JPS63166825A - Clear gel drug preparation containing urea in stable state - Google Patents

Abstract

PURPOSE:To obtain a gel drug preparation containing urea in stable state, storable over a long period with extremely low pH variation and having high safety, by using a combination of a polyhydric alcohol, a carboxyvinyl polymer, a pH modifier and water as a base. CONSTITUTION:(A) 0.5-30wt.% urea is used as an active component and compounded with a base consisting of (B) 25-80% (especially 35-55%) polyhydric alcohol (preferably glycerol from the view point of skin stimulation), (C) 0.1-5% carboxyvinyl polymer, (D) 0.02-3% (especially 0.3-1.5%) pH modifier, preferably an organic base such as triethanolamine, arginine, of an amount to control the pH of the composition to 3-9, preferably 6-8 and (E) 20-70% (especially 35-55%) water. The gel preparation is useful as a remedy for hyperkeratosis, ichythyosis, atopic dermatitis, senile xeroderma, etc. It can be used as a cosmetic, quasi-drug, drug or their base.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a transparent gel preparation stably containing urea. More specifically, the present invention relates to a transparent gel preparation that contains urea as an active ingredient and has improved stability of urea. Urea has pharmacological effects such as moisturizing, proteolytic and denaturing, and antibacterial effects, and topical preparations containing urea are effective against atopic eczema.

Keratosis, fish! It is widely used in the field of dermatology as a therapeutic agent for conditions such as /i wandering.

(b) Problems to be Solved by the Present Invention Urea is a water-soluble compound, but it gradually decomposes in an aqueous solution to produce carbon dioxide gas and ammonia.

Similarly, when urea is added to a cream or gel base, urea gradually decomposes, resulting in deterioration of the quality of the cream or gel. In particular, when filled into a tube, depending on the storage conditions, the tube may expand and the contents may spill out, or in severe cases, the tube may burst and lose its commercial value.

In particular, since gel bases usually contain a large amount of water, it is difficult to suppress the decomposition of urea.

(c) Conventional technology The prior art of gel preparations containing urea is
9-20217 discloses an example in which an ammonium compound is blended as a stabilizer for urea, but even with this method, urea is not stabilized sufficiently, and ammonia, which is a decomposition product of urea, is The upper bound of pH is not suppressed. The transparent gel preparation containing urea of the present invention can achieve urea stability without adding special additives, and is completely different from conventional urea stabilization methods. be.

(d) Means for Solving the Problems The present inventors have conducted various studies on gel bases that keep urea stable, and as a result, they have developed carboxyvinyl polymer.

The present invention was completed based on the discovery that stabilization of urea can be achieved with a simple combination of polyhydric alcohol, pH adjuster, and water. That is, by using a carboxyvinyl polymer as a gelling agent, minimizing the amount of water blended, and blending a large amount of polyhydric alcohol instead, stability of urea in the gel base could be achieved.

Although the mechanism of action of stabilizing urea in the gel base of the present invention is not clear, fl) A salt consisting of a carboxyvinyl polymer and a base acts as a buffer and suppresses the increase in pH.

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

This seems to be due to the following reasons.

The amount of urea, which is an active ingredient in the gel preparation of the present invention, is 0.
5 to 30% by weight is preferred. 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 crystals will occur, which is not preferable in terms of formulation. The active ingredient of the gel preparation of the present invention is urea, and in addition to urea, steroidal anti-inflammatory agents such as clobetasol propionate, betamezazone valerate, fluocinonide, etc.1 indomexin, ketoprofen, flurbiprofen,
When combined with nonsteroidal anti-inflammatory agents such as sulprofen, loxoprofen sodium, ibuprofen, and felbinac, or antibacterial agents such as tolnaftate and clotrimazole, the formulation becomes even more useful as a therapeutic agent for skin diseases.

The base component of the present invention will be explained in more detail below.

Polyhydric alcohols used as moisturizers include propylene glycol, glycerin, polyethylene glycol,
■, 3-butylene glycol, ethylene glycol 1
Diethylene glycol, triethylene glycol, polypropylene glycol, polyglycerin, sorbitol aqueous solution, etc. are used, but glycerin is most suitable from the viewpoint of skin irritation. The amount of these polyhydric alcohols is 2
It is blended in an amount of 5 to 80% by weight, preferably 35 to 55% by weight. The carboxyvinyl polymer blended as a gelling agent is a water-soluble polymer, such as Carboball 934.940.941 from Goodlynch Chemicals or Hivis Wako 103.104°105 from Wako Pure Chemical Industries, Ltd. It is selected according to the prescription. In addition, the amount of carboxyvinyl polymer to be blended is 0.1 to 5% by weight, preferably 0.3% by weight, taking into full consideration conditions such as physical thermal stability, transparency, consistency, and feeling of use of the gel preparation. ~1.5% by weight is blended.

Examples of p II m1 moderators include inorganic bases such as sodium hydroxide, potassium hydroxide, and aqueous ammonia, triethanolamine, jetanolamine, diisopropanolamine, and triisopropanolamine.

Examples include organic bases such as arginine, and organic bases are particularly preferred.

These ρII il! The amount of moderation agent is based on the p of the gel preparation.
0.02 so that l+ is 3 to 9, preferably 6 to 8
It is added in a range of ~3%. The amount of water blended may be adjusted appropriately depending on the other base materials, but it is preferably 20 to 70% by weight, preferably 35 to 55% by weight.

In addition to the above-mentioned essential ingredients, auxiliary ingredients such as preservatives, oily ingredients, and antioxidants may be added. As preservatives, methylparaben, ethylparaben, propylparaben, butylparaben, thymol, chlorcresol, ortho-phenylphenol, isopropylmethylphenol, pionin, etc. are blended in the concentration range commonly used. Oily components are added to improve the feeling of use, and an example of these is isopropyl palmitate.

Butyl stearate, isopropyl myristate.

Esters such as diethyl phthalate, myristyl lactate, diisopropyl adipate, cetyl myristate, cetyl lactate, 2-hexyldecanol, oleyl alcohol,
Higher alcohols such as 2-octyldodecanol, hydrocarbons such as squalane and liquid paraffin, eucalyptus oil, peppermint oil, and olive oil.

Fats and oils 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 reduce the transparency of the gel preparation.

In addition, as an antioxidant, dibutylhydroxytoluene,
Erythorbic acid, d! -α-tocopherol and the like.

Next, the method for producing the gel preparation of the present invention will be described.

To produce the gel preparation containing urea of the present invention, first, carboxyvinyl polymer is dissolved in water, polyhydric alcohol is added thereto and stirred, and then an aqueous solution of a pH adjuster is gradually added until the mixture becomes uniform. Stir. Next, add an aqueous solution containing urea and stir until the mixture becomes uniform. Note that the order of the manufacturing steps in the above method is not particularly limited, and it is possible to manufacture the same in the same manner even if the order is partially changed.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Test Examples below.

Example! .

0.7 g of carboxyvinyl polymer was added to 31 g of water and dissolved by stirring. 42.6 g of glycerin and 0.2 g of methylparaben were added to this and stirred. Next, add 5 liters of water to this
A solution of diisopropanolamine was added to g and stirred. Next, add 10g of urea to this and 1L of water.
A transparent gel preparation containing urea was obtained by adding the solution dissolved in OG and stirring until uniform.

Example 2.

0.6 g of carboxyvinyl polymer was added to 28 g of water and dissolved by stirring. 45 g of glycerin and 0.2 g of methylparaben were added to this and stirred. Next, a solution of 1 g of arginine and 0.2 g of triethanolamine dissolved in 10 g of water was added and stirred. Next, a solution of 10 g of urea dissolved in 7 g of water was added to the mixture and stirred until it became uniform, to obtain a transparent gel preparation containing urea.

Example 3.

0.8 g of carboxyvinyl polymer was added to 16.6 g of water and dissolved by stirring. To this were added 58 g of glycerin, 2 g of propylene glycol, 0.2 g of methylparaben, and 0.002 g of hypionine, and the mixture was stirred. Next, a solution of 0.5 g of triethanolamine dissolved in 5 g of water was added and stirred. Next, a solution of urea log dissolved in 5 g of water was added thereto and stirred until 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. To this were added 47 g of glycerin, 0.15 g of methylparaben, 0.03 g of propylparaben, and Ig of diisopropyl sebacate, and the mixture was stirred. Next, 5 g of 1% sodium hydroxide solution was added to this and stirred. next,
A solution of 10 g of urea dissolved in 5.82 g of water was added to this and stirred until uniform, to obtain a transparent gel preparation containing urea.

Example 5.

0.7 g of carboxyvinyl polymer was added to 27.13 g of water and dissolved by stirring. Add to this 61g of glycerin, 0.13g of methylparaben, 0.05g of propylparaben.
was added and stirred. Next, a solution of 0.7 g of diisopropanolamine dissolved in 10 g of water was added to this and stirred until uniform, to obtain a transparent gel base.

Add 10 g of urea to the above transparent gel base and 20 g of water. A transparent gel preparation containing urea was obtained by adding the solution dissolved in the solution and stirring until uniform.

Example 6.

0.85 g of carboxyvinyl polymer was added to 26.5 g of water and dissolved by stirring. Add to this 50g of glycerin, 2g of propylene glycol, and 0.15 methylparaben.
g was added and stirred. Next, a solution of 0.6 g of triethanolamine dissolved in 5 g of water was added and stirred. Next, a solution of 5 g of urea dissolved in 10 g of water was added to this and stirred until it became uniform. A transparent gel formulation was obtained.

Practical Example 7 Carboxyvinyl Polymer 18 was added to 20.4 g of water and stirred to dissolve. To this, 1,3-butylene gellicol 4
5 g and 0.1 g of methylparaben were added and stirred.

Next, add 5 g of water and 0.0 g of triisopropanolamine.
Next, a solution of 15 g of urea dissolved in 13 g of water was added and stirred until the mixture became homogeneous to obtain a transparent gel preparation containing urea.

Example 8 1.5g of carboxyvinyl polymer was added to 27.13g of water and R? I-character? I solved 8. Add this to 61g of glycerin
1 Methylparaben 0.13. , propylparaben 0.
05g 'E: Added and stirred 0 Next, a solution of 0.7g of triethanolamine dissolved in 10g of water was added thereto and stirred until homogeneous to obtain a transparent gel base. A solution of 20 g of urea dissolved in 20 g of water was added to 60 g of this transparent gel base and stirred until uniform, to obtain a transparent gel preparation containing urea.

Reference Example 1 25 g of white vaseline, 20 g of stearyl alcohol, 60.4 g of polyoxyethylene hydrogenated castor oil, and Ig of glyceryl monostearate were heated on a water bath to dissolve, stir, and maintain at about 75°C. Add 0.1g of methylparaben and 1g of propylparaben O to this in advance.
was processed into 12 g of propylene glycol, heated, dissolved, added to 27.8 g of water, and the solution heated to 75° C. was added and stirred. This was cooled to 45°C while stirring, and urea was added to this.
A solution of 0 g dissolved in 10 g of water was added, and the mixture was further stirred and cooled until it became cream-like, to obtain a urea-containing cream preparation.

Test example! , (Thermal stability test of urea) Example 1. Gel formulation of Reference Example 1. The thermal stability of urea was investigated for a cream formulation containing 10% of urea and a commercially available cream formulation containing 10% urea.

(Test method) Each formulation filled in a 10g tube was stored at 40°C, and the ρ11 value of each formulation was measured over time, and changes in appearance were observed.

As can be seen from the results in Table 1, the urea-containing gel formulation of the present invention has better urea stability than the cream formulation of Reference Example 1 and commercially available cream formulations, so there is very little change in pH value. , no swelling of the tube was observed.

Test example 2. (Skin irritation test) Example 1. Gel formulation and reference example 1. A batch test was conducted on healthy adult males for the cream formulation.

(Test method) Finch Qmber, 5 on the back of a healthy adult male.
A closed batch was run for 48 hours using camportape.

The results are shown in Table 2.

Judgment: No reaction (-) Slight erythema (±) Obvious erythema (+) Erythema + papules or edema (family) Erythema + papules, edema + small drops (e.g.) Effect of the invention The urea of the present invention Since the gel preparation contains urea stably, there is very little change in pH value even after long-term storage, and no changes in appearance such as tube swelling are observed. Furthermore, since carboxyvinyl polymer is blended as a gelling agent, it has good thermal stability and has very little change in viscosity or consistency over time. In addition, since it does not contain a base that is highly irritating to the skin, it has the advantage of being extremely safe and less irritating to the skin.

Furthermore, since it has excellent moisturizing properties, it can be used as a therapeutic agent for keratosis, fish Hm, atopic dermatitis, senile xeroderma, etc. Moreover, it has excellent transparency and good stability.
Because of its wide range of uses, it can also be used as a base for cosmetics, quasi-drugs, and pharmaceuticals. In particular, it is more useful to incorporate an anti-inflammatory agent or an antibacterial agent because urea acts as an absorption enhancer or an action enhancer.

From the above, the gel preparation of the present invention has industrially useful effects as cosmetics, quasi-drugs, and pharmaceuticals, or as a base thereof.

Claims (1)

[Claims] 0.5-30% by weight of urea as an active ingredient, 25-80% by weight of polyhydric alcohol as a base, 0.1-5% by weight of carboxyvinyl polymer, 0.02-3% by weight of pH adjuster, and 20-20% by weight of water. A transparent gel formulation consisting of 70% by weight.