CN102525904B - Stable felbinac gel and preparation method thereof - Google Patents

Abstract

The invention relates to a stable felbinac preparation, in particular to stable felbinac gel and a preparation method of the stable felbinac gel. Trolamine is used as pH conditioning agents and solubilizers, glycerol is used as dissolving assisting, moisture preservation, stability and absorption promoting agents and ethanol and water are used as solvents for forming a solvent system to be combined with a preparation process, so few relevant substances are degraded in the felbinac preparation process, and the finally prepared felbinac gel has the advantages that the color and luster are translucent, pure white effect, stability and no stimulation are realized, and the prepared felbinac gel is suitable for industrial production.

Description

A kind of stable felbinac gel and preparation method thereof

Technical field

The present invention relates to a kind of stable felbinac preparation, further relate to a kind of stable felbinac gel and preparation method thereof.

Background technology

Felbinac (Felbinac) is NSAID (non-steroidal anti-inflammatory drug) (NSAID), it is the active metabolite of fenbufen (Fenbufen), be widely used in osteoarthrisis deformans knee, scapulohumeral periarthritis, tenosynovitis, tennis elbow, peritendinitis, myalgia clinically, the easing pain and diminishing inflammation of soft tissue injury, traumatic swelling pain etc.Can cause gastrointestinal upset during oral NSAID, but transdermal administration can be avoided above untoward reaction effectively.At present, some percutaneous absorption type NSAID that abroad gone on the market are noticeable, and the felbinac ointment (3%) that goes on the market in Japan is exactly one of them.Felbinac ointment is developed by Pfizer, and trade name was first in Japan's listing in 1986 Be applied to affected part in right amount 2 to 4 times every day.Felbinac ointment is directly brought into play drug effect at target site by a kind of drug delivery, it is applied to pars affecta skin, the felbinac of effective dose is soaked into be diffused into pathological tissues, the easing pain and diminishing inflammation effect that performance is local, avoided the systemic side effects such as gastrointestinal tract disorder of oral NSAID, its effectiveness and safety obtain clinical extensive approval.

Ointment selects for use diisopropanolamine (DIPA) and an amount of ethanol/water as solvent system, and wherein diisopropanolamine (DIPA) is carbomer as pH regulator agent, ethanol/water as solvent, ointment base.The said preparation composition is used and is promoted in China and is subject to many limitations, and on the one hand, diisopropanolamine (DIPA) does not have legal source in China, is not suitable for final production and the listing of medicine; Carbomer is the strongest in pH6～12 o'clock viscosity on the other hand, contradicts with the dissolubility of felbinac; Moreover, felbinac is as nonsteroidal antiinflammatory drug, to wet, heat is responsive, and the gelation process of carbomer must just can be finished by heating, in this process, need heating to impel the quick and complete swelling of gel to shorten the manufacturing cycle of product on the one hand, the physicochemical property of considering felbinac self on the other hand must guarantee principal agent stability again, and its related substance is not significantly improved in preparation process, and this is a technological challenge beyond doubt to one skilled in the art.

Summary of the invention

The object of the present invention is to provide a kind of few solvent composition of principal agent felbinac catabolite in preparation process of guaranteeing.

The object of the present invention is to provide that a kind of appearance character is excellent, stable good, the felbinac gel that is fit to suitability for industrialized production of the quality of the pharmaceutical preparations.

The object of the present invention is to provide the preparation method of above-mentioned felbinac gel.

A first aspect of the present invention is to provide a kind of few solvent composition of felbinac catabolite in preparation process of guaranteeing, this solvent composition is glycerol, triethanolamine, ethanol-water solution.Wherein triethanolamine plays pH regulator agent and the felbinac solubilising of gel, and glycerol plays solubilising, stablizes, preserves moisture, promotes absorbent, and alcohol-water is solvent, and concentration of ethanol has played antibacterial antiseptical effect.

Above-mentioned solvent system is characterised in that: the concentration of glycerol is 2～5%, and the concentration of triethanolamine is 3.6～6.5%, and alcoholic solution is selected from 30～50% alcoholic solution.

Through contrasting with diisopropanolamine (DIPA)-ethanol/water system, the stability of felbinac in solvent system of the present invention obviously is better than the latter.Its advantage is the system stability of preparation, is in particular in that preparation has good appearance character: placed 10 days for 0～4 ℃ at 60 ℃ of high temperature and low temperature, and not stratified; Principal agent is non-crystallizable separates out invariant color.Its related substances is lower and have a higher Transdermal absorption curative effect.

Second aspect of the present invention provides a kind of prescription of stable felbinac gel and forms and preparation method thereof.

Described felbinac gel is characterized in that the prescription of this gel consists of felbinac, carbomer 934, triethanolamine, glycerol, ethanol and water.

Described felbinac gel, it is composed as follows to it is characterized in that writing out a prescription, and is that 100g is in the prescription gross weight:

The preparation method of described felbinac gel is characterized in that being that this preparation method may further comprise the steps:

1. the carbomer of recipe quantity is put in an amount of purified water, abundant swelling adds the glycerol of recipe quantity, stirs, and the triethanolamine that adds half amount more fully stirs and makes into blank gel, and is standby;

2. the felbinac of recipe quantity is put in an amount of 30～50% ethanol, added the surplus triethanolamine, stirring and dissolving;

3. medicinal liquid is slowly poured in the blank gel, and incorporated into gel with ethanol water flushing and add to full dose, constantly stir;

4. flexible pipe sterilization, standby;

5. product are measured pH value and content in the middle of;

6. filling sleeve;

7. inspection entirely, packing, warehouse-in.

The advantage that the present invention gives prominence to is to have developed gel at the existing issue of felbinac ointment formulation, by selecting good solvent system, namely adopt triethanolamine be pH regulator agent and solubilizing agent, glycerol as solubilising, preserve moisture, stable and absorption enhancer, ethanol/water as the solvent system of solvent composition in conjunction with preparation technology, make felbinac related substance degraded in preparation process less, the felbinac gel color and luster that finally makes is translucent, pure white, stable, non-stimulated, is suitable for suitability for industrialized production.

The specific embodiment

Further specify the present invention by the following examples, but do not limit summary of the invention.

The stability of embodiment one felbinac in different basifier system

Kind and the consumption of table 1 felbinac gel organic amine

As seen from the above table: 1. since monoethanolamine than large usage quantity, intrinsic colour is darker, prepare for yellow translucent, because the color of solution can influence the color of gel.And diisopropanolamine (DIPA), triethanolamine consumption are less relatively, and intrinsic colour is shallow, and the gel outward appearance of making is better than monoethanolamine.Triethanolamine is than the diisopropanolamine (DIPA) medicinal specification that more is easy to get, and the source cost that is easy to get is lower, is final selection therefore.2. the adding of ethanol has improved dissolubility and the dissolution velocity of felbinac, has synergism, and 20% ethanol has antibiotic antisepsis concurrently simultaneously, is the composition of stablizing and simplifying of this gel systems.

Embodiment two carbomer 934 consumptions are selected

The consumption of table 2 carbomer 934 is determined

Carbomer 934 concentration is 1.0～1.2%, best 1.2%.Less than this ratio, gel viscosity is not enough, and smearing the thin local application of medicine layer drug level can't guarantee.Increase for the time of production gelation greatly greater than this ratio, be unfavorable for producing and realize.This gel is piece grain even, fine and smooth, no cementation, keeps gluey when room temperature, does not dry up and does not liquefy.

Embodiment three cutaneous permeable agent kinds and consumption are selected

Table 3 cutaneous permeable agent kind and consumption are determined

The result shows, 1. when in the prescription when no ethanol and glycerol, transdermal absorption factor is below 1%, and when containing in the gel when having an appointment 40% ethanol and 2% glycerol, transdermal absorption factor is increased to about 19%, and the raising effect is obvious; 2. after adding azone, transdermal absorption factor does not have significant change, in view of glycerol preserve moisture and with the collaborative hydrotropy effect of triethanolamine, short cutaneous permeable agent selects for use the glycerol consumption to select 2% at least.

The related substance contrast of embodiment quaterphenyl acetic acid in the different solvents system

According to the detection method in the felbinac gel quality affects standard in the British Pharmacopoeia, the stability of felbinac in the different solvents system is investigated.

Table 4 related substance contrast test solvent for use system

Annotate: felbinac is 3.0g in the amount of every kind of solvent system, and 50% ethanol adds to 100g.

The stability of table 5 felbinac in the different solvents system

The stability of the content of felbinac in solvent system B, related substance, pH value all is better than solvent system A.

Prescription and the preparation technology of embodiment quinquephenyl acetic acid gel

Prescription is formed: gross weight is that 100g is to write out a prescription

The optimizing prescriptions of table 6 felbinac gel

Preparation technology:

1. the carbomer of above-mentioned recipe quantity is put in an amount of purified water, abundant swelling adds the glycerol of recipe quantity, stirs, and the triethanolamine that adds half amount more fully stirs and makes into blank gel, and is standby;

2. the felbinac of recipe quantity is put in an amount of 30%～50% ethanol, added the surplus triethanolamine, stirring and dissolving;

3. medicinal liquid is slowly poured in the blank gel, and incorporated into gel with ethanol water flushing and add to full dose, constantly stir;

4. flexible pipe sterilization, standby;

5. product are measured pH value and content in the middle of;

6. filling sleeve;

7. inspection entirely, packing, warehouse-in.

Embodiment six felbinac gel influence factors test

Get test preparation 1 and reference preparation 1 (

Ointment, 3%) an amount of sample was placed 10 days under low temperature (about 4 ℃) high temperature (40 ℃, 60 ℃), high humidity (RH75%, RH92.5%) and illumination (4500lx) condition respectively, and in the 10th day take a sample to check pH value, content and related substance, the result was as follows:

Table 7 felbinac gel influence factor result of the test

Annotate: character: under 4 ℃, it is that white is translucent that sample is placed 10 days gels, not layering, and principal agent is crystallize not; Under 60 ℃, sample is placed 10 days gels and is become faint yellow; Under 40 ℃, sample is placed 10 days outward appearances significant change.

The result shows that test preparation and reference preparation unification show the temperature and humidity sensitivity, and related substance changes more obvious, but the test preparation amplitude of variation is significantly less than reference preparation, and from the result, test preparation is better than reference preparation.

Embodiment seven felbinac gel accelerated stability tests

It is an amount of to get test preparation 1 sample, 30 ± 2 ℃ of temperature, carries out accelerated stability test under 65 ± 5% conditions, takes a sample in 0 month, 1 month, 2 months, 3 months, 6 months and carries out the mensuration of character, pH value, content and related substance, and the result is as follows:

Table 8 felbinac gel accelerated stability result

Comprehensive above-mentioned result of the test can draw, the felbinac gel adopts that triethanolamine, glycerol, ethanol/water are excellent as the product appearance character that solvent system and corresponding preparation technology make, quality stability good, related substance is few, compares existing product and has a clear superiority in.

Claims (3)

1. solution that comprises felbinac, it is characterized in that this solution composition is felbinac, glycerol, triethanolamine, ethanol-aqueous solution, wherein, the concentration of felbinac is 3%, the concentration of glycerol is 2 ~ 5%, the concentration of triethanolamine is 3.6 ~ 6.5%, and alcoholic solution is selected from 30 ~ 50% alcoholic solution.

2. stable felbinac gel, the gross weight that it is characterized in that writing out a prescription be 100g for counting, the prescription of this gel is composed as follows:

Felbinac 3g

Carbomer 934 1.0 ~ 1.2g

Glycerol 2 ~ 5g

Triethanolamine 3.6 ~ 6.5g

30 ~ 50% ethanol add to 100g.

3. the preparation method of felbinac gel according to claim 2 is characterized in that may further comprise the steps:

1. the carbomer of recipe quantity is put in an amount of purified water, abundant swelling adds the glycerol of recipe quantity, stirs, and the triethanolamine that adds half amount more fully stirs and makes into blank gel, and is standby;

2. the felbinac of recipe quantity is put in an amount of 30 ~ 50% ethanol, added the surplus triethanolamine, stirring and dissolving;

3. medicinal liquid is slowly poured in the blank gel, and incorporated into gel with ethanol water flushing and add to full dose, constantly stir;

4. flexible pipe sterilization, standby;

5. product are measured pH value and content in the middle of;

6. filling sleeve;

7. inspection entirely, packing, warehouse-in.