CN1903174A - Clotrimazole gel, and its prepn. method - Google Patents

Abstract

A mycosporin gel with high percutaneous absorptivity and stability and its preparing process are disclosed.

Description

Clotrimazole gel and preparation method thereof

Technical field

The present invention relates to a kind of clotrimazole gel preparation and preparation method thereof.

Background technology

(Clotrimazole is to be applied to clinical broad-spectrum antifungal medicine the earliest clotrimazole) to clotrimazole.Be applied to the topical treatment of skin monilial infection at present, as tinea corporis, tinea unguium, tinea pedis, tinea versicolor etc.; The mucosa monilial infection infects as lip, oropharynx, anus, pudendum, between referring to; Vaginitis due to vaginal candida infects, and tinea manus and pedis, auditory meatus and vaginomycosis.Also effective to trichomonal vaginitis.Metabolism is slow in vivo for it, and toxicity is low, good effect.

In 95 editions pharmacopeia, the preparation of clotrimazole has suppository, tablet, medicine membrane of oral cavity, ointment, solution; In ministry standard, the preparation of clotrimazole has Mycoporin vaginal effervescent tablet (WS-1001-(HD-0097)-2002), clotrimazole spray (WS-1001-(HD-0231)-2002), Mycoporin vaginal sheet (WS-1001-(HD-1204)-2002).Disclose a kind of liniment of clotrimazole among the Chinese patent CN1053546A, be mainly used in external.

But when clotrimazole is being used for gynecological, during by the vagina topical, vaginal suppository storage inconvenience requires protecting below 30 ℃, uses at some high temperature severe cold areas to be subjected to certain restriction.And comprise other vaginal preparation of vaginal suppository, as fast disintegrating tablet, effervescent tablet, capsule, suppository, foam, ointment, membrane, ubiquity easily comes off from tract, the tract inner membrance is had zest, is difficult to shortcomings such as long-time storage-stable.In order better to improve patient's adaptability, should on the prescription basis of clotrimazole bolt, carry out modified form to it, address these problems.Simultaneously, existing only have a kind of dosage form of clotrimazole bolt to go on the market, and dosage form is single, can not satisfy the medication demand of vast female patient.

Gel is a kind of new formulation that grows up for meeting clinical needs in recent years, it is that the medical high-molecular additive (as carbomer, Carboxymethyl cellulose sodium, polyvinylpyrrolidone, polyvinyl alcohol etc.) that utilizes some new punishment is made gel with medicine, improve medicine local concentration, the release of prolong drug or the purpose of diffusion process thereby reach, have than other dosage form bioavailability height, good stability, the characteristics that untoward reaction is few.With medicine dissolution or be dispersed in and be gel in the gel, it can the long period and the site of action tight adhesion, and better biocompatibility is arranged, and method for making is simple, uses comfortable." Chinese pharmacopoeia 2000 editions has defined gel in two notes on the use: " gel is meant the latex glop or the semi-solid preparation of homogeneous, suspendible or emulsion-type that medicine and the adjuvant that can form gel are made." in modern pharmacy, be slow release, the controlled release form of substrate with the gel; obtained comprehensive research as gastric retention controlled release system, gel matrix tablet, exterior-applied gel etc.; the medicine that is applicable to the gel delivery system has hydrophilic medicament, hydrophobic drug, acidic drug, cationic drug, macromolecular drug, cell tissue etc.; can be from the oral cavity, number of ways administration such as nasal cavity, eye mucosa, gastrointestinal mucosal, vagina, rectum, skin; Chinese medicine gel generally mostly is percutaneous or mucosa delivery, is usually used in aspects such as anti-inflammatory and antalgic, antiviral, pain relieving at present.

But in the gel dosage form, also there are some problems,, usually need to use to promote penetrating agent, as azone for example in order to promote the osmotic absorption of drug administration position to medicine.And existing report azone causes it to make cell membrane function produce irreversibility and changes owing to similar with cell membrane constituent on its chemical constitution.And use too much promotion penetrating agent also can cause release inhomogeneous.Have zest to local mucous membrane for some medicines when drug level is too high in addition, this can greatly reduce patient's adaptability.Stability during the depositing of gel also is the problem that needs solve in addition.

Therefore, for clotrimazole, in order to solve the problem that exists in existing vaginal preparation such as the suppository, though it can be made gel according to conventional thinking, but still need on choice of base, pay performing creative labour, make that clotrimazole gel curative effect on the basis that addresses the above problem is reliable, the patient uses comfortable.

Summary of the invention

The objective of the invention is to overcome the deficiency of prior art, a kind of scalable, good effect that has is provided, the Empecid of nonirritant, compliance advantages of higher, the standard of improving the quality of products simultaneously further satisfies and ensures the medication demand of vast female patient.

Another object of the present invention provides the preparation method of described clotrimazole gel.

Purpose of the present invention can take following method to realize: a kind of clotrimazole gel is characterized in that it comprises clotrimazole and pharmaceutically acceptable gel substrate.

By weight: clotrimazole 3-5% substrate 0.1-15%

Its formula optimization is:

By weight: clotrimazole 5% substrate 10.4%

Described pharmaceutically acceptable gel substrate is following one or more: aqueous gel substrate such as water, glycerol, propylene glycol, cellulose derivative (as methylcellulose, sodium carboxymethyl cellulose etc.), carbomer and alginate, tragacanth, pectin, gelatin, xanthan gum, agar; Non-cellulosic polysaccharide such as chitin, ethene polymers, acrylic resin, polyvinyl alcohol and carbopol etc.; Oil-base gel agent such as liquid paraffin and polyoxyethylene or fatty oil colloid silicon or wrong soap, zinc soap.

Preferred gel substrate is the mixed-matrix of carbomer and glycerol.

If desired, gel of the present invention stabilizing agents such as adding wetting agent, antiseptic, pH value regulator, and additives that promote skin, mucosa absorption.Wetting agent preferably glycerine wherein.The pH value regulator is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, triethanolamine etc.Preferred triethanolamine.Antiseptic is selected from benzyl alcohol, methyl hydroxybenzoate.Ethyl hydroxybenzoate, propyl hydroxybenzoate, phenol, chlorobutanol, thimerosal etc.Preferred ethyl hydroxybenzoate.

The preparation method of clotrimazole gel of the present invention is as follows:

(1) distilled water boiling sterilization takes by weighing ethyl hydroxybenzoate 1.5g, is dissolved in the 2100ml hot water (80 ℃), puts and is chilled to 40 ℃, and is standby;

(2) get carbomer 12g in addition, gradation is spread in the above-mentioned solution, is stirred to be uniformly dispersed, and leaves standstill 2h, and is standby;

(3) take by weighing triethanolamine 15g, slowly add in the above-mentioned solution with distilled water (420ml) dilution back; Add glycerol again, be stirred to translucent homogeneous system, the white gel of having leisure;

(4) take by weighing clotrimazole fine powder 150g, evenly spread in the blank gel, be stirred to homogeneous system;

(5) gel is sub-packed in the vaginal administration device, promptly.

Institute's referenced patents document and non-patent literature all are hereby incorporated by with its full content among the application.

The present invention is clotrimazole arbitrarily, all can with pharmaceutically acceptable acid reaction, form corresponding salt.Preferred and the salifiable example of mineral acid shape comprises and formed salt such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid.Preferably with the salifiable example of organic acid institute shape comprise and formed salt such as formic acid, acetic acid, trichloroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, P-toluene sulfonic acide.Comprise and formed salt such as arginine, lysine, ornithine with the formed salt of basic amino acid that preferably the example of the salt of preferred and acidic amino acid institute property comprises formed salt such as glutamic acid, aspartic acid.

The present invention adopts through the preparation technology who optimizes, and determines the rational proportion of principal agent and adjuvant, improves curative effect of medication; Adopt gel technology, utilize gel and site of action closely to stick, have the characteristics of better bioadhesive, the increase medicine contacts with site of action, improves the curative effect of medicine; Adopt vagina administration, the onset piece.The clotrimazole gel preparation transdermal absorption factor height that adopts the present invention to make, steady quality, curative effect is reliable.

To more be expressly understood purpose of the present invention, characteristics and other advantage by the detailed description of carrying out, but they do not attempt in office where face limits the scope of the invention below in conjunction with embodiment.

Describe when of the present invention when the reference specific embodiments, it is evident that those skilled in the art without departing from the spirit and scope of the present invention down, will carry out multiple variation and modification to these embodiments.

Embodiment

One, the selection of gel substrate

The quality that the main investigation index of studying for medicament gelling agent is exactly its transdermal performance.Select suitable substrate to help to improve the Transdermal absorption ability of medicine.The application adopts clotrimazole as index, absorb method of testing (as Wu Wanying etc. with reference to conventional transdermal test in vitro, the research of Radix Sophorae Flavescentis total alkaloids percutaneous rate under the different pH value, the Chinese medicine journal, 1999 (2), 61-62), the Transdermal absorption of clotrimazole in the clotrimazole gel of selecting different gel substrate for use is tested comparison.

1. grouping and administration

60 of Wister male rats, body weight 255.8 ± 29.6 is divided into 6 groups at random by body weight.With the clotrimazole bolt respectively with carbomer 934, Acritamer 940, Carbopol 941, methylcellulose, sodium carboxymethyl cellulose, cross linked sodium polyacrylate, make corresponding clotrimazole gel preparation according to above-mentioned preparation technology, the final content of its mesostroma is 0.4%, and clotrimazole content is 5%.

2. method is with reference to Wu Wanying etc., the research of Radix Sophorae Flavescentis total alkaloids percutaneous rate under the different pH value, Chinese medicine journal, 1999 (2), the disclosed method of 61-62.

3 results

Group	Accumulation infiltration equation (μ g/cm 2)	J(μg/cm 2h)	r
				Carbopol 941	Q＝-112.939+92.654t	92.654	0.9875

Acritamer 940	Q＝-18.339+21.765t	21.765	0.9616
				Carbomer 934	Q＝-97.521+82.869t	82.869*	0.9876
Methylcellulose	Q＝-53.597+46.325t	46.325	0.9766
				Sodium carboxymethyl cellulose	Q＝-88.199+54.756t	54.756	0.9428
Cross linked sodium polyacrylate	Q＝-76.130+51.968t	51.968	0.9857

Annotating 1:J is the percutaneous rate constant, the transdermal throughput of unit are in the unit interval of display-object chemical compound.

Annotate each group of 2:* and other and compare p＜0.05 respectively.

This shows that the substrate of clotrimazole gel is the most excellent with carbomer 934 on the promotion Transdermal absorption.

Two, stable contrast test

Because preparation of the present invention is a semi-solid preparation, also there is the characteristic of liquid simultaneously in existing solid characteristic, so need to investigate the stability of gel preparation of the present invention.Now 6 kinds of gel preparations that obtained in the selection with gel substrate carry out light durability relatively.

Get the above-mentioned preparation of respectively organizing, Continuous irradiation 10 days respectively at sampling in 0,5,10 day, is checked its appearance character, content, the results are shown in following table.

The result is investigated in the light durability test

Group	0 day	5 days	10 days
				Carbopol 941	4.75	4.24	4.01
Acritamer 940	4.49	4.21	4.00
				Carbomer 934	4.84	4.78	4.27
Methylcellulose	5.02	4.45	4.12
				Sodium carboxymethyl cellulose	5.07	4.34	4.04
Cross linked sodium polyacrylate	4.94	4.12	4.05

Annotate: data are clotrimazole content in the table, by weight percentage.

Use the prescription stability of carbomer 934 obviously to be better than other each group as can be known by data in the table.

Three, example of formulations

1.pH value is investigated:

Investigating carbomer and triethanolamine under the different proportion situation and pH value, is index with pH value 6-7.5, establishes

The meter test:

Interpretation of result:

Carbomer and triethanolamine ratio are that 1: 1 o'clock pH value meets the requirements.

2 viscositys are investigated:

Investigate the carbomer of different amounts and triethanolamine 1: 1 o'clock viscosity size.

The design single factor experiment:

Carbomer and triethanolamine consumption	Clotrimazole	Glycerol	Ethyl hydroxybenzoate	Viscosity
					3％	5％	10％	0.06％	Very big preparation difficulty
2％	5％	10％	0.06％	Bigger
					1％	5％	10％	0.06％	Suitable
0.8％	5％	10％	0.06％	Less
					0.6％	5％	10％	0.06％	Less, flowability is arranged
0.4％	5％	10％	0.06％	Very little, flowability is arranged

By above result of the test as can be known: carbomer and triethanolamine 1: 1, consumption are that to make clotrimazole gel viscosity at 1% o'clock suitable.

Comprehensive above-mentioned investigation result of the test can draw preparation prescription and adopt clotrimazole (5%), glycerol (10%), and Ka Baimu 934 (1%), triethanolamine (1%), the preparation of ethyl hydroxybenzoate (0.06%) mixture.

Preferred embodiment 1:

Clotrimazole 150g 5%

Glycerol 300g 10%

Ka Baimu 934 12g 0.4%

Ethyl hydroxybenzoate 1.5g 0.05%

Triethanolamine 15g 0.5%

Distilled water adds to 3000g in right amount to 100%

Technology:

(1) distilled water boiling sterilization takes by weighing ethyl hydroxybenzoate 1.5g, is dissolved in the 2100ml hot water (80 ℃), puts and is chilled to 40 ℃, and is standby.

(2) get carbomer 12g in addition, gradation is spread in the above-mentioned solution, is stirred to be uniformly dispersed, and leaves standstill 2h, and is standby.

(3) take by weighing triethanolamine 15g, slowly add in the above-mentioned solution with distilled water (420ml) dilution back; Add glycerol again, be stirred to translucent homogeneous system, the white gel of having leisure.

(4) take by weighing clotrimazole fine powder 150g, evenly spread in the blank gel, be stirred to homogeneous system.

(5) gel is sub-packed in the vaginal administration device, promptly.

Preferred embodiment 2:

Clotrimazole 150g 5%

Glycerol 300g 10%

Ka Baimu 934 15g 0.5%

Ethyl hydroxybenzoate 1.5g 0.05%

Triethanolamine 15g 0.5%

Distilled water adds to 3000g in right amount to 100%

Technology is with preferred embodiment 1

In sum, gel preparation of the present invention all is better than conventional the selection at aspects such as stability, Transdermal absorption, and these effects obviously are not medicine or adjuvants itself, or dosage form itself is brought.Therefore, the application's technical scheme is paid creative work than prior art.Thereby the application's technical scheme is creative.

Claims (3)

1, a kind of clotrimazole gel preparation, it comprises clotrimazole 3-5%, substrate 0.1-15%.

2, clotrimazole gel preparation as claimed in claim 1, it is composed as follows: in parts by weight

Clotrimazole 5%

Glycerol 10%

Ka Baimu 934 0.4%

Ethyl hydroxybenzoate 0.05%

Triethanolamine 0.5%

Distilled water is in right amount to 100%

Wherein:

(1) distilled water boiling sterilization takes by weighing ethyl hydroxybenzoate 1.5g, is dissolved in the 2100ml hot water (80 ℃), puts and is chilled to 40 ℃, and is standby;

(2) get carbomer 12g in addition, gradation is spread in the above-mentioned solution, is stirred to be uniformly dispersed, and leaves standstill 2h, and is standby;

(3) take by weighing triethanolamine 15g, slowly add in the above-mentioned solution with distilled water 420ml dilution back; Add glycerol again, be stirred to translucent homogeneous system, the white gel of having leisure;

(4) take by weighing clotrimazole fine powder 150g, evenly spread in the blank gel, be stirred to homogeneous system;

(5) gel is sub-packed in the vaginal administration device, promptly.

3, the preparation method of clotrimazole gel preparation as claimed in claim 1 or 2 is characterized in that: gets the various raw materials of capacity (1) distilled water boiling sterilization ready, takes by weighing ethyl hydroxybenzoate 1.5g, be dissolved in the 2100ml80 ℃ of hot water, put and be chilled to 40 ℃, and standby;

(2) get carbomer 12g in addition, gradation is spread in the above-mentioned solution, is stirred to be uniformly dispersed, and leaves standstill 2h, and is standby;

(3) take by weighing triethanolamine 15g, slowly add in the above-mentioned solution with distilled water 420ml dilution back; Add glycerol again, be stirred to translucent homogeneous system, the white gel of having leisure;

(4) take by weighing clotrimazole fine powder 150g, evenly spread in the blank gel, be stirred to homogeneous system;

(5) gel is sub-packed in the vaginal administration device, promptly.