Pharmaceutical ointment without irritation to the skin and its preparation

 

(57) Abstract:

The invention relates to medicine and relates to pharmaceutical ointments, which does not irritate the skin. The invention lies in the fact that copper contains, wt%: piroxicam 0.5 to 10; hydrophobic carrier (s) 15 - 30; hydrophilic carrier (s) 60 - 75; additives (additives) of 0.1 - 10; emulsifiers consisting of poly(ethylene glycol)alkylboron or alkenilovyh simple ether and complex sorbitnogo ester or fatty oleic acid in a mass ratio 3:1 - 1: 3, 2 - 5. Proposed ointment has improved stabilnosti and has no harmful to skin, even with prolonged use. 2 S. and 4 C.p. f-crystals, 1 table.

The invention relates to pharmaceutical ointments that do not have irritant effect on the skin and containing 0.5 - 10 wt.% piroxicam, 15 to 30 wt.% hydrophobic media (media), 60 to 75 wt.% hydrophilic media (media) of 0.1 to 10 wt.% additives and emulsifiers, as well as the method of production of this ointment. The ointment, which is the subject of the invention has an extremely high local anti-inflammatory activity.

Piroxicam is an international non-proprietary name N-(2-estiem (U.S. patent N 3591584). Piroxicam can be effectively used for the local treatment of rheumatism in the form of pharmaceutical ointments.

Known spooling under which piroxicam dissolved in a mixture of water, ethanol and polyole(polyala), and consistency resembling ointment get using carboxyvinyl polymer used as a gelling agent [1]. Known exposure more like a gel than a cream, and its use has very adverse effects on the skin surface. It has a pH value in the region of 6.5 to 9.0, and thus, in some cases, pH is known spooling is much higher than the natural pH of the skin, namely 4 - 6. As indicated in the examples known exposure contains 25 to 40 wt.% ethanol, dissolve fat Horny layer of the skin. Thus, when using the known spooling surface of the skin becomes fragile. Therefore, if in the General case, the skin surface was treated systematically over a longer time-inflammatory preparation to prevent rheumatic conditions, are often caused by skin irritation due to the high ethanol content and adverse pH region.

WPI is MOU carbon and the stability of the composition provide 10 to 25 wt.% emulsifier [2].

With long-term treatment with high content of emulsifier causes similar "drying" effect on the skin surface that when using spooling with high ethanol content, is known from [1]. Another disadvantage cream spooling is that the original white cream yellow for a short time when stored at room temperature. This property of local compositions containing piroxicam was already noted in [1]. The color change is explained by the formation of hydrate of piroxicam in the presence of moisture. This product is yellow in color and reduces the absorption of piroxicam through the skin.

In addition, patients refuse to trust pharmaceutical compositions that change color during treatment.

The purpose of the invention is to provide pharmaceutical ointment containing piroxicam as an active agent, and the above-mentioned ointment has improved stability and that it does not become yellow during storage in General terms and is not dangerous to the skin even with prolonged use.

It was not primarily the acquisition, containing 0.5 - 10 wt. % piroxicam, 15 to 30 wt.% hydrophobic media (media), 60 to 75 wt. % hydrophilic media(media) of 0.1 to 10 wt.% additives(additives) and 2 to 5 wt.% emulsifiers consisting of:

1) poly(ethylene glycol) alkylboron or alkenilovyh simple ether;

2) of ester sorbitan fatty acids or oleic acid in a mass ratio of 3:1 to 1:3.

Hydrophobic carriers are known carriers having a hydrophobic character, pharmaceutical ointments, such as hydrocarbons, for example liquid paraffin or petrolatum; silicones, such as liquid poly(dimethylsiloxane); saturated or unsaturated alkanols with a long chain, for example cetyl alcohol, lauric alcohol, ministerului alcohol, stearyl alcohol or oleic alcohol; fatty acids, for example lauriola acid, maistrova acid, palmitic acid or stearic acid; esters, such as isopropyl myristate, isopropyl palmitate or vegetable oil; ethers, such as poly(propylene glycol); lanolin and so on, or mixtures thereof.

Preferred hydrophobic carriers are: liquid paraffin, petrolatum, fatty acids such as stearic acid, fatty alcohols such about the nature of pharmaceutical ointments, such as water or organic solvents, miscible with water, for example alcohols, preferably of polyole, such as glycerin, sorbitol, propylene glycol, liquid poly(ethylene glycol), etc. or mixtures thereof.

In the pharmaceutical ointments, which are the subject of the invention, the preferred hydrophilic carrier is water.

Additives are known additives for pharmaceutical ointments, such as agents that form the structural matrix, such as solid paraffin, ceresin, polyethylene, silicates, such as colloidal aluminum silicate or colloidal magnesium aluminum silicate, cholesterol, wax or palm wax; agents that increase the viscosity, for example colloidal silicon dioxide, agar, methylcellulose, carboxymethylcellulose, microcrystalline cellulose or carboxyvinyl polymers; preservative agents, such as alkyl, proxy-benzonate, butylacetyl, butylacetamide, benzyl alcohol, phenylethanol, sorbic acid, citric acid or a metal salt of the above acids; antioxidants, such as vitamin E; buffers; perfumery agents, etc.

The system of the emulsifiers of the invention is a mixture of two components in mass otnosheniia version poly(ethylene glycol) (C10-20alkilany or alkenilovyh) simple ether, in which poly(etilenglikolevye) residue consists, in General, 2-23 oxyethylene groups. Emulsifiers of this type are known under the trade name of, for example, Brij(R); preferred materials for ointments, which are the subject invention are the following:

Brij(R)56: poly(ethylene glycol) cetyl simple ether (degree of polymerization: 10) and/or

Brij(R)78: poly(ethylene glycol) stearyl simple ether (degree of polymerization: 20) and/or

Brij(R)58: poly(ethylene glycol) cetyl simple ether (degree of polymerization: 20) and/or

Brij(R)72: poly(ethylene glycol) stearyl simple ether (degree of polymerization: 2) and/or

Brij(R)35: poly(ethylene glycol) lauric simple ether (degree of polymerization: 23) and/or

Brij(R)92: poly(ethylene glycol) alerby simple ether (degree of polymerization: 2) and/or

Brij(R)96: poly(ethylene glycol) alerby simple ether (degree of polymerization: 10) and/or

Brij(R)98: poly(ethylene glycol) alerby simple ether (degree of polymerization: 20).

Another component of the mixture of emulsifiers in accordance with the present invention explicitly or triavir sorbitan. Emulsifiers of this type are known under the trade name of, for example, Span(R); preferred materials in accordance with the invention for the proposed pharmaceutical ointments are the following:

Span(R)20: monolaurate sorbitol, and/or

Span(R)40: monopalmitate sorbitan, and/or

Span(R)60: monostearate sorbent, and/or

Span(R)65: tristearate of sorbent, and/or

Span(R)80: monooleate sorbitan, and/or

Span(R)85: trioleate sorbitan.

Pharmaceutical ointment of the invention are produced by mixing a first hydrophobic holder(s), hydrophilic holder(s), additives(additives) and emulsifiers, and then stirred piroxicam with mixture. In a preferred embodiment, the piroxicam is used in micronized form.

In a preferred embodiment, proceed as follows:

a) on a separate stage, the hydrophobic carrier(s), ester sorbitan and additives dissolved only in the fatty phase, stirred while heating to a temperature not exceeding 80oC;

b) other additives, if any, and poly(etilenglikolevye) simple ester is dissolved in a hydrophilic carrier(carry is up with oily phase;

C) the mixture is cooled slowly adding piroxicam, then the ointment, the resulting, cooled to room temperature and fill in the appropriate containers, such as tubes.

Component poly(etilenglikolevykh) simple broadcast system emulsifiers in accordance with the invention can be mixed with a hydrophobic carrier(carriers) together with a complex ester sorbitan.

Unexpected is the fact that the system of emulsifiers in accordance with the invention is sufficient in amount of 2 to 5 wt.%, to provide a stable ointment, due to the fact that, in accordance with [2] requires the presence of at least 10 wt.% emulsifier, in order to avoid separation of the components of the ointment.

The stability of ointments, which are the subject of the invention corresponding to examples 1 to 6 were analyzed using the wrest them at 40oC for 12 weeks (this test is called "accelerated test for stability", as in practice, the pharmaceutical composition does not contain at a temperature of approximately 40oC). Not noted any discoloration or change in consistency of the samples ointment. The entire quantity of the ointment, extracted from the tube">

Pharmaceutical ointment, which is the subject of the invention corresponding to examples 1 to 6, and kept at room temperature for more than a year without reducing stability.

Unexpected was also the fact that the pharmaceutical ointment of the invention is not irritating to skin with prolonged treatment, as it was found that similar samples have essentially the same composition, but containing partially other emulsifiers, severely irritate the skin if skin irritation test.

This test used the adult males and females rabbits from New Zealand. At the beginning of the test, the body weight of animals was 2500 g of 20%. Rabbits were kept separately in cages for rabbits at a temperature of 20 3oC and a relative humidity of 50-70%. Animals were fed with standard feed for rabbits and watered with tap water without restrictions. Before the test the animals were observed for a period of weeks: body weight was determined and observed their behavior. For the tests were selected only healthy animals, no abnormal clinical symptoms. The day before the processing of the dorsal skin of the rabbit dailymobile on 3 areas, each of which has a size of 2.5 cm 3 is one of nepilirovanny areas of the dorsal surface of the skin was used as untreated control sample; another nepilirovanny area covered 100 mg test ointments; third nepilirovanny area covered 100 mg control ointment containing the active material, i.e. piroxicam (the last control ointment contained water instead of piroxicam). The same composition was tested on 6 rabbits. The treated area of skin covered with antiseptic pieces of gauze that was fixed with waterproof adhesive. After 4 h gauze pieces were removed and the treated area was washed away any remnants feel ointment using physiological salt solution. Such processing was carried out 14 times, every day, once a day, using the following composition:

a) ointment of example 1;

b) ointment of example 4;

in) ointment of example 5;

g) ointment of example 6.

Ointment used for comparison.

Their composition is consistent with the composition of example 1 with the difference that instead of a 1: 1 mixture of poly(ethylene glycol) of cetyl simple ether and monostearate sorbitan emulsifier system consisted of:

d) 2 wt. % poly(ethylene glycol) stearate (degree of polymerization: 3) (Myrj(R));

2 wt.% the monostearate sorbitan (Span(R)60);

e) 2 wt. % poly(ethylene glycol) stearate (the degree polymerization polymerization: 4) (Myri(R)53);

2 wt.% the monostearate sorbitan (Span(R)60);

C) wt.% poly(ethylene glycol) sorbitan of monolaurate (Tween(R)20);

2 wt.% the monostearate sorbitan (Span(R)60);

and 1 wt. % poly(ethylene glycol) stearate (degree of polymerization: 3) (Myrj(R)52);

1.5 wt.% poly(ethylene glycol) of cetyl simple ether (Brij(R)58);

1.5 wt.% the monostearate sorbitan (Span(R)60).

Changes on the dorsal surface of the animal skin or no change in the table.

No skin changes has not been established for the control of ointments, which correspond to the ointments (a), b) and C), but did not contain piroxicam.

In the case of the control of ointments, which correspond to the ointments g) - h), used for comparison, but do not contain piroxicam, the symptoms of inflammation can be detected on 1 or 2 days rather than the application itself compared preparaci.

No changes on the skin surface was not observed on areas that are of control and could not be processed.

From the table we can see that if the emulsifiers tested pharmaceutical ointments consist of a system of emulsifier in accordance with the invention, negatory differ from the system of emulsifier, used in accordance with the invention, it is possible to find serious skin irritation. This skin irritation can be attributed to the presence of piroxicam, as in the case of the control of the ointments used for comparison, the irritation starts earlier.

Thus, pharmaceutical ointment is the subject of the invention has no irritant effect on the skin and remains stable for a long time.

Example 1. Received pharmaceutical ointment having the following composition, g:

Piroxicam (micronized) - 1,0

Methyl para-oxybenzoic - 0,1

Brij(R)58 [poly(ethylene glycol)cetyl simple ether - 2,0

Water (distilled) - 71,9

Stearic acid - 3,0

Paraffin (liquid) to 12.0

Cetyl stearic alcohol - 3,0

Vaseline (white) - 5,0

Span(R)60 (monostearate sorbitan) - 2,0

Total - 100,0

White vaseline, liquid paraffin, monostearate sorbitan and cetyl stearyl alcohol was transferred into a suitable crucible and melted at 80oC, to obtain the fatty phase. Methyl para-oxybenzoic and poly(ethylene glycol)cetyl simple ether was dissolved in distilled water at 90ooC and it was filled tubes.

The pH of the water, which was shaken together with a specimen of the ointment, the resulting equivalent 4,43.

Example 2. Received pharmaceutical ointment having the following composition, g:

Piroxicam (micronized) - 1,0

Methyl para-oxybenzoic - 0,1

Brij(R)78 [poly(ethylene glycol)stearyl simple ether] - 2,4

Water (distilled) - 71,9

Stearic acid - 3,0

Paraffin (liquid) to 12.0

Cetyl stearyl alcohol - 3,0

Vaseline (white) - 5,0

Span(R)85 (Triolet sorbitan) - 1,6

The components were mixed as described in example 1 with the difference that only methyl para-oxybenzoic was dissolved in distilled water, and poly(ethylene glycol) stearyl simple ether was added directly to the components of the oily phase before melting.

Knowledge of the pH of the water, which was dissolved in a sample obtained ointments are 5.36 equivalent.

Example 3. Pharmaceutical ointment having the following composition (g), obtained as described in example 1:

Piroxicam (This ether] - 2,1

Water (distilled) was 72.9

Stearic acid - 3,0

Paraffin (liquid) to 12.0

Cetyl stearyl alcohol - 3,0

Vaseline (white) - 5,0

Span(R)65 (monostearate sorbitan) - 0,9

Total - 100,0

The pH of the water, which was dissolved in a sample obtained ointment, equivalent 4,91.

Example 4. Pharmaceutical ointment having the following composition (g), obtained as described in example 1:

Piroxicam (micronized) - 10,0

Propyl para-oxybenzoic - 0,1

Brij(R)[poly(ethylene glycol)lauric simple ether] - 1,5

Water (distilled) - 62,1

Stearic acid - 3,0

Paraffin (liquid) to 12.0

Cetyl stearyl alcohol - 3,0

Vaseline (white) - 5,0

Span(R)20 (monolaurate sorbitan) - 3,3

Total - 100,0

The pH of the water, which was dissolved in a sample obtained ointment, equivalent to 5.13.

Example 5. Pharmaceutical ointment having the following composition (g), obtained as described in example 1:

Piroxicam (micronized) - 5,0

Methyl para-oxybenzoic - 0,2

Brij(R)96 [poly(ethylene glycol) oleic simple ether] - 1,0

Water (distilled) - 69,8

Stearic acid - 3,0

Paraffin (liquid) to 12.0<1,0

Total - 100,0

The pH of the water which was dissolved in a sample obtained ointment, equivalent 4,36.

Example 6. Pharmaceutical ointment having the following composition (g), obtained as described in example 1;

Piroxicam (micronized) - 1,0

Methyl para-oxybenzoic - 0,1

Brij(R)56 [poly(ethylene glycol) cetyl simple ether] - 3,1

Water (distilled) is 71.5

Stearic acid - 3,0

Paraffin (liquid) to 12.0

Cetyl stearyl alcohol - 3,0

Vaseline (white) - 5,0

Span(R)80 (monostearate sorbitan) - 1,3

Total - 100,0

The pH of the water, which was dissolved in a sample obtained ointment, equivalent 5,12.

1. Anti-inflammatory ointment, not having irritating to the skin, containing piroxicam, hydrophobic carriers, water, additive and emulsifier, wherein the emulsifier consists of alkylboron or alkenilovyh ether of polyethylene glycol and complex sorbitnogo ester or fatty oleic acid in a mass ratio of 3 : 1 to 1 : 3 in the following ratio, wt.%:

Piroxicam - 0,5 - 10,0

Hydrophobic media - 15,0 - 30,0

Water - 60,0 - 75,0

Supplements - 0,1 - 10,0

Emulsifier - 2,0 - 5,0

2. Ointment under item 1, the OIC or alkenilovyh chain and 2 - 23 group oxyethylene.

3. Ointment on p. 2, characterized in that the ether is etilovym, stearyl or lauralover.

4. Ointment on p. 2, characterized in that alkenilovyh ether is alerby.

5. Ointment p. 1, wherein the fatty acid is stearic or palmitic.

6. The method of obtaining anti-inflammatory ointment, not having irritating to the skin by mixing a hydrophobic carrier, water, additives and emulsifiers when heated to a temperature not exceeding 80oC, with subsequent adulteration to the resulting mixture piroxicam, characterized in that the mixed hydrophobic carrier in the amount of 15 to 30 wt.%, water in the amount of 60 to 75 wt.%, additives in an amount of 0.1 - 10.0 wt.% and emulsifier comprising alkilany or alkenilovyh ether of polyethylene glycol and complex arbitarily ether or fatty oleic acid in a mass ratio of 3 : 1 to 1 : 3 in an amount of 2 to 5 wt.% and piroxicam in the amount of 0.5 to 10.0 wt.%.

 

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