KR100483227B1 - Fushidine acid external spray composition - Google Patents

Abstract

The present invention relates to a novel fusidic external spray composition containing a fusidic acid salt. More specifically, the present invention promotes washing of at least one hydrophilic polymer selected from a film-forming water-soluble polymer, a plasticizer, polyethylene glycol, polyvinylpyrrolidone, polyhydroxyethyl methacrylate, etc. It is a new fusidic external injection that can dissolve in ethanol and spray on the surface of the skin to penetrate through the skin at high speed.

Description

Fusidic acid external spray composition

The present invention relates to a novel fusidic external spray composition containing fusidate. More specifically, the present invention promotes washing of at least one hydrophilic polymer selected from a film-forming water-soluble polymer, a plasticizer, polyethylene glycol, polyvinylpyrrolidone, polyhydroxyethyl methacrylate, etc. It is a new fusidic external injection that can dissolve in ethanol and spray on the surface of the skin to penetrate through the skin at high speed.

Fusidic acid or its sodium salt is an anti-infective agent and antibiotic used as a topical, oral and intravenous drug, especially as a topical agent for burns, acne, pyoderma and other skin trauma. have. Oral medications are used as antibiotics for the treatment of osteomyelitis, sepsis, cystic fibrosis and bronchial pneumonia, but when taken in tablets and syrups, liver and gastrointestinal disorders and jaundice may occur. There is a high probability of developing phlebitis.

However, the use of this drug as an external ointment reduces treatment time, especially compared to other topical therapies (Rietchie IC, Clinical trials J. 3, 529 (1966)), boils, swelling and scabies inflammation (Parkrooh, H, Current medical research and opion, 5, 289, (1978)). It is also known to be more effective in oral administration of antibiotics such as clindamycin, erythromycin and flucloxacin in the treatment of topical skin infections (Vickers CFH, British J. of Dermatology, 81, 902, (1969). These ointments have been widely used in recent years, especially as home medicines.

However, existing ointment preparations are inconvenient to operate due to infiltration of contaminants from outside when they are applied to the skin or remain sticky even after application, and the wound and drug administration sites are exposed. There are problems such as being unsafe and hampering activities. In addition, when using a cloth such as a gauze dressing, it is problematic to attach the surface of the affected part to a wide area, to complicated the shape of the affected part, or to expand or contract the affected part. There are issues that cause such side effects. In addition, since the coating agent and adhesive tape, etc. must be used together with the drug, it is inconvenient to use and adhesive strength is also a problem.

Meanwhile, in the anti-inflammatory analgesic research, external injection agents for administering anti-inflammatory analgesic drugs by forming a film on the skin surface using a film-forming polymer are being developed, and double cellulose derivatives (Japanese Patent No. 55-49570) and polyvinylacetate and anti-inflammatory analgesic It is known to use external preparations (Japanese Patent No. Hei 1-165521, Hei 1-230514), but these have problems in film forming ability, stability, etc., and there is no specific mention of the characteristics when forming the film. Also, in Korea, compositions of sustained-release solution pars (notification No. 94-670), water-soluble film forming agents, moisturizers, moisture evaporation accelerators and water compositions (notification No. 96-8225) are known, but mainly anti-inflammatory analgesics Therefore, the skin irritation of these compositions is overlooked.

Therefore, the present invention minimizes skin irritation and protects the wound, while rapidly infiltrating the drug into the wound, while maintaining the stability of the film during the drug release time, irritating the skin and washing with water after the drug release is possible and can be removed. It relates to a fusdine external injection. In addition, the present invention, in order to solve the problems appearing in the ointment or envelope as described above, the effect of sodium fudinate is expressed in a fast time, can be sustained for a long time, convenient to use, almost no skin irritation and easy to remove the film after use One fusidic external spray was invented.

Accordingly, the present invention is prepared by dissolving 5 to 15% by weight of a film-forming water-soluble polymer, 1 to 5% by weight of a hydrophilic polymer, and 0.1 to 1% by weight of polyethylene glycol as a plasticizer in an appropriate amount of ethanol. It relates to an external propellant composition.

In this case, the film-forming water-soluble polymer is characterized by Eudragit E100, an aminoalkyl methacrylate copolymer, and the hydrophilic polymer is characterized by being at least one hydrophilic polymer selected from polyvinylpyrrolidone or polyhydroxyethylmethacrylate. Polyethylene glycol, which is a plasticizer, is characterized by being a polyethylene glycol having a molecular weight of 300 to 1000.

Hereinafter, the present invention will be described in more detail.

The inventors noted that Eudragit E100, an economical polymer that is harmless to the human body, is biocompatible, and is used as a skin-repellent or sustained-release mechanism in pharmaceuticals, is a water-soluble, easy-to-clean polymer. Aminoalkyl methacrylate cationic copolymer (molecular weight 150,000) consisting of dimethylaminoethyl methacrylate and methacrylate, easily soluble in water and stable for at least 3 years at room temperature This is an easy substance. In particular, Eudragit E100 was selected as a material suitable for the purpose of the external spray agent requiring film forming and dissolving ability because it is easily dissolved in aqueous solution and alcohol, and has excellent permeability and film forming ability. In particular, Eudragit is a S and L type registered in the USP and is used in many formulations, but its low solubility is not appropriate, and only E100 (sold by German company), which belongs to type E, has high solubility in water and is excellent in washability. I chose to. Therefore, the Eudragit E100 5-15% ethanol solution was prepared and examined for film formation. In the case of 5% or less solution, a smooth film was formed when sprayed on the skin, but it tended to flow. It was not smooth. The film film formed by Eudragit E100 ethanol solution was volatile when applied to the skin, so that a thin and transparent film film was formed immediately upon spraying, but it was fragile and pulled, and polyethylene glycol was added to give the film film some elasticity.

The amount of polyethylene glycol was added 0.1-1% of the total composition. When the amount of the polyethylene glycol was 1% or more, the film was cracked and the film was not formed well, and when the amount was less than 0.1%, the pulling degree of the film was not improved. In addition, the molecular weight of the polyethylene glycol also affected the film formation, and the polyethylene glycol having a molecular weight of 300 to 1,000 exhibited excellent film formation. When the polyethylene glycol having a molecular weight of 1,000 or more was used, film formation was not smooth. When the polyethylene glycol 400 having a molecular weight of 400 was used, the film having the highest adhesion to the skin was formed. Therefore, it was possible to make a mixed solution composed of Eudragit E100, polyethylene glycol 400, and ethanol in the optimum conditions to form a film without disparate skin.

At this time, the amount of drug affects the film formation, and the drug concentration was not smooth at 5% or more of the total composition, so the amount was adjusted to 1-5%, and the ideal concentration was 2% of the total composition.

Hydrophilic polymers such as polyvinylpyrrolidone, polyhydroxyethyl methacrylate, and the like were introduced to facilitate removal of the film film formed by the above mixed solution. Polyvinylpyrrolidone has excellent biocompatibility and hydrophilicity so that it is well soluble in ethanol as well as water.

As a result of testing the washability of the film film by controlling the amount of Eudragit E100 and polyvinylpyrrolidone, polyvinylpyrrolidone was most suitable in the range of 1 to 5% of the total composition. Less than 1% did not have a great effect on washability, and more than 5% did not form a film. Polyhydroxyethyl methacrylate is a polymer that is currently used for medical purposes and is an excellent material. The solution containing polyhydroxyethyl methacrylate also had a quick film film and excellent cleaning property when sprayed. This is because the addition of polyvinylpyrrolidone and polyhydroxyethyl methacrylate to the Eudragit E100 solution causes the two hydrophilic substances to be intermolecularly bonded with Eudragit E100 to further improve the washability. .

That is, the present invention has advantages in that the polymers used have excellent bioadhesive power, fast drying time, and rapid and long-term expression of fusdinic acid or its sodium salt. In addition, it can be said that it is superior to the conventional fusidic acid sodium salt preparations in many aspects, such as the convenience, persistence and stability of film formation, and the ease of film removal after drug expression.

The composition is sprayed on the wound site as a spraying agent, and the spraying range can be adjusted according to the wound size, and it can be applied to non-fixed areas such as knees and elbows. It is suitable as zero.

(Examples 1-6) (Comparative Example 1) Preparation of External Spray Composition

A sodium fusidate external spray composition was prepared in the composition shown in Table 1. Performance test of the prepared composition is shown in the following experimental example.

TABLE 1 Comparative Example 1 and Example 1-6

Experimental Example 1 Washability Test

600 μl of each of the compositions of Comparative Example 1 and Example 1 was evenly deposited on the slide glass to form a film. The slide glass coated with the film was washed for a predetermined time (1, 3, 5, 7, 9, and 15 seconds), and then the weight of the slide glass before and after the experiment was measured. The washability of the compositions using the formula of × 100] is shown in FIG.

The composition of Example 1 with polyvinylpyrrolidone showed 87% washability within 5 seconds, and the composition of Comparative Example 1 without polyvinylpyrrolidone contained 44% washability and After 9 seconds the washability was 93% and 46%, respectively. That is, when the composition of Comparative Example 1 was applied, it exhibited 46% of washability in 10 seconds, whereas when the formulation of Example 1 was applied, it showed excellent cleaning power of 90% or more in 10 seconds. Therefore, polyvinylpyrrolidone improves the cleaning power of the composition when the film is removed after the drug expression.

Experimental Example 2 Skin irritation test

Nine male rabbits weighing 3.0 ± 0.5 kg are used to remove hair from the back of each animal 24 hours before application of the test substance, and the rabbits are fixed to the immobilizer. Determine 4 test sites about 2 × 2cm in size up, down, left and right around the spine. Set up the rubbing part and cut the stratum corneum by using a needle in two places. Among them, one part of abrasion, and one part of skin and one part of skin shall be the control compartment. A commercially available sodium fusidate ointment (fusidine ointment of Donghwa Chemical, hereinafter “ointment composition”) as a control substance was applied to the test material by applying 0.5 g of the composition of Example 1 to each gauze (lint) as a test substance. It is adhered to and fixed with a non-breathable tape. After removing the gauze applied 24 hours and 72 hours after application of the test substance, skin reaction evaluation was observed by dividing into erythema, skin and edema using “Toxicity Test Standards of Drugs” (National Institute of Health Notice No. 94-3). Determination of the degree of skin irritation was calculated using the commonly used Draize method (Draize, JH, J. Pharmacol. Exp. Ther., 82, 377, 1944). As shown in Table 2, both the ointment composition and the composition of Example 1 had mild erythema and crust within 24 hours, edema was insignificant, and at 72 hours, no erythema and crust and edema were found, and the scratches of the skin were almost recovered. Indicated. As a result of calculating the reaction degree of each sample using the Draize value, 0.50 was applied at the site where the composition of Example 1 was applied, and 0.53 at the time of applying the ointment composition. There was very little irritation to the skin because of its extremely low value.

Table 2 Skin irritation in rabbits

Experimental Example 3 Skin Permeation Experiment

In order to investigate the drug release properties of the composition, skin permeation experiments were performed using Franz-type diffusion cells. The volume of the diffusion cell was about 20.0 mL, the diffusion area was 3.14 cm ^2, and the receiving solution was used as a phosphate buffer solution (pH 7.4) and the experiment was maintained at a constant temperature of 36.5 ° C. The composition of Examples 1 and 3 was applied to a pig skin equipped with a diffusion cell by a predetermined amount (0.5 g) and dried to confirm film formation, and then the receiving solution was collected to measure the amount of drug released through the skin by HPLC. Ointment composition is also applied to pig skin with a certain amount (0.5g) in the diffusion cell and tested in the same way. Pig skin was used after 6 months of age and carefully removed and washed the subcutaneous fat inside the skin. The amount of drug penetrating the pig skin is shown in FIG. In 120 hours, the ointment composition contained 1.45% of the instilled amount and the composition of Example 1 released 13.6%, indicating that the compositions of Examples 1 and 3 had better skin permeability than the ointment composition.

Experimental Example 4 Measurement of Residual Drug Amount on Skin Surface and Inside

In order to measure the amount of drug remaining on the surface and inside of porcine skin after the skin permeation experiment, the composition containing the drug was wiped several times with gauze after the experiment, and the ointment composition was water: ethanol: heptane (1: 3: The residue of the composition of Example 1 in the mixture of 1.5) is dissolved in ethanol, respectively, and the amount of drug is measured by HPLC. In addition, in order to measure the amount of drug present in the skin, which was not completely permeated after the skin permeation experiment, the pig skin was homogenized in an acetonitrile: water (1: 1) mixture containing butylparaben, an internal standard, after the experiment. . The homogenized skin was centrifuged (3,000 rpm, 20 min), the supernatant was collected, filtered and the amount of drug was measured by HPLC. As a result of measuring the amount of the drug present on the skin surface and the skin after the skin permeation experiment, the ointment composition was 92.6%, 5.9%, and the composition of Example 1 was 31.4% and 55% (FIG. 3). In other words, the ointment composition remained on the skin surface with a much larger amount of drug permeate than the composition of Example 1 (92.6%), whereas the composition of Example 1 was found to have a stratum corneum and an epidermis of the skin. It is judged that it is more effective than the ointment composition for the treatment of wounds because there is much more drug (55%) than the ointment composition (5.9%).

Experimental Example 5 Drug Test

On the day of infection, rats are anesthetized with keramine [keramine: xylazine = 60: 2.5 (mg / kg)] and the back hair is removed with an electric razor. Make a 2cm cut on your back and stretch the epidermal layer to the root of your skin. Directly on the wound ^{10 4 ~10 6 cfu (inoculum size} ; 1.12 × 10 6) of the suture and the wound was injected with the bacteria and then infected with Staphylococcus aureus in 1 degree sweat temporarily. Make sure that your anesthesia breaks and do not touch your back. From the day after infection, the ointment composition and the composition of Example 1 were treated twice daily (0.15 g / kg / time). On the 2nd and 3rd day of infection, carefully remove the tissue, including the wound (2 × 2 cm). The skin tissue plate is homogenized for a long time in 10ml of sterile saline solution, the supernatant is serially diluted, smeared on the agar plate, and then grown 18 hours later to determine the therapeutic effect. The bacteria used at this time were S. aureus ATCC 6538P, which was plated on neutral agar and incubated at 37 ° C. for 18 hours to be used as the infectious bacteria solution. In addition, rats (7 weeks, 200-250 g) were freely supplied with water and food in a clean rack system, and randomized extraction was used in the experiment divided into a treatment group, the ointment composition treatment group and the treatment group of the composition of Example 1. In the untreated rats, the number of bacteria was the highest on the second day after infection, but the number of bacteria began to decrease from the third day after infection, and natural healing occurred on the seventh day. The composition and ointment composition of Example 1 had the highest bacterial count on the first day of infection, and began to decrease on the second day of infection, and healed on the third day. That is, the composition of Example 1 has a similar or better infection treatment effect compared to the ointment composition (Table 3, 4).

Table 3 Therapeutic Effect of S. aureus ATCC 6538P on Composition (n = 3)

a: values represent log ₁₀ CFU per skin homogenate.

The effect of the present invention is to minimize the skin irritation and protect the wound area, while infiltrating the drug into the wound area at high speed, while maintaining the stability of the film during the drug expression time, irritating the skin and can be removed by washing with water after drug expression. The new fucidin external spray was developed. In addition, the present invention is to develop a fusidic acid external injection agent that the medicinal effect of sodium fucidinate is expressed in a fast time, can be sustained for a long time, easy to use, almost no skin irritation and easy to remove the film after use.

1 is a chart showing the effect of the polyvinylpyrrolidone on the washability of the fusidic external injection for the washability test results according to the composition of Example 1 and Comparative Example 1.

2 is a table showing the results of skin permeation experiments according to the ointment composition and the compositions of Examples 1 and 3.

3 is a chart showing the amount of drug remaining in the skin after the skin permeation experiment according to the ointment composition and the composition of Example 1.

4 is a diagram showing the results of the drug test according to the ointment composition and the composition of Example 1.

Claims (3)

1 to 5% by weight of fusidate, 5 to 15% by weight of aminoalkyl methacrylate copolymer, 1 to 5% by weight of one or more polymers selected from polyvinylpyrrolidone or polyhydroxyethyl methacrylate and a plasticizer Fusidic acid external propellant composition prepared by adding 0.1-1% by weight of polyethylene glycol and dissolving in ethanol According to claim 1, wherein the aminoalkyl methacrylate copolymer is characterized in that the monomer of butyl methacrylate, (2-dimethylaminomethyl) methacrylate, methyl methacrylate is polymerized in a 1: 2: 1 ratio. External propellant composition The method of claim 1, wherein the plasticizer polyethylene glycol is a fumed acid external propellant composition, characterized in that the polyethylene glycol having a molecular weight of 300 to 1000.

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