JPH0621061B2 - Clear gel formulation containing urea stably - Google Patents

Description

TECHNICAL FIELD The present invention relates to a transparent gel preparation containing urea stably. More specifically, the present invention provides a moisturizing action,
It has a proteolytic effect, a pharmacological action such as an antibacterial action, and contains urea as an active ingredient whose external preparation is widely used in the dermatological field as a therapeutic drug for atopic eczema, keratosis, ichthyosis, etc., The present invention relates to a transparent gel preparation having improved urea stability.

(Prior art and its problem) As described above, urea has a moisturizing action, a pharmacological action such as an antibacterial action, and it is known to mix it into an external preparation. It is a volatile compound that gradually decomposes in an aqueous solution to produce carbon dioxide and ammonia. Similarly, when urea is added to a cream or gel base, carbon is gradually decomposed, and the cream or gel is deteriorated. In particular, when filled in a tube, the tube may expand and the contents may fly out depending on storage conditions, or in severe cases, the tube may burst and lose commercial value.

In particular, in the case of a gel base, it is difficult to suppress the decomposition of urea because the amount of water is usually large.

As a gel preparation for the purpose of containing such urea stably, with carboxyvinyl polymer,
An ammonium compound is added as a stabilizer for urea, and p
An example in which H is set to 5.5 to 7.5 is known (JP-A-59-59).
However, even in this case, the stabilization of urea was not sufficient, and p was caused by ammonia, which is a decomposition product of urea.
The reality is that the rise in H is not suppressed.

Therefore, an object of the present invention is to solve the above-mentioned drawbacks of the conventional techniques and to provide a new transparent gel preparation containing urea, which can further improve the stability of urea.

(Means for Solving the Problems) In order to solve the above problems, the present invention provides 0.5 to 30% by weight of urea as an active ingredient, 25 to 80% by weight of a polyhydric alcohol as a base, and a carboxyvinyl polymer.
0.1-5% by weight, inorganic or organic basic substance 0.02-3
Provided is a transparent gel formulation consisting of wt% and water 20-70 wt%. That is, the present invention improves the stability of urea in the gel base by using carboxyvinyl polymer as a gelling agent, reducing the amount of water as much as possible, and instead adding a large amount of polyhydric alcohol. Is.

Although the mechanism of action of urea stabilization in the gel base of the present invention is not clear, (1) a salt consisting of a carboxyvinyl polymer and a base serves as a buffer to suppress an increase in pH.

(2) A large amount of polyhydric alcohol instead of water acts to suppress hydrolysis of urea.

It seems that it is due to the reasons such as.

Urea, the active ingredient of the gel formulation of the present invention, is 0.5 to 30
It is blended by weight%. If it is less than 0.5% by weight, the moisturizing effect of urea will not be exhibited, and if it is more than 30% by weight, problems such as precipitation of urea bonds will occur, which is not preferable in terms of formulation. Also,
In the gel preparation of the present invention, the active ingredient is urea having the above-mentioned mixing ratio, but in addition to this urea, steroidal anti-inflammatory agents such as clobetasol propionate, betamethasone oxalate, and fluocinonide, indomethacin, ketoprofen. , Flurbiprofen, sulprofen, loxoprofen sodium, ibuprofen,
A non-steroidal anti-inflammatory agent such as felbinac, or an antibacterial agent such as tolnaftate or clotrimazole is added together in an appropriate ratio to provide a more useful preparation as a therapeutic agent for skin diseases.

To describe the base component in more detail, first, a polyhydric alcohol is added as a moisturizing agent. Examples of such polyhydric alcohol include, for example, propylene glycol, glycerin, polyethylene glycol,
Examples thereof include 1,3-butylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polypropylene glycol, polyglycerin, and sorbitol aqueous solution. Among them, glycerin is most suitable from the viewpoint of skin irritation. The amount of these polyhydric alcohols is 25 to 80% by weight as described above, but preferably 35 to 55% by weight. Carboxyvinyl polymer blended as a gelling agent is a water-soluble polymer, for example, Carbopol 934, 940, 941 from Goodrich Chemicals, or Hibis Wako 103, 104, 105 from Wako Pure Chemical Industries. Etc. are commercialized and are selected according to the prescription. The content of the carboxyvinyl polymer is 0.1 to 5% by weight, preferably 0.3 to 5% by weight, in consideration of physical heat stability, transparency, consistency, and feeling of use of the gel preparation.
~ 1.5% by weight.

The inorganic or organic basic substance is added to adjust the pH, and specifically, sodium hydroxide,
Examples include inorganic bases such as potassium hydroxide and aqueous ammonia, and organic bases such as triethanolamine, diethanolamine, diisopropanolamine, triisopropanolamine, and arginine. Of these, organic bases are particularly preferable.

The blending amount of these inorganic or organic basic substances is adjusted so that the pH of the gel preparation is 3 to 9, preferably 6 to 8.
It is added in the range of 02 to 3%. Furthermore, although the blending amount of water is appropriately adjusted depending on the other base, 20 to 70% by weight, preferably 35 to 55% by weight is blended.

In addition to the essential components, auxiliary components such as antiseptics, oily components and antioxidants can be appropriately added to the transparent gel preparation of the present invention as described above. As the preservative, methylparaben, ethylparaben, propylparaben, butylparaben, thymol, chlorcresol, orthophenylphenol, isopropylmethylphenol, pionine and the like are mixed in a concentration range usually used. The oily component is mixed for the purpose of improving the feeling of use, and examples thereof include isopropyl palmitate, butyl stearate, isopropyl myristate and diethyl phthalate.
Esters such as myristyl lactate, diisopropyl adipate, cetyl myristate, cetyl lactate, etc., higher alcohols such as 2-hexyldecanol, oleyl alcohol, 2-octyldodecanol, hydrocarbons such as squalane, liquid paraffin, eucalyptus oil, mint oil, olive oil,
Oils and fats such as avocado oil and jojoba oil, as well as benzyl alcohol, phenylethyl alcohol, crotamiton, etc. are added in a concentration range that does not impair the transparency of the gel preparation.

As the antioxidant, dibutylhydroxytoluene,
Erythorbic acid, d1-α-tocopherol and the like can be mentioned.

In order to produce a gel preparation containing the urea of the present invention having the above-described composition, first, a carboxyvinyl polymer is dissolved in water, a polyhydric alcohol is added to the solution, and the mixture is stirred. Add an aqueous solution of the substance slowly and stir until homogeneous. Next, an aqueous solution in which urea is dissolved is added, and the mixture is stirred until it becomes even. The order of the manufacturing steps in the above method is not particularly limited, and similar manufacturing is possible even if part of the order is changed.

Examples and test examples will be shown below to explain the transparent gel preparation of the present invention in more detail.

Example 1 0.7 g of carboxyvinyl polymer was added to 31 g of water and dissolved by stirring. To this, 42.6 g of glycerin and 0.2 g of methylparaben were added and stirred. Next, a solution prepared by dissolving 0.5 g of diisopropanolamine in 5 g of water was added and stirred. Next, a solution prepared by dissolving 10 g of urea in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a transparent gel preparation containing urea.

Example 2 0.6 g of carboxyvinyl polymer was added to 28 g of water and dissolved by stirring. To this, 45 g of glycerin and 0.2 g of methylparaben were added and stirred. Next, a solution prepared by dissolving 1 g of arginine and 0.2 g of triethanolamine in 10 g of water was added to this and stirred. Next, 10g of urea and 7g of water
The solution dissolved in was added and stirred until uniform to obtain a urea-containing transparent gel preparation.

Example 3 0.8 g of carboxyvinyl polymer was added to 16.6 g of water and dissolved by stirring. 58 g of glycerin, 2 g of propylene glycol, 0.2 g of methylparaben and 0.0 of pionine.
02 g was added and stirred. Next, a solution prepared by dissolving 0.5 g of triethanolamine in 5 g of water was added and stirred. Next, a solution prepared by dissolving 10 g of urea in 5 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a transparent gel preparation containing urea.

Example 4 1 g of carboxyvinyl polymer was added to 20 g of water and dissolved by stirring. 47g of glycerin and methylparaben
0.15 g, propylparaben 0.03 g and diisopropyl sebacate 1 g were added and stirred. Next, 5 g of a 1% sodium hydroxide solution was added to this and stirred. Next, a solution prepared by dissolving 10 g of urea in 5.82 g of water was added thereto and stirred until uniform to obtain a urea-containing transparent gel preparation.

Example 5 0.7 g of carboxyvinyl polymer was added to 27.13 g of water and dissolved by stirring. To this, 61 g of glycerin, 0.13 g of methylparaben and 0.05 g of propylparaben were added and stirred.
Next, add 0.7 g of diisopropanolamine to 10 parts of water.
A transparent gel preparation was obtained by adding the solution dissolved in g and stirring the mixture until uniform.

A solution prepared by dissolving 10 g of urea in 20 g of water was added to the transparent gel base and stirred until uniform to obtain a urea-containing transparent gel preparation.

Example 6 0.85 g of carboxyvinyl polymer was added to 26.5 g of water and dissolved by stirring. 50 g of glycerin, 2 g of propylene glycol, and 0.15 g of methylparaben were added to this and stirred. Next, add 0.6g of triethanolamine to 5g of water.
Was added and the solution was stirred. Next, add 5g of urea
Was added to 10 g of water, and the mixture was stirred until it became uniform to obtain a urea-containing transparent gel formulation.

Example 7 1 g of carboxyvinyl polymer was added to 20.4 g of water and dissolved by stirring. 45 g of 1,3-butylene glycol
And 0.1 g of methylparaben were added and stirred. Next, a solution prepared by dissolving 0.5 g of triisopropanolamine in 5 g of water was added thereto and stirred. Next, add 15 g of urea to 1 part of water.
A solution dissolved in 3 g was added and stirred until uniform to obtain a urea-containing transparent gel preparation.

Example 8 1.5 g of carboxyvinyl polymer was added to 27.13 g of water and dissolved by stirring. To this, 61 g of glycerin, 0.13 g of methylparaben and 0.05 g of propylparaben were added and stirred.
Next, a solution prepared by dissolving 0.7 g of triethanolamine in 10 g of water was added thereto, and the mixture was stirred until it became uniform to obtain a transparent gel base. To 60 g of this transparent gel base, 20 g of urea is added to 2 parts of water.
A solution dissolved in 0 g was added and stirred until uniform to obtain a urea-containing transparent gel preparation.

Reference Example 1 Take 25 g of white petrolatum, 20 g of stearic alcohol, 60.4 g of polyoxyethylene hydrogenated castor oil and 1 g of glyceryl monostearate, heat on a water bath to dissolve,
Stir and keep at about 75 ° C. To this, 0.1 g of methylparaben and 0.1 g of propylparaben were added in advance to 12 g of propylene glycol to dissolve them, and 27.8 g of water was added thereto, and a liquid heated to 75 ° C. was added and stirred. While stirring, the mixture was cooled to 45 ° C., and 10 g of urea was added thereto.
The solution dissolved in g was added, and the mixture was further stirred and cooled until it became a creamy form to obtain a urea-containing cream preparation.

Reference Example 2 A transparent gel preparation having the same formulation composition as in Example 1 except that glycerin was omitted was produced.

Reference Example 3 In Example 7, a transparent gel preparation having the same formulation composition except that 1,3-butylene glycol was removed was produced.

Test Example 1 (Urea Thermal Stability Test) The thermal stability of urea was examined for the gel preparation of Example 1, the cream preparation of Reference Example 1 and the cream preparation containing 10% of commercially available urea.

(Test Method) Each formulation filled in a 10 g tube was stored at 40 ° C., and the pH value of each formulation was measured over time, and the change in appearance was observed.

As can be seen from the results in Table 1, since the urea-containing gel preparation of the present invention has better urea stability than the cream preparation of Reference Example 1 and the commercially available cream preparation, the change in pH value is very small, and No swelling of the tube was observed.

Test Example 2 The gel preparation of Example 1, the gel preparation of Reference Example 2 which is a gel preparation obtained by removing glycerin from Example 1, and Example 7.
The stability test of urea was performed on the gel preparation of Example 1 and the gel preparation of Reference Example 3 in which 1,3-butylene glycol was removed from the gel preparation of Example 7.

(Test Method) Each formulation filled in a 10 g tube was stored at 50 ° C., and the amount of urea in each formulation was measured over time by a liquid chromatograph method to determine the residual rate relative to the initial value. The results are shown in Table 2.

(Urea quantification method) 1.0 g of the gel preparation was precisely weighed and shake-extracted with 35 ml of an acetonitrile / water mixture (6: 4) for 30 minutes. This solution was transferred to a volumetric flask and mixed with acetonitrile / water (6:
4) was adjusted to 50 ml, 10 ml of this solution was accurately weighed to 50 ml with an acetonitrile / water mixture (6: 4), and the test was carried out by the liquid chromatography method under the following conditions.

Operating conditions; Detector: UV absorptiometer (Measurement wavelength: 203
nm) column: 5 μm in diameter with aminopropyl group as a packing material in a stainless steel column having an inner diameter of about 6 mm and a length of about 15 cm.
m silica gel.

Temperature: Constant temperature around 40 ° C Mobile phase: A mixture of acetonitrile and water (8: 2) Flow rate: Adjust so that the retention time of urea is about 5 minutes.

As can be seen from the results in Table 2, the gel formulations of the present invention shown in Examples 1 and 7 are more stable than the gel formulations of Reference Examples 2 and 3 containing no polyhydric alcohol when stored at 50 ° C. Was excellent. When commercialized, the residual rate is required to be 90% or more at room temperature for 3 years, but the gel preparation of the present invention is 94 ° C in accelerated aging test at 50 ° C for 1 month.
It shows a residual rate of ~ 95%, and it is considered that there is no problem in storage at room temperature for 3 years. On the other hand, the gel formulations of Reference Examples 2 and 3 are 5
The residual rate is already below 90% at 0 ° C for one month, and the stability at room temperature for 3 years cannot be maintained.

Test Example 3 (Skin irritation test) The gel preparation of Example 1 and the cream preparation of Reference Example 1 were subjected to a patch test in healthy adult males.

(Test Method) A closed batch was performed on the back of a healthy adult male for 48 hours using a Fin chamber and a scanport tape.

The results are shown in Table 3.

(Effect of the invention) As described in detail above, the urea-containing gel preparation of the present invention contains urea in a stable manner. There is no change in appearance. In addition, since carboxyvinyl polymer is blended as a gelling agent, it has good thermal stability and very little change in viscosity and consistency over time. Since it does not contain a base having strong skin irritation, it also has an advantage that the irritation to the skin is very weak and the safety is high.

Since the gel preparation of the present invention has an excellent moisturizing property, it can be used as a therapeutic agent for keratoses, ichthyosis, atopic dermatitis, senile xerosis and the like. In addition, it is excellent in transparency, stable, and has a good feeling in use, so that it can be applied as a base material for cosmetics, quasi drugs, or pharmaceuticals. In particular, the addition of an anti-inflammatory agent or an antibacterial agent is more useful because urea acts as an absorption promoter or action promoter.

From the above, the gel preparation of the present invention has an industrially useful effect as a cosmetic, a quasi drug, a drug, or a base thereof.

 ─────────────────────────────────────────────────── --Continued from the front page (56) References JP-A-59-20217 (JP, A) JP-A-58-150509 (JP, A) JP-A-59-62518 (JP, A) JP-B-56- 30327 (JP, B2) Pharmaceutical Additives Study Group Practical Pharmaceutical Additives P. 5 Published by Kagaku Kogyo Co., Ltd. (1974) New Formulation Development System Comprehensive Technology-Bases and Additives-P. 50 R & D planning issued (1985)

Claims (1)

[Claims] 1. 0.5 to 30% by weight of urea as an active ingredient
And 25 to 80% by weight of a polyhydric alcohol as a base, 0.1 to 5% by weight of carboxyvinyl polymer, 0.02 to 3% by weight of an inorganic or organic basic substance, and 20 to 70% of water.
A transparent gel formulation consisting of 10% by weight.