JP2001278791A - Gel composition for treating skin disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound material of hyaluronic acid with zinc- containing gel composition used for the treatment of a skin disease. SOLUTION: This gel composition for treating skin diseases is characterized by containing the compounded material of hyaluronic acid with zinc as an active ingredient and adding hydroxypropylmethyl cellulose made as hydrophobic.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a gel composition for treating skin diseases.

[0002]

2. Description of the Related Art Hyaluronic acid, which is a component of the zinc hyaluronate complex, is an acidic polysaccharide that is commonly found in the umbilical cord, synovial fluid, vitreous body, and skin, and its solution is colorless, odorless, and highly viscous. Have. Hyaluronic acid also plays an important role in maintaining skin elasticity and homeostasis due to its high water retention capacity. In the process of skin tissue regeneration, the local concentration of hyaluronic acid increases, giving optimal conditions for the activation, migration and proliferation of cells involved in tissue regeneration.

[0003] On the other hand, zinc is involved in formation of granulation tissue, promotion and formation of collagen, and also in protein synthesis in a living body, and is considered to be necessary for the wound healing process.

[0004] Zinc hyaluronate is a novel compound used by Gedeon Richter (Hungary) as a novel compound for the treatment of skin ulcers of the lower leg (Patent Registration No. 2571312), and promotes granulation proliferation in rats. Its effects and angiogenesis have been confirmed, and therapeutic effects on various wounds are expected. In Hungary, it is marketed as a treatment for leg ulcers, pressure ulcers, intractable wounds and general wounds with the approval of the authorities.

At present, in medical practice, ointments containing fibrinolytic enzymes or nucleases, creams containing silver sulfadiazine, and the like for treating chronic skin wounds such as pressure sores.
Paste ointments containing purified sucrose and povidone-iodine, ointments containing bucladecin sodium, ointments containing tortinointocopheryl, and the like are frequently used. However, since the preparation itself is not transparent, it is difficult to observe the wound surface when it is applied thickly.Especially for a yellow or brown preparation, it is not only difficult to observe the wound surface even if it is applied thinly, but also as a purulent wound surface. There is a risk of making a mistake. Further, in the case of a preparation containing an oily base, it is difficult to wash off the coating agent with water or a physiological saline solution, and it is difficult to observe the progress of the wound surface. In the case of a preparation containing a water-soluble purified sucrose, washing is easy, but resistance when applying is large,
Rough or rough, causing pain to the patient,
The wound surface may be exacerbated, and application is not easy. Furthermore, after application, some compositions may decompose to give off odor.

No. 2,571,312 describes injectable solutions, solutions for topical administration, gels for topical administration, creams and ointments for topical administration, purifying purulent wounds and burns as administration forms. And examples of formulations for scarring are described. Among these, we focused on gels as therapeutic agents for skin diseases. Gels are colorless and transparent, have low resistance when applied, can be easily washed away with water or physiological saline, and have excellent properties such as lack of stringiness. Is considered to be the most suitable formulation for the treatment of chronic skin wounds.
Further, since the gel has lower resistance when applied than an ointment, it can be easily applied to pressure ulcers with any ulcers such as shallow ulcers, deep ulcers and pocket wounds. Furthermore, because of the high viscosity, even when the patient changes his or her body position, there is little fear that the drug will flow down like a liquid.
From these facts, it was considered that a gel was most suitable as a therapeutic agent for skin diseases containing a zinc hyaluronate complex. However, in the gel of Patent No. 2571312, an acrylic acid polymer is used, and it is known that divalent metal ions adversely affect the stability of the acrylic acid polymer. It is not preferable as a gel base for the zinc complex.

Accordingly, as a gel base replacing the acrylic acid polymer, natural additives such as agar, sodium alginate, xanthan gum, tragacanth, potato starch, pullulan, gelatin, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl Intensive studies were conducted using semi-synthetic polymers such as methylcellulose and propylene glycol alginate. As a result, a gel having a viscosity far higher than the viscosity capable of realizing a retention property and a shape retention property to the extent that colorless and transparent and extensible only when using hydrophobized hydroxypropylmethylcellulose and not falling off when applied is applied. Preparation was possible. With other additives, when agar and gelatin were used, a colorless and transparent gel was obtained, but no extensibility was observed and only those which could not be applied were obtained. Also, sodium alginate, xanthan gum,
When tragacanth, potato starch, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and propylene glycol alginate are used, they are colorless and transparent, but do not show the properties of a gel and stay in such a degree that they do not run off when applied. None reached a viscosity that could achieve the properties and shape retention.

[0008] It is known that hyaluronic acids are hydrolyzed in a pH-dependent manner during storage and have a property of decreasing the molecular weight. For example, sodium hyaluronate has a pH of 7
The molecular weight decrease is least likely to occur near
It is adjusted to around 7.4. Phosphate buffer is used to adjust the pH, but it is known that hyaluronic acid still gradually decreases in molecular weight during storage at room temperature even in such pH-adjusted preparations. Patents have been filed for preparations in which the stability is improved by suppressing the decrease in molecular weight (JP-A-8-104642, JP-A-9-76020). In JP-A-8-104642, citric acid or citrate is added to a solution obtained by dissolving sodium hyaluronate in a phosphate buffer to improve stability.In JP-A-9-176020, glycerin is further added. To increase stability.
In addition, it has been reported that mannitol and polyphenol, which are hydroxy radical scavengers, are effective as hyaluronic acid stabilizing substances.

In the case of the zinc hyaluronate complex as well, it has been found that the solution has the least decrease in molecular weight at around pH 7. However, since turbidity occurs at pH 8, it is necessary to adjust the pH to 7.5 or less to avoid this. On the other hand, a phosphate buffer commonly used as a buffer near pH 7 causes precipitation in the range of pH 6 to 8, so that another buffer must be sought. Further, similarly to the case of sodium hyaluronate, the decrease in the molecular weight of hyaluronic acid occurs at a pH of about 7 even though it is small. Therefore, among the pharmaceutical additives, various organic acids and amines as buffering agents, mannitol and glycerin reported as stabilizers of sodium hyaluronate solution were examined, and citric acid, maleic acid and salts thereof were converted. Only when it was used, it was found that it was possible to maintain the pH without causing precipitation, and also to suppress hyaluronic acid from becoming low molecular weight, thereby stabilizing the preparation.

The present invention is based on these new findings,
An object of the present invention is to provide a gel composition for treating a skin disease containing a zinc hyaluronate complex suitable for general treatment of a skin disease, particularly for treatment of a chronic wound such as a pressure sore.

[0011]

DISCLOSURE OF THE INVENTION The present invention relates to a gel composition containing a zinc hyaluronate complex for use in treating skin diseases. The details will be described below.

The zinc hyaluronate complex used in the gel composition of the present invention can be obtained, for example, by using sodium hyaluronate as a starting material by a method disclosed in a patent (Patent Registration No. 2571312). It is not limited and may be obtained by any method.

The source of sodium hyaluronate used for the synthesis of the zinc hyaluronate complex is not limited, but may be chicken cocks, microorganisms, or any other sources.

The molecular weight of the zinc hyaluronate complex used in the gel composition of the present invention is not specified, and any available molecular weight can be used. In the gel of the present invention, the content of the zinc hyaluronate complex is 0.01% to 3%, preferably 0.05%.
~ 2%.

Hydrophobic hydroxypropylmethylcellulose is hydroxypropylmethylcellulose (hereinafter HP)
This is a derivative of HPMC obtained by adding a mixed solvent of isopropanol and water as a reaction solvent to MC) and reacting stearyl glycidyl ether in the presence of an alkali catalyst. HPMC2208 (JP 13) and HPMC2910
(JP13) as a starting material. Each of the three grades has a long chain alkyl group content of 0.3%, 1.5% and 3%, and the lower the long chain alkyl group content, the higher the hydrophilicity. Among them, the starting material for the hydrophobized hydroxypropylmethylcellulose used in the gel composition of the present invention may be any one, but a water-soluble one having a long-chain alkyl group content of 0.3% is preferred. The hydrophobized hydroxypropyl methylcellulose is sold, for example, by Sankyo Chemical Co., Ltd. under the trade name "San Jellose".

In the gel composition of the present invention, the content of hydrophobized hydroxypropylmethylcellulose is from 0.7% to
3% is preferred.

The gel composition of the present invention suppresses the reduction of the molecular weight of the zinc hyaluronate complex by adding citric acid, maleic acid or a salt thereof and adjusting the pH to 5.7 to 7.5. can do. Citric acid, maleic acid, and salts thereof used in the gel composition of the present invention are physiologically acceptable substances for humans and animals, and any substance that dissolves in water can be used. It doesn't matter.
Specific examples include citric acid, sodium citrate, potassium citrate, sodium dihydrogen citrate, sodium hydrogen citrate, potassium hydrogen citrate, potassium dihydrogen citrate, maleic acid, sodium maleate and the like. These contents are preferably 2 mmol / L or more as citric acid or maleic acid. Additives used for pH adjustment may be acids and bases commonly used in pharmaceuticals, but preferably the acid is hydrochloric acid,
Sodium hydroxide can be used as the base.

In the gel composition of the present invention, if necessary,
Additives such as glycerin and propylene glycol and preservatives such as methylparaben and propylparaben can be added within a range that does not significantly affect stability, transparency and viscosity.

[0019]

According to the present invention, by adding hydrophobic hydroxypropyl methylcellulose to a zinc hyaluronate complex having a wound healing effect, it is colorless and transparent, has excellent spreadability when applied, and retains and retains on the applied surface. It is possible to provide a gel composition having a high formability and an excellent washing property of the applied medicine. Therefore, compared to other drugs currently used in medical practice, it is possible to reduce the time required for application to the wound surface, and because it is colorless and transparent, it is easy to observe the wound surface after application, and after application There is no fear of running off, and the time for washing the applied gel composition can be reduced.

Further, by containing citric acid, maleic acid or a salt thereof as a stabilizer and adjusting the pH to 5.7 to 7.5, the decrease in molecular weight of the zinc hyaluronate complex is extremely small, and Can provide a gel composition containing a zinc hyaluronate complex that can be stored for a long period of time. Therefore, there is no need for the operation of taking out of the refrigerator and returning it to room temperature when applying, or the storage place in the refrigerator.

Furthermore, it was confirmed that the gel composition of the present invention was excellent in releasing the zinc hyaluronate complex as the main drug, and had extremely ideal properties for wound treatment. The gel composition is irritating in rabbit skin primary irritation test, rabbit cumulative (28 days) skin irritation test, rabbit ocular mucosal irritation test, guinea pig skin sensitization test, guinea pig photosensitization test, etc. No sensitization, no photosensitivity, and excellent safety as a preparation.

Accordingly, the present invention has excellent stability and convenience in use not found in conventional products, and is excellent in release and safety of an active ingredient, for treating skin diseases, especially chronic skin wounds such as pressure sores. To provide a gel composition containing a zinc hyaluronate complex for use.

Hereinafter, the present invention will be described more specifically by showing Examples of the present invention together with Experimental Examples and Comparative Examples.

[0024]

EXAMPLES Example 1 Formulation

[Table 1] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 70 ° C., and hydrophobic hydroxypropylmethylcellulose was added little by little and dispersed. The suspension was made up to 1000 g with purified water, and then cooled to room temperature to form a gel. This gel was filled in an aluminum laminate tube and sealed.

Example 2 Formulation

[Table 2] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 70 ° C., and hydrophobic hydroxypropylmethylcellulose was added little by little and dispersed. The suspension was made up to 1000 g with purified water, and then cooled to room temperature to form a gel. This gel was filled in an aluminum laminate tube and sealed.

Example 3 Formulation

[Table 3] Preparation method Purified water and concentrated glycerin were mixed, and a zinc hyaluronate complex was added little by little to dissolve the mixture. The mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. The suspension was made up to 1000 g with purified water, and then cooled to room temperature to form a gel. This gel was filled in an aluminum laminate tube and sealed.

Example 4 Formulation

[Table 4] Preparation method Purified water and concentrated glycerin were mixed, and a zinc hyaluronate complex was added little by little to dissolve the mixture. The mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. The suspension was made up to 1000 g with purified water, and then cooled to room temperature to form a gel. This gel was filled in an aluminum laminate tube and sealed.

Example 5 Formulation

[Table 5] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 6 Formulation

[Table 6] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 7 Formulation

[Table 7] Preparation Method All of the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 7.2. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 8 Formulation

[Table 8] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel is filled in a polypropylene container, sealed, and placed in a shower sterilizer (approximately 105
C) to give a single-use preparation.

Example 9 Formulation

[Table 9] Preparation Method All of the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 7.2. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel is filled in a polypropylene container, sealed, and placed in a shower sterilizer (approximately 105
C) to give a single-use preparation.

Example 10 Formulation

[Table 10] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel is filled in a polypropylene container, sealed, and placed in a shower sterilizer (approximately 105
C) to give a single-use preparation.

Example 11 Formulation

[Table 11] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and a vial and sealed.

Example 12 Formulation

[Table 12] Preparation Method All of the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 7.2. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 13 Formulation

[Table 13] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 14 Formulation

[Table 14] Preparation Method All of the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 7.2. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 15 Formulation

[Table 15] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and an aluminum tube and sealed.

Example 16 Formulation

[Table 16] Preparation Method All of the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 7.2. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

Example 17 Formulation

[Table 17] Preparation method All the ingredients except the zinc hyaluronate complex and the hydrophobized hydroxypropylmethylcellulose in the above formulation were dissolved in about 800 g of purified water, and the pH was adjusted to about 6.5. The zinc hyaluronate complex was added to this solution little by little to dissolve it, and the mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. After making this suspension 1000 g with purified water,
The gel was cooled to room temperature. This gel was filled in an aluminum laminate tube and sealed.

[0041]

[Experimental Example] Experimental Example 1 Comparison of Bases As candidates for water-soluble polymers that can be used as bases for gels, seven types were selected from natural polymers and seven types from synthetic polymers (Table 18). Attempts were made to compare the finish and physical properties. As a result, only in Example 1, a colorless and transparent gel could be formed (Table 19). Next, the flow characteristics were compared with those of Example 1 for Comparative Examples 3 and 13 having relatively high viscosities. The analysis of the flow characteristics was performed by the method described below. As a result, Comparative Examples 3 and 13
It was found that the gel did not show properties as a gel lower than about 10,000 mPas, which is a viscosity (μ) value for realizing retention and shape retention to the extent that it did not flow down after coating, but in Example 1, It was found to be much larger than this value, about 5 times, and it was found that only Example 1 exhibited the properties of a gel having retentivity and shape retention, and having spreadability (Table 20).

Gel base candidate

[Table 18]

Properties of the prepared preparation

[Table 19]

Comparison of flow characteristics

[Table 20] * Viscosity μ: Viscosity at shear rate D = 1S ^-1

<Method of Analyzing Flow Characteristics> Tester: RE110H rotational viscometer (Toki Sangyo) Cone rotor: 3 ° × R14 Temperature: 25 ± 0.1 ° C. Preheat time: 60 seconds Rotation speed: 0 rpm → 1. 0 rpm → 0 rpm (shift every 0.1 rpm,
(The holding time at each rotation speed is 30 seconds.) Test method: Approximately 0.5 mL of a sample was collected, set in a sample cup of a viscometer, and measured. Data processing and analysis: Data obtained by the measurement was processed and analyzed by analysis software "TOP2B", and plotted using a plotter. The formulations and preparation methods of Comparative Examples 1 to 13 are shown below.

Comparative Example 1 Formulation

[Table 21] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 90 ° C and agar was added little by little to dissolve. This solution was made up to 1000 g with purified water, and then cooled to room temperature.

Comparative Example 2 Formulation

[Table 22] Preparation method Zinc hyaluronate complex and sodium alginate were added to purified water and stirred.

Comparative Example 3 Formulation

[Table 23] Preparation method Zinc hyaluronate complex and xanthan gum were added to purified water and stirred.

Comparative Example 4 Formulation

[Table 24] Preparation method Zinc hyaluronate complex and togalant powder were added to purified water and stirred.

Comparative Example 5 Formulation

[Table 25] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, potato starch was added little by little and dispersed, and heated to about 90 ° C. to dissolve the potato starch. This solution was made up to 1000 g with purified water, and then cooled to room temperature.

Comparative Example 6 Formulation

[Table 26] Preparation method Zinc hyaluronate complex and pullulan were added to purified water and stirred.

Comparative Example 7 Formulation

[Table 27] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 90 ° C. and gelatin was added little by little to dissolve. This solution was made up to 1000 g with purified water, and then cooled to room temperature.

Comparative Example 8 Formulation

[Table 28] Preparation method After adding and dissolving the zinc hyaluronate complex to purified water little by little, the mixture was heated to about 70 ° C. and methyl cellulose was added little by little to disperse. This solution is made up to 10 with purified water.
After that, the mixture was cooled to room temperature.

Comparative Example 9 Formulation

[Table 29] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, it was heated to about 70 ° C., and hydroxypropyl cellulose was added little by little and dispersed. This solution was made up to 1000 g with purified water, and then cooled to room temperature.

Comparative Example 10 Formulation

[Table 30] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, it was heated to about 70 ° C., and HPMC2208 was added little by little and dispersed. This solution is made up to 10 with purified water.
After that, the mixture was cooled to room temperature.

Comparative Example 11 Formulation

[Table 31] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 70 ° C. and HPMC2908 was added little by little and dispersed. This solution is made up to 10 with purified water.
After that, the mixture was cooled to room temperature.

Comparative Example 12 Formulation

[Table 32] Preparation method After adding the zinc hyaluronate complex to purified water little by little and dissolving it, the mixture was heated to about 70 ° C and HPMC2910 was added little by little and dispersed. This solution is made up to 10 with purified water.
After that, the mixture was cooled to room temperature.

Comparative Example 13 Formulation

[Table 33] Preparation method Zinc hyaluronate complex and propylene glycol alginate were added to purified water and stirred.

[0059]

EXPERIMENTAL EXAMPLE Experimental Example 2 Hydrophobic Hydroxypropyl Methyl Cellulose Concentration, Flow Characteristics and Transparency Hydrophobized Hydroxypropyl Methyl Cellulose Concentration of 0.7% to 3%, Preparation of Examples 1 to 4 and Comparison of 4% The formulation of Example 14 was prepared, and the flow characteristics were compared in the same manner as in the flow characteristics analysis method performed in Experimental Example 1.
As a result, all formulations (Examples 1-4 and Comparative Example 14)
In this case, the viscosity (μ) value, which achieves a retention property and a shape retention property that does not flow down after application, was about 10,000 mPa · s. Next, transparency was compared using the preparations of Examples 1 to 4 and Comparative Example 14 by the method described below. As a result, the preparations of Examples 1 to 3 were evaluated as “extremely transparent”, and the preparation of Example 4 was evaluated as “highly transparent”.
Was evaluated as "low transparency". From the above results, it was found that when the concentration of the hydrophobized hydroxypropylmethylcellulose was in the range of 0.7% to 3%, a gel having high transparency was obtained, having retention and shape retention properties after coating (Table 34). .

(Evaluation Method of Transparency) A white copy paper in which each letter of each of 10 to 19 was printed at random in a size of 9 points was prepared, and about 3 g of the preparation was put therein. Place the cell for use (hereinafter referred to as a cell) with the light transmitting surface of the cell in contact with the printed circle number, observe the circle number through the cell under illumination of about 1,000 lx for about 2 seconds, and read The transparency was compared based on the number of figures that could be obtained. In the evaluation, the value of the average number N of numbers that could be read in the test performed by 10 people was:
The case of N = 0 is “extremely low transparency”, the case of 0 <N ≦ 2 is “low transparency”, the case of 2 <N ≦ 5 is “slightly low transparency”, and the case of 5 <N <8. “Slightly high transparency”, 8 ≦ N <10, “High transparency”, N = 1
A case of 0 was defined as “extremely transparent”.

The concentration, flow characteristics and transparency of the hydrophobized hydroxypropylmethylcellulose

[Table 34] * Measurement was not possible due to high viscosity.

Comparative Example 14 Formulation

[Table 35] Preparation method Purified water and concentrated glycerin were mixed, and a zinc hyaluronate complex was added little by little to dissolve the mixture. The mixture was heated to about 70 ° C., and hydrophobic hydroxypropyl methylcellulose was added little by little and dispersed. The suspension was made up to 1000 g with purified water, and then cooled to room temperature.

[0063]

[Experimental example] Experimental example 3 Stability of pH and zinc hyaluronate complex (1) Zinc hyaluronate complex was added to GTA buffer adjusted to pH 5 to 8 so as to be 0.1% and dissolved. , 6
Stored at 0 ° C. for 20 days. The solution before and after storage was 0.2 mol /
The sample solution was diluted 10-fold with L sodium chloride test solution. In addition, sodium hyaluronate having a molecular weight of about 1,000,000 was added to and dissolved in 0.2 mol / L sodium chloride test solution to a concentration of 0.01% to obtain a standard solution. Perform high-performance liquid chromatography on the sample solution and the standard solution under the conditions described below, calculate the ratio between the retention time of the sample solution and the retention time of the standard solution, and assume that the lower molecular weight of hyaluronic acid proceeds in the primary reaction. The apparent decomposition rate constant k was calculated by the following equation.

As a result, in this pH range, pH 5 had the highest decomposition rate, and as the pH increased, the decomposition rate decreased, but when the pH exceeded 7, the decomposition rate tended to increase again. At pH 8, cloudiness was observed (FIG. 1). ln [ratio after storage] = -kt + ln [ratio before storage]----(formula) t: time (20 days) [ratio before storage]: retention time of sample solution and standard solution before storage Ratio [Ratio after storage]: Ratio of retention time between sample solution and standard solution after storage k: Apparent decomposition rate constant (condition of high performance liquid chromatography) Column: TSKgel G6000PW (manufactured by Tosoh) Eluent: 0.2 mol / L sodium chloride TS Flow rate: about 0.5 ml / min Detector: Differential refractometer Column temperature: 40 ° C Sample injection volume: 50 μL

(Preparation method of GTA buffer) 0.2 mol / L of β, β′-dimethylglutaric acid, 2-amino-2-methyl-1,3-propanediol and tris (hydroxymethyl) aminomethane 25 mL of each aqueous solution was accurately measured and mixed, adjusted to a target pH with a 0.2 mol / L hydrochloric acid TS or a 0.2 mol / L sodium hydroxide TS, and then water was added to 200 mL.

(2) The zinc hyaluronate complex itself has a pH
7 was found to be the most stable. Next, in order to find out what kind of stability is exhibited at a pH lower than pH 7, the pH of the formulation of Example 5 was adjusted in the range of 5.1 to 6.9. A modified gel of Table 36 was prepared and filled into vials for 5
Stored at 0 ° C. for 15 days. 4mol / L gel before and after storage
After diluting 10-fold with a sodium chloride test solution, the mixture was shaken for 5 hours, and filtered with a membrane filter having a pore size of 0.8 μm to obtain a sample solution. In addition, the molecular weight of about 1,000,000 and about 200
Ten thousand sodium hyaluronate was added and dissolved in a 4 mol / L sodium chloride test solution to a concentration of 0.02% to obtain a standard solution. Perform high-performance liquid chromatography under the conditions described below for the sample solution and the standard solution, calculate the molecular weight of the sample solution using the calibration curve obtained from the retention time and the molecular weight of the standard solution, The ratio of the molecular weights was determined as the residual molecular weight ratio. As a result, pH 5.
It was found that the molecular weight of hyaluronic acid was low when the molecular weight was 7 or more (Table 37).

(Conditions for high performance liquid chromatography) Column: TSKgel G6000PW (manufactured by Tosoh) Eluent: 0.2 mol / L sodium chloride TS Flow rate: about 0.6 ml / min Detector: Differential refractometer Column temperature: 40 ° C. Sample injection Volume: 150μL

Formulation of formulations with different pH

[Table 36] * Hydrophobic hydroxypropyl methylcellulose is abbreviated as hydrophobic HPMC.

Stability of formulations with different pH (50 ° C., 15 days)

[Table 37]

[0070]

[Experimental Example] Experimental Example 4 Comparison of the effect of suppressing the decrease in molecular weight of hyaluronic acid by various additives A gel was prepared by replacing citric acid in the composition of Example 5 with the additive shown in Table 38, and filled into vials. Along with Example 5 and Example 11, it was stored at 50 ° C. for 15 days. The gel before and after storage was evaluated by the same method as in the experiment of Experimental Example 3 (2). As a result, it was found that the residual ratios of the molecular weights of Example 5 (citric acid) and Example 11 (maleic acid) were high, and that citric acid and maleic acid had a high molecular weight reduction suppressing effect. Additives other than citric acid and maleic acid did not show a molecular weight reduction inhibitory effect (Table 39).

Additives to be added in place of citric acid and their amounts

[Table 38] * The organic acid was added so as to be 10 mmol / L, and the sugar and sugar alcohol were added so as to be 100 mmol / L.

The effect of suppressing the decrease in molecular weight of each additive

[Table 39]

[0073]

[Experimental example] Experimental example 5 Comparison of release properties 4 of Example 5, Comparative example 15, Comparative example 16 and Comparative example 17
Using about 4.25 g of each kind of preparation, a release test was performed under the conditions described below, and the release rate of the zinc hyaluronate complex was determined by quantifying the amount of zinc in the release liquid sampled by 2 mL each over time. The release rates were compared. As a result, in the preparation of Example 5, about 80% was obtained after 4 hours.
Release was observed. At this time, the gel state was maintained. On the other hand, in Comparative Example 16 (cream using hydrophilic ointment) which is a cream-like ointment,
Approximately 40% release was observed 4 hours after the start of the test, at which point the formulation was emulsified and passed through a membrane filter, which was considered to have been measured. In Comparative Examples 15 and 17 (creams based on water-absorbing ointment and hydroplastibase), which were cream-like ointments similar to Comparative Example 16, no release was observed.

From the above results, the gel of Example 5 has a very high release property of the zinc hyaluronate complex from the preparation compared with Comparative Examples 15 to 17 which are cream-like ointments, It was considered to be extremely excellent as a preparation containing the complex.

<Release test conditions> Test device: Suppository release tester TDS-30P (Toyama Sangyo) Sample: 4.25 g of each of the above five types was applied on the membrane filter of the cell of the suppository release tester Release solution: 0 2.9% aqueous sodium chloride solution 200 mL Temperature: 30 ± 0.1 ° C. Stirring speed: 100 ± 1 times / min Membrane filter: Straight hole type, pore size 10.0 μm

Quantitative determination of zinc: HEPES buffer was added to 2 mL of the sampled solution to make exactly 20 mL, which was used as a sample. Separately, 4 mL of a zinc standard solution (1000 ppm) was accurately measured, and HEPES buffer was added to make exactly 100 mL. Each of 1, 2, 3, 4 and 5 mL of this solution was accurately measured, and HEPES buffer was added to make exactly 100 mL, which was used as a standard solution. 0.1 mL of sample and standard solution respectively
cylaminoethyl-cyclen solution (Dancylaminoethyl-cyclen
0.56 mg was dissolved in HEPES buffer to make 20 mL. ) A test was performed on the solution to which 0.1 mL was added by a fluorescence measurement method (excitation wavelength: 323 nm, measurement wavelength: 528 nm), and the solution was quantified by a calibration curve obtained from a standard solution.

The formulations and preparation methods of Comparative Examples 15 to 17 are shown below. Comparative Example 15 Formulation

[Table 40] Preparation method The zinc hyaluronate complex was dissolved in purified water, purified water was added to make the total amount 50.0 g, and then 50.0 g of water-absorbing ointment was added and kneaded to obtain an ointment.

Comparative Example 16 Formulation

[Table 41] Preparation method The zinc hyaluronate complex was dissolved in purified water, purified water was added to make the total amount 50.0 g, and hydrophilic ointment 50.0 g was added and kneaded to obtain an ointment.

Comparative Example 17 Formulation

[Table 42] Preparation method The zinc hyaluronate complex was dissolved in purified water, purified water was added to make the total amount 50.0 g, and hydroplastibase 50.0 g was added and kneaded to obtain an ointment.

[0080]

[Experimental Example] Experimental Example 6 Detergency The detergency of the formulation of Example 6, competitor A and competitor B was compared by the following method. As a result, it was shown that the preparation of Example 6 can be washed in an extremely short time of about 15 seconds, while the preparations of other companies A and B take 8 minutes or more.

<Cleaning Test> A butyl rubber cylinder (vial rubber stopper L200-F) having a Teflon-laminated surface
10, a material No. 713, a columnar portion that fits into the bottle mouth of coating B2-40) was filled with about 1.2 mL of the preparation, and the surface of the preparation was flattened. Put 100 mL of physiological saline solution into a 200 mL beaker, and set a cylinder at a position of about 27 mm below the water surface so that the surface of the preparation faces down.
(Diameter: about 8 mm, length: about 30 mm), the mixture was stirred at a speed of about 600 revolutions / minute, and the time required for the filled preparation to completely disappear from the cylinder was measured, and was defined as the washing time.

[0082]

[Experimental example] Experimental example 7 Primary skin irritation test in rabbits The primary skin irritation test in the examples was carried out using Japanese white male rabbits (K
bs: JW). 0.5 mL of the preparation of Example 7 was occluded and applied to the skin of the back of six rabbits (abraded skin and non-abraded skin) for 24 hours, followed by visual observation up to 72 hours after application, and the irritation was evaluated according to the Draize method. as a result,
It was determined that the preparation of Example 7 was not irritating.

[0083]

[Experimental example] Experimental example 8 Cumulative skin irritation test in rabbit for 28 days The cumulative skin irritation test in the example was carried out using a Japanese white rabbit (Kbs: J
W). 0.5 mL of the formulation of Example 7 was repeatedly applied to the back skin (abraded skin and non-abraded skin 1 site / animal) of rabbits of 6 males and 6 females a group for 6 days a day for 28 days. Macroscopic observation was made and the irritation was evaluated according to the Draize method. As a result, it was determined that the preparation of Example 7 had no irritation.

[0084]

[Experimental example] Experimental example 9 Ocular mucosal irritation test in rabbits The ocular mucosal irritation test of the examples was carried out using Japanese white male rabbits (Kb
s: JW). 0.1 mL of the preparation of Example 7 and physiological saline were instilled into the conjunctival pocket of three rabbits per group, and a fluorescein test was performed at 1, 24, 48, 72 hours and 7 days after instillation. As a result, the preparation of Example 7 and the physiological saline were determined to be "non-irritants" for the eyes of rabbits.

[0085]

[Experimental example] Experimental example 10 Skin sensitization test in guinea pig A skin sensitization test (Adjuvant and Patch Test) was performed using a 4-week-old Hartley female guinea pig. The primary sensitization was performed by 0.1 mL / site of the preparation of Example 7 for continuous occlusion for 3 days, and the secondary sensitization was performed by application of 0.2 mL of the preparation of Example 7 for 48 hours by occlusion. In addition, 1-
Chloro-2,4-dinitrobenzene (DNCB) was used. As a result, it was determined that the preparation of Example 7 did not show skin sensitization to guinea pigs.

[0086]

[Experimental Example] Experimental Example 11 Skin photosensitization test in guinea pig A skin photosensitization test (Adjuvant and Strip Method) was performed using a 4-week-old female Hartley guinea pig. In the photosensitization, ultraviolet rays (UV-A) were irradiated once a day for 5 consecutive days, about 30 minutes after application of the preparation of Example 7, so that the irradiation dose was about 10 J / cm ^2. Then, the inducing was performed in Example 70.
Approximately 30 minutes after the application of 02 mL, irradiation was carried out by irradiating ultraviolet rays (UV-A) at about 10 J / cm ² . In addition, 6-methylcoumarin (6-MC) was used as a positive control substance. As a result, it was determined that the preparation of Example 7 did not show skin photosensitization.

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of pH on the stability of an aqueous solution of a zinc hyaluronate complex.

FIG. 2 is a graph showing the release properties of the zinc hyaluronate complex of the composition of the present invention.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Akiyoshi Ozaki 15-3 Bessho-cho, Omiya-shi, Saitama Takada Pharmaceutical Bessho Dormitory F-term (reference) 4C076 AA09 CC19 DD42Q DD42Z DD43Q DD43Z EE32A EE32P FF35 FF61 FF65 4C086 AA01 AA02 EA25 HA28 MA02 MA03 MA05 MA28 NA14 ZA89

Claims (4)

[Claims] 1. A gel composition for treating a skin disease, wherein the active ingredient is a zinc hyaluronate complex, and hydrophobized hydroxypropylmethylcellulose is added. 2. The content of the zinc hyaluronate complex is 0.0.
The gel composition for treating skin diseases according to claim 1, wherein the content is 1% to 3%, preferably 0.05% to 2%. 3. The gel composition for treating a skin disease according to claim 1, wherein the content of the hydrophobized hydroxypropylmethylcellulose is 0.7% to 3%. 4. One or more selected from citric acid, maleic acid and salts thereof as citric acid or maleic acid.
The gel composition for treating a skin disease according to any one of claims 1 to 3, wherein the gel composition contains at least mmol / L and the pH is adjusted to 5.7 to 7.5 to suppress a decrease in the molecular weight of the zinc hyaluronate complex.