CN105106179A - Preparation method of amorolfine hydrochloride liniment - Google Patents
Preparation method of amorolfine hydrochloride liniment Download PDFInfo
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- CN105106179A CN105106179A CN201510543869.5A CN201510543869A CN105106179A CN 105106179 A CN105106179 A CN 105106179A CN 201510543869 A CN201510543869 A CN 201510543869A CN 105106179 A CN105106179 A CN 105106179A
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- hydrochloric acid
- acrylic resin
- amorolfine
- liniment
- amorolfine hydrochloride
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Abstract
The invention discloses a preparation method of amorolfine hydrochloride liniment. The method includes: dissolving amorolfine hydrochloride in appropriate amount of anhydrous ethanol, adding acrylic resin RL100, stirring to allow the acrylic resin RL100 to dissolve, then adding ethyl acetate, butyl acetate and glyceryl triacetate, adding anhydrous ethanol to reach fixed volume, and filtering and split charging to obtain the amorolfine hydrochloride liniment. In the amorolfine hydrochloride liniment, each 2.5mL of ethanol contains 100-150mg of amorolfine hydrochloride, and the mass ratio of the amorolfine hydrochloride, the acrylic resin RL100, the ethyl acetate, the butyl acetate and the glyceryl triacetate is 100-150:290-330:22-29:361-390:125-129. The method has the advantages that the water-soluble acrylic resin RL100 is used, so that a layer of tough film can form on the surface of a diseased nail favorably after solvent volatilizes to encapsulate the diseased nail and keep the effective drug concentration of a nail bed; the method is simple and suitable for industrial production, and the prepared liniment is good in stability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of preparation method of hydrochloric acid amorolfine liniment.
Background technology
Hydrochloric acid amorolfine is a kind of morpholine kind compound, chemistry rac-4 [3-[4-(1 by name, 1-Dimethyl-propyl) phenyl]-2-methylpropane]-2,6-Dimethyl-morpholin hydrochlorate, is used for the treatment of the superficial mycosis caused by fungus such as dermatophytosis, yeast, mycete, scotospore bacterium, cryptococcus.
Mainly by changing, the biosynthesis that forms fungal cell membrane lipid realizes for the bacteriostasis of amorolfine, by disturbing the activity of △ 14 reductase and △ 8 → △ 7 isomerase, make the gatherings such as ergosterol shortage, Squalene, ignosterol, Determination of ergosterol is reduced, and then permeability of cell membrane is changed, affect the metabolic process of fungus, the accumulation of atypia lipid causes the morphologic change of fungal cell membrane and organelle, thus realizes bacteriostasis.Its structural formula is:
Tinea unguium is a kind of commonly encountered diseases, frequently-occurring disease, accounts for 30% of all tinea, accounts for 50% of onychonosus.China's tinea unguium prevalence is 15.6%, at some special population, as in old people and the weakened patient of immunity of organisms, its sickness rate presents the trend of rising.Tinea unguium more than 90% is infected by dermatophytosis and causes, and only has 5% ~ 6% to be caused by yeast infection, and 2% ~ 3% is caused by the fungal infection of non-skin tinea bacterium, and 1% is mixed infection.Dermatophytosis and mycete the most often involve toenail, and yeast often involves fingernail.
Clinical experiment shows that amorolfine has extraordinary therapeutic effect to tinea unguium, and therefore the preparation of hydrochloric acid amorolfine class has a wide range of applications and wide market prospect.
Summary of the invention
The present invention proposes a kind of new method preparing hydrochloric acid amorolfine liniment.In new method, employ raw material cheap and easy to get, and obtain the extremely excellent hydrochloric acid amorolfine liniment of the high and performance of yield through optimization technological process and formula proportion.
For achieving the above object, technical scheme of the present invention is as follows:
A preparation method for hydrochloric acid amorolfine liniment, concrete steps are as follows:
First hydrochloric acid amorolfine is dissolved in appropriate dehydrated alcohol, then add acrylic resin RL100, after stirring and dissolving, add ethyl acetate, butyl acetate, glyceryl triacetate, add dehydrated alcohol standardize solution subsequently, after filtering, namely subpackage obtains hydrochloric acid amorolfine liniment.
Wherein, containing 100 ~ 150mg hydrochloric acid amorolfine in the ethanol of every 2.5mL, the mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 100 ~ 150:290 ~ 330:22 ~ 29:361 ~ 390:125 ~ 129.
As preferred version of the present invention, the mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 139.4:312.5:25:372.5:127.
Compared with prior art, the present invention utilizes ethanol as volatile solvent, in use after solvent volatilization, the active ingredient hydrochloric acid amorolfine concentration in medicine can be made to reach more than 25%, promote the diffusion in sick first of medicine; Utilize non-water-soluble resin-acrylic resin RL100, after being beneficial to solvent volatilization, form the tough and tensile thin film of one deck on sick first surface, encapsulate disease first, maintain nail matrix active drug concentration, filming performance is better, make medicine be attached to above nail matrix for a long time, slowly penetrate in nail matrix; In addition glyceryl triacetate is as plasticizer, is conducive to liniment and is in use shaped rapidly, and have elasticity, have and well encapsulate effect; In a preferred version of the present invention, the content of hydrochloric acid amorolfine reaches 55mg/mL, and active constituent content significantly increases, and is beneficial to the long-term stability of medicine and plays therapeutic effect lastingly.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail further.
Embodiment 1
Prescription 1
The mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 100:290:22:361:125.
Preparation technology:
(1) the hydrochloric acid amorolfine taking 100mg is put in Agitation Tank, adds dehydrated alcohol 1ml and stirs, make complete drug dissolution;
(2) add the acrylic resin RL100 of 290mg, place about 4h and make acrylic resin fully swelling;
(3) stir, acrylic resin is dissolved;
(4) add 22mg glyceryl triacetate, 361mg ethyl acetate, 125mg butyl acetate, stir;
(5) add dehydrated alcohol and be settled to 2.5mL, stir;
(6) filter;
(7) divide with filling machine and be filled in vial.
Embodiment 2
Prescription 2
The mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 125:298:24:369:128.
Preparation technology:
(1) the hydrochloric acid amorolfine taking 125mg is put in Agitation Tank, adds dehydrated alcohol 1.6mL and stirs, make complete drug dissolution;
(2) add the acrylic resin RL100 of 298mg, place about 4h and make acrylic resin fully swelling;
(3) stir, acrylic resin is dissolved;
(4) add 24mg glyceryl triacetate, 369mg ethyl acetate, 128mg butyl acetate, stir;
(5) add dehydrated alcohol and be settled to 2.5mL, stir;
(6) filter;
(7) divide with filling machine and be filled in vial.
Embodiment 3
Prescription 3
The mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 139.4:312.5:25:372.5:127.
Preparation technology:
(1) the hydrochloric acid amorolfine taking 139.4mg is put in Agitation Tank, adds dehydrated alcohol 2ml and stirs, make complete drug dissolution;
(2) add the acrylic resin RL100 of 312.5mg, place about 4h and make acrylic resin fully swelling;
(3) stir, acrylic resin is dissolved;
(4) add 25mg glyceryl triacetate, 372.5mg ethyl acetate, 127mg butyl acetate, stir;
(5) add dehydrated alcohol and be settled to 2.5mL, stir;
(6) filter;
(7) divide with filling machine and be filled in vial.
Embodiment 4
Prescription 4
The mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 150:330:29:390:129.
Preparation technology:
(1) the hydrochloric acid amorolfine taking 150mg is put in Agitation Tank, adds dehydrated alcohol 2mL and stirs, make complete drug dissolution;
(2) add the acrylic resin RL100 of 330mg, place about 4h and make acrylic resin fully swelling;
(3) stir, acrylic resin is dissolved;
(4) add 29mg glyceryl triacetate, 390mg ethyl acetate, 129mg butyl acetate, stir;
(5) add dehydrated alcohol and be settled to 2.5ml, stir;
(6) filter;
(7) divide with filling machine and be filled in vial.
Test example
1. withinday precision
Chromatographic condition
Instrument: Shimadzu2010AHTHPLC chromatograph, LCSolution chromatographic work station
Chromatographic column: ShimadzuVP-ODS post (4.6 × 250mm, 5 μm)
Mobile phase: 0.02mol/L phosphate buffer (by 1mol/L phosphoric acid adjust ph to 3.0)-methanol (35:65)
Flow velocity: 1.0ml/min
Sensitivity: 0.05aufs
Determined wavelength: 215nm
Column temperature: 30 DEG C
Get hydrochloric acid amorolfine liniment in prescription 3, under room temperature, rapid precision takes in right amount (being about equivalent to amorolfine 6.25mg), put in 25ml measuring bottle, add mobile phase vibration to dissolve, standardize solution, shake up (containing amorolfine 0.25mg in every 1ml), filter, as need testing solution with 0.45 μm of filter membrane.Measure its peak area respectively at 0,3,6,9h, the results are shown in Table 1, show the peak area of hydrochloric acid amorolfine solution in 9 hours without significant change, illustrate that this product solution is stable in 9h.
Table 1 hydrochloric acid amorolfine measures the stability of solution
2. replica test
Get above-mentioned need testing solution, continuous sample introduction measures 6 times.The results are shown in Table 2, show that the repeatability of content assaying method is good.
Table 2 replica test
3. day to day precision
Get need testing solution, in 5 days, measure its peak area every day, the results are shown in Table 3, show that this method precision is good.
Difference test between table 3 day
Meanwhile, this test hydrochloric acid amorolfine liniment that each prescription is obtained and commercial preparation (
) carry out the quality research of following aspect, result of study is as shown in table 4.
Table 4 hydrochloric acid amorolfine liniment quality research result
As can be seen from Table 4, the hydrochloric acid amorolfine liniment that the present invention prepares is similar to commercial preparation in character, relative density, color, meets the standard of pharmacopeia to liniment.
4. assay
According to Chinese Pharmacopoeia version in 2010 two annex V D high effective liquid chromatography for measuring.
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica, with citric acid-hydrochloric acid-sodium hydrate buffer solution: acetonitrile: methanol (35:30:35, V/V/V) (buffer: get citric acid 0.63g, hydrochloric acid 0.6ml, sodium hydroxide 0.24g, be diluted with water to 1000ml, this solution-water-triethylamine mixes in (25:175:0.3) ratio, pH to 3.0 is regulated again with dilute hydrochloric acid) for mobile phase, determined wavelength is 215nm.Number of theoretical plate calculates should be not less than 1500 by hydrochloric acid amorolfine peak.
The preparation of need testing solution: get prescription 1 to prescription 4 and commercially available product (
) precision takes in right amount (being about equivalent to amorolfine 6.25mg) rapidly under room temperature, puts in 25ml measuring bottle, adds mobile phase vibration dissolving, standardize solution, shake up, filter, precision measures subsequent filtrate 1.0ml and puts in 10ml measuring bottle, use mobile phase standardize solution, shake up, as need testing solution.
The preparation of reference substance solution: get hydrochloric acid amorolfine reference substance and be about 13.9mg, accurately weighed, put in 25ml measuring bottle, add dissolve with methanol and be diluted to scale, shaking up.Precision measures 0.5ml and puts in 10ml measuring bottle, is diluted to scale with mobile phase, shakes up, in contrast product solution.
Algoscopy: measure need testing solution and each 20 μ l injection liquid chromatographies of contrast solution respectively, measures peak area, by external standard method with calculated by peak area.
Measurement result is as shown in table 5.As seen from the table, in the hydrochloric acid amorolfine liniment of prescription 3, the content of hydrochloric acid amorolfine is higher than commercial preparation, and active constituent content significantly increases, and is beneficial to the long-term stability of medicine and plays drug effect lastingly, illustrates that the quality of prescription 3 is better than commercially available liniment.
Table 5 hydrochloric acid amorolfine assay result
Claims (2)
1. the preparation method of a hydrochloric acid amorolfine liniment, it is characterized in that, concrete steps are as follows: be first dissolved in appropriate dehydrated alcohol by hydrochloric acid amorolfine, then acrylic resin RL100 is added, after stirring and dissolving, add ethyl acetate, butyl acetate, glyceryl triacetate, add dehydrated alcohol standardize solution subsequently, after filtering, namely subpackage obtains hydrochloric acid amorolfine liniment, wherein, containing 100 ~ 150mg hydrochloric acid amorolfine in the ethanol of every 2.5mL, hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, the mass ratio of butyl acetate is 100 ~ 150:290 ~ 330:22 ~ 29:361 ~ 390:125 ~ 129.
2. the preparation method of hydrochloric acid amorolfine liniment as claimed in claim 1, it is characterized in that, the mass ratio of hydrochloric acid amorolfine, acrylic resin RL100, glyceryl triacetate, ethyl acetate, butyl acetate is 139.4:312.5:25:372.5:127.
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| CN201510543869.5A CN105106179A (en) | 2015-08-28 | 2015-08-28 | Preparation method of amorolfine hydrochloride liniment |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053732A (en) * | 2018-09-30 | 2020-04-24 | 上海通用药业股份有限公司 | A cream-gel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1703246A (en) * | 2002-09-05 | 2005-11-30 | 盖尔德马公司 | Solution for ungual and peri-ungual application |
| CN103816194A (en) * | 2014-03-13 | 2014-05-28 | 金陵科技学院 | Heat-clearing antipyretic coating agent for pigs and preparation method of heat-clearing antipyretic coating agent |
-
2015
- 2015-08-28 CN CN201510543869.5A patent/CN105106179A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1703246A (en) * | 2002-09-05 | 2005-11-30 | 盖尔德马公司 | Solution for ungual and peri-ungual application |
| CN103816194A (en) * | 2014-03-13 | 2014-05-28 | 金陵科技学院 | Heat-clearing antipyretic coating agent for pigs and preparation method of heat-clearing antipyretic coating agent |
Non-Patent Citations (3)
| Title |
|---|
| 卢洪洲等: "《袖珍抗感染用药手册第2版》", 31 July 2014 * |
| 崔福德: "《药剂学第7版》", 31 August 2011 * |
| 张超云等: "《药剂学》", 31 October 2013 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053732A (en) * | 2018-09-30 | 2020-04-24 | 上海通用药业股份有限公司 | A cream-gel |
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Application publication date: 20151202 |