normal saline.
Operation sequence:
By 0.5g/kg dosage, test medicine being inserted animal intravaginal gently, control animals normal saline makees same process.As stated above, it was administered once every 24 hours, continuous 7 days.
After last is administered 24 hours, putting to death animal by aeroembolism method, cut open the belly and take out complete uterus, longitudinally slit, whether perusal has hyperemia, edema etc. to show, reference during for pathologic sampling.Then vagina is put in 10% formalin solution and fix more than 24 hours, choose the tissue film-making at three positions in vagina two ends and central authorities, after HE dyeing, carry out histopathological examination.
Result of the test: the sample of embodiment 1 to 5 and commercially available Nitric acid butoconazole emulsifiable paste GYNAZOLE 1 is to the equal nonirritant of laboratory animal vaginal mucosa, and laboratory animal is showed no obvious edema, hyperemia, erosion, and safety is good.
In sum, the spacetabs type Nitric acid butoconazole vertical compression tablet of embodiment 1 to 5 shows gratifying release behavior.Meanwhile, the spacetabs type Nitric acid butoconazole vertical compression tablet quality of embodiment 1 to 5 is stable, and effect duration expectation is 3 to 5 years, and to experimental animal vaginal mucosa nonirritant, safety is high.It follows that spacetabs type Nitric acid butoconazole vertical compression tablet involved in the present invention and preparation method thereof possesses effectively substitutes existing Nitric acid butoconazole slow release emulsifiable paste, sustained-release gel, and the potentiality of corresponding wet granulation type slow releasing tablet and preparation method thereof.
Claims (12)
1. a spacetabs type Nitric acid butoconazole vertical compression tablet, comprises:
A. active component Nitric acid butoconazole；
B. unitary type or compound vertical compression slow-release material；With
C. hydrophilic carrier material.
2. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 1, wherein said unitary type vertical compression slow-release material is selected from vertical compression type HPMC, vertical compression type ethyl cellulose, Glyceryl Behenate, carbomer or its mixture, and compound vertical compression slow-release material is HPMC and the spray drying complex of lactose composition.
3. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 1, wherein the weight ratio of unitary type or compound vertical compression slow-release material and active component Nitric acid butoconazole is 10:1 to 1:3.
4. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 3, wherein the weight ratio of unitary type or compound vertical compression slow-release material and active component Nitric acid butoconazole is 6:1 to 1:2.
5. vertical compression tablet Nitric acid butoconazole vertical compression tablet according to claim 1, wherein hydrophilic carrier material is selected from Pu Luoshamu, mannitol, PVP, PEG or its mixture, and its weight ratio with active component Nitric acid butoconazole is 8:1 to 1:4.
6. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 5, wherein hydrophilic carrier material is 4:1 to 1:2 with the weight ratio of active component Nitric acid butoconazole.
7. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 1, also includes the pharmaceutically acceptable solid preparation molding adjuvant being selected from diluent, fluidizer, lubricant.
8. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 7, wherein said diluent is selected from vertical compression lactose, vertical compression microcrystalline Cellulose or its mixture, and its consumption is less than the 90% of whole weight of material.
9. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 8, wherein said diluent consumption is less than the 70% of whole weight of material.
10. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 7, wherein said fluidizer is micropowder silica gel, and its consumption is the 0.5% to 2.0% of whole weight of material.
11. spacetabs type Nitric acid butoconazole vertical compression tablet according to claim 7, wherein said lubricant is selected from magnesium stearate, stearic acid, fixed oil, Pulvis Talci or its mixture, and consumption is the 0.5% to 2.0% of whole weight of material.
12. the method for the spacetabs type Nitric acid butoconazole vertical compression tablet that a kind is prepared according to any one of claim 1-11, comprise the following steps: first Nitric acid butoconazole is ground with hydrophilic carrier material mixing and sieve, mix homogeneously with unitary type or compound vertical compression slow-release material, optional pharmaceutically acceptable diluent, fluidizer again, it is eventually adding direct powder compression after lubricant mixes, optional coating or not coating.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101698101A (en) * | 2008-12-02 | 2010-04-28 | 济南宏瑞创博医药科技开发有限公司 | Medicine composite for treating vaginitis |
| CN103071157A (en) * | 2006-06-29 | 2013-05-01 | 波利化学公司 | Use of a hydrophilic matrix comprising a polyacrylic acid derivative, a cellulose ether and a disintegrant for the manufacture of a medicament for treating female genital disorders |
| CN103830228A (en) * | 2012-11-26 | 2014-06-04 | 四川滇虹医药开发有限公司 | Zaltoprofen sustained-release medicinal composition, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103071157A (en) * | 2006-06-29 | 2013-05-01 | 波利化学公司 | Use of a hydrophilic matrix comprising a polyacrylic acid derivative, a cellulose ether and a disintegrant for the manufacture of a medicament for treating female genital disorders |
| CN101698101A (en) * | 2008-12-02 | 2010-04-28 | 济南宏瑞创博医药科技开发有限公司 | Medicine composite for treating vaginitis |
| CN103830228A (en) * | 2012-11-26 | 2014-06-04 | 四川滇虹医药开发有限公司 | Zaltoprofen sustained-release medicinal composition, and preparation method and application thereof |
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