JPWO2008050491A1 - Film formulation that forms a film on the skin - Google Patents

Abstract

[PROBLEMS] To improve the percutaneous absorption of the contained drug to the affected area, enhance the local therapeutic effect, and protect the affected area with a film to prevent external physical and chemical irritation and bacterial infection. There is provided a film formulation for forming a film on the skin on which a film close to the skin tissue is formed on the necessary skin. Nitrocellulose is dissolved in 3-methylbutyl acetate, isobutyl acetate, acetone, or a mixture thereof, and a drug whose main purpose is medicinal effect is added to a solubilizing agent to which ethyl alcohol is further added. A film preparation for forming a film on the skin in which the affected area is sealed by forming a transparent or translucent film on the skin. [Selection] Figure 2

Description

  This invention forms a film on the skin to seal the affected area, improves the transdermal absorbability of the contained drug to the affected area, enhances the local therapeutic effect, and further protects the affected area with a film from the outside. The present invention relates to a film preparation that forms a film on the skin that prevents physical and chemical irritation and bacterial infection and reduces the side effects and effects on the body including the skin.

The topical therapy is a therapy for the purpose of healing a lesion by transdermally administering a drug, but has been developed as a treatment method for a skin lesion by administering the drug transdermally.
Since this drug can administer the drug directly to the lesion, the drug concentration in the lesion can be freely manipulated, it is easy to achieve a therapeutically effective concentration in the lesion, and treatment can be performed while constantly observing the response to treatment of the lesion It has been established as a therapeutic method having various advantages. In recent years, a drug delivery system (DDS) has been developed that allows drugs to reach not only the skin but also deeper, and has been clinically applied not only to steroids but also to the treatment of diseases in the orthopedic field by non-steroidal anti-inflammatory drugs. ing.
By the way, the most important point in external therapy is how the drug applied to the skin surface is percutaneously absorbed so as to reach an effective concentration. The three major factors that affect the percutaneous absorption of a topical drug include the properties of the drug, the type of external drug base that holds the drug, and the properties of the skin on which the drug is applied.

Healthy skin has a stratum corneum covered with a fat film (skin surface lipid) in the outermost layer of the skin, and the fat film and the stratum corneum prevent entry of foreign substances from the outside into the skin. From the viewpoint of topical medicine, it is an obstacle that reduces percutaneous absorption. In many skin disease lesions, this obstruction is often partially or completely removed, increasing the degree of percutaneous absorption of the drug. Therefore, a drug more than expected is absorbed through the skin and various side effects are manifested, making it very difficult to determine the drug concentration in the topical drug. Therefore, many clinical trials are conducted to determine the appropriate concentration of topical drugs.
In addition, there are bases that retain external medicines as a factor that affects the absorption of external medicines, but those that have a good feeling when used externally as well as promoting percutaneous absorption of drugs are used. It is like that. The basic principles are (1) stabilization of the drug, (2) promotion of percutaneous absorption, (3) protection of topical topical use, and (4) good use feeling as well as the action of the drug in the external part. Development of bases with emphasis on sustained release of drugs for long-term use is also underway.

Bases are broadly divided into (1) ointment, (2) cream, (3) mud, (4) lotion, (5) plaster and tape, (6) spray, and (7) powder. Ointments, creams and lotions are generally used, and a surfactant is required to dissolve the drug in these bases. Further, a preservative (such as paraaminobenzoic acid) is required to prevent the external preparation from decaying. However, these chemical substances have mild skin irritation and have a great influence on sensitive skin, so they tend to avoid compounding, but they are essential ingredients to ensure the quality of drugs. .
Furthermore, the transdermal absorption of topical drugs is greatly affected by the skin site and the skin properties of the site, and the skin of infants and the elderly has a thin epidermal layer and the stratum corneum is not sufficiently developed. Tends to increase. The percutaneous absorption of drugs is enhanced at sites where sweat easily accumulates, such as the neck, heels, knees, elbows, and vulva. In particular, topical use of steroids requires attention in use because the absorbed amount of the drug on the face, neck, and genital area is different from other parts of the body.

In dry skin, the stratum corneum is cracked, the skin surface lipid is deficient, and the skin protective membrane is in a state of being damaged, so that percutaneous absorption of the drug is enhanced. In addition, the skin permeation, erosion, and ulcer skin exhibiting an inflammatory reaction are in a state where the percutaneous absorption of the drug is enhanced.
The current topical treatment is a treatment that cures the lesion by administering the necessary concentration of the drug to the skin lesion area, and can minimize the influence of the drug on the skin and other organs other than the lesion, Moreover, it is an excellent treatment method capable of performing treatment while always observing changes in the lesion.
The topical therapy gives a slightly complicated feel to the procedure, from simple application of drugs to multi-layer therapy, sealing therapy, etc., especially in the case of a wide range of lesions, it places a great burden on the practitioner There is.

Products (golf gloves, supporters, socks, katato cream, etc.) aimed at protecting physically stimulated limbs have a certain effectiveness, but have a sense of incongruity in wearing, It takes a lot of time to put on and take off, and at the time of wearing, it has the disadvantage that it is unclean with the occurrence of odor due to stuffiness of the affected area and bacterial propagation.
In addition, this inventor is providing the following patent documents 1-3 as a formulation containing the component which forms a film on skin.
Japanese Patent Application No. 2005-136740 Japanese Patent Application No. 2005-198556 Japanese Patent Application No. 2005-254415

As described above, conventional preparations for external use are roughly divided into (1) ointment, (2) cream, (3) mud, (4) gel, (5) lotion, (6) plaster and tape, (7) There are Pap, (8) Spray, and (9) Powder, but there are the following problems.
Ointments, cream gels and mud are semi-solid preparations that are paste-like (paste), making it difficult to apply a certain amount. Effective depending on the state of application (area / quantity) and application method (number of rubbing / rubbing, etc.) It is easy to be affected. The effects (effects and side effects) are particularly noticeable on damaged skin, and the treatment progress after application is likely to be affected. Moreover, clothes etc. are easy to get dirty after application | coating, As a result of wiping off the plaster with clothes etc., it is difficult to maintain the fixed quantity applied for exhibiting effectiveness. Furthermore, since the plaster is washed away by washing the body such as bathing or showering, it is necessary to reapply it in order to maintain the drug effect in the affected area. There was a problem that bathing contaminated the hot water in the bathtub and caused trouble for people who took a bath later.

  Plasters, tapes, and poultices are generally established as adhesives, but often cause skin disorders such as rashes in the affected area to seal the affected area. In particular, since plaster and tape use a base with high skin adhesion, in addition to the skin irritation of the base itself, physical irritation at the time of peeling may cause rash, redness, itching, etc. High risk of side effects. In addition to skin disorders such as eczema, it has the disadvantage that it cannot be used on damaged skin. Furthermore, since the drug after use almost retains its original form, there is a problem that a great deal of cost is required for its processing and disposal.

A spray is a simple and non-staining preparation, but it is difficult to administer a certain amount of drug because the drug diffuses in the form of a mist. There is also a risk of distribution to the lungs through mucous membranes and airways. In addition, since a special filling container is used, there is a cost in the collection and disposal of the container after use.
In the powder preparation, it is extremely difficult to keep the drug on the affected skin area, and the affected area that can be used is limited to a wet state. In addition, there is a high possibility that the surroundings will be contaminated with powder during use, and it is often difficult to use safely.

In addition, external therapy is complicated by simple application of applied drug, multi-layer therapy and sealing therapy, and depending on the application method and the state of the affected area, the affected area may be worsened by physical stimulation. In particular, in sealing therapy, a drug must be applied and then covered with a non-breathable material such as a polyethylene film, which requires time and effort for treatment and its continuous maintenance. Further, since the air permeability of the affected area is blocked by maintaining the sealed state, there is a problem that skin damage such as rash is likely to occur.
Products intended to protect the limbs (gloves, supporters, socks, etc.) have the functionality of protecting the limbs against physical stimuli, but are uncomfortable to wear, causing odors due to stuffiness and bacterial growth at the time of wearing and filth As a result, there was a problem that early replacement and washing became a burden on the user.

  The problem to be solved by the present invention is that preparations that require surfactants and preservatives (ointments, creams, gels, In order to solve the various disadvantages of the above-mentioned preparations for external application listed above, it is necessary to form a film close to the skin tissue (especially the stratum corneum) on the necessary skin. is there.

  The present inventor considered various new simple preparations that had more effects, safety, and convenience without degrading the properties and effects of external preparations and limb protection products, repeated experiments and trial production, A new gel dosage form with a composition that takes advantage of the characteristics of gel, spray and patch (form before use of gel, spray composition, dosage form after use of patch) was tried. When the new gel formulation was applied to the skin, it was a semi-solid gel before use, and after a thin coating on the skin, a film close to a thin patch was formed on the skin. As a result of further research based on this fact, the present inventor has found that the film formed on the skin of the affected area works to solve the above problems, and arrives at the present invention. I was able to.

  The film preparation according to the present invention solves the above-mentioned problems, and the invention of claim 1 is a solution in which nitrocellulose is dissolved in 3-methylbutyl acetate, isobutyl acetate, or acetone, or a mixture thereof, On the skin, the affected area is sealed by adding a drug with the main purpose of medicinal effect to a solubilizing agent to which ethyl alcohol is added, and forming a transparent or translucent film on the skin at the application site. It is a film preparation that forms a film.

Since it is such a film preparation, the solvent is volatilized after it is applied to the skin, and the affected part is sealed by forming it on the skin of the affected part where a transparent or translucent film is applied. Increase the effect of the affected area by preventing direct contact between the affected area and water, and at the same time prevent side effects (rash, redness, blistering, etc.) of the affected area. In addition, the drug applied to the affected area can be covered with a coating to prevent the drug from flowing out by bathing or showering, and the effect can be expected to last. In addition, infection with third parties via water is uncomfortable. Is solved. In addition, since it is non-aqueous, the contained drug has high stability, and there is no need to use a preservative or surfactant that has a risk of adversely affecting the skin. Of course, other auxiliary components may be added to the above preparation.
In addition, as a drug-free preparation, the role of the stratum corneum of the skin (protection against physical and chemical invasion from the outside), sweating control, and body odor (by sterilization and disinfection by base components (such as ethyl alcohol)) It is also possible to prevent sweat odor).

  In addition, an appropriate amount of a water-soluble polymer such as polyvinyl alcohol or polyvinyl pyrrolidone may be added to the film preparation for forming a film on the skin of the present invention for the purpose of adjusting the friction coefficient and strength of the film. After the solvent is evaporated, the affected area is sealed by forming a transparent or translucent film on the skin at the application site, and the percutaneous absorbability (permeability) of the contained drug to the affected area by the ODT effect (sealing effect) By improving the local treatment effect and enhancing the local therapeutic effect, and further protecting the affected area with a film, it is possible to prevent external physical and chemical irritation and bacterial infection, and to reduce the effects and side effects on the outside of the body including the skin.

The film preparation for forming a film on the skin of the present invention may contain an external antibiotic as a drug in the solubilizing agent, whose main medicinal effect is to prevent infection of the affected area. Gentamicin sulfate, fradiomycin sulfate, colistin sulfate, chloramphenicol, chromy P, erythromycin, oxytetracycline hydrochloride, bacitracin, sodium fusidate.
The film preparation for forming a film on the skin of the present invention may contain, as a drug in the solubilizing agent, an external antifungal agent whose main medicinal effect is treatment of diseases caused by the growth of various bacteria and fungi. The antifungal agents for external use include amorolfine hydrochloride, croconazole hydrochloride, terbinafine hydrochloride, neticonazole hydrochloride, butenafine hydrochloride, clotrimazole, ketocon, siccanin, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, miconazole, tolcyclate, There are tolnaftate, bifonazole, pimaricin, ranoconazole, and rilanaphthalate.
Similarly, an external synthetic antibacterial agent may be contained, and examples of the external synthetic antibacterial agent include sulfadiazine, silver sulfadiazine, sulfisomidine, and nadifloxacin.

  In addition, the film preparation for forming a film on the skin of the present invention has an original skin color by regenerating or depositing an enzyme having an action of dissolving blood coagulation in the solubilizing agent and melanin pigment of the skin. It may contain methoxalene and keratosis treatment, which have an action to revert, and there are etretinate, calcipotriol, tacalcitol, vitamin A, maxacalcitol as well as keratolysis. An active agent may be included, and therefore urea and salicylic acid may be included, and an antiallergic external preparation may be included. For this purpose, there are isothipenzil hydrochloride, crotamiton, diphenhydramine, diphenhydramine lauryl sulfate, and external use. It may contain the flame retardants azulene, alcloxa, cephalanthin, and zinc oxide. However, it may contain an anti-inflammatory enzyme that is used to treat skin ulcers such as wounds, trauma, etc. For this purpose, there are lysozyme chloride and bromelain, vascularization, granulation formation, and skin formation promoting action of bucladecin Sodium, alprostadil alphadex, which promotes blood flow in the skin ulcer and granulation / skin formation, tretinoin tocopheryl, iodine with sustained bactericidal and cleansing action, human base made by genetic engineering technology A drug that helps normalize the skin, such as trafermin, a natural fibroblast growth factor, and tacrolimus hydrate, a therapeutic agent for atopic dermatitis, can be contained.

  Furthermore, in the film preparation for forming a film on the skin of the present invention, a polyhydric alcohol (alkanediol, erythritol, glycerin, xylitol, diglycerin, dipropylene glycol, 1,3-propylene) is used as a moisturizer in the solubilizer. Butylene glycol, propylene glycol, hexanediol, polyglycerin, D-mannitol, etc.), sericin, urea, uric acid, hyaluronic acid, hydrolyzed collagen gel, DMAE (dimethylaminoethanol), lecithin, soybean lecithin, egg yolk lecithin, chitin / chitosan One or more moisturizing agents such as the above may be contained to improve the skin moisturizing property after film formation.

The invention of claim 2 contains, as a drug dissolved in the solubilizer of claim 1, an external non-steroidal anti-inflammatory drug as an anti-inflammatory agent or a topical corticosteroid for external use mainly for suppressing inflammation of the affected area The film preparation for forming a film on the skin according to claim 1.
Examples of the above-mentioned topical corticosteroids include amcinonide, prednisolone valerate acetate, dexamethasone valerate, betamethasone valerate, diflorazone acetate, hydrocortisone acetate, diflupredonate, betamethasone dipropionate, dexamethasone, triamcinolone acetonide, halcinonide, hydrocortisone, hydrocortisone Flumethasone, pudesonide, mometasone furanate, fluocinonide, fluocinolone acetonide, fludroxycortide, prednisolone, alclomethasone propionate, clobetasol propionate, dexamethasone propionate, deprodon propionate, beclomethasone propionate, betamethasone butyrate Hydrocortisone, hydrocortisone butyrate propionate, propionate butyrate There is a least one compound selected from the group consisting.
The non-steroidal anti-inflammatory drugs for external use include indomethacin, ufenamate, glycyrrhetinic acid, ketoprofen, diclofenac sodium, suprofen, piroxicam, felbinac, bufexamac, flurbiprofen, bendazac, methyl salicylate, and salicylic acid.

The invention of claim 3 contains at least one of natural oils such as perilla oil, sesame oil, sesame oil, olive oil, horse oil, hinoki oil, and castor oil as a drug dissolved in the solubilizer of claim 1. The film preparation for forming a film on the skin according to claim 1, characterized in that the strength and flexibility of the film during formation and the ODT effect are enhanced.
The invention of claim 4 includes a polyhydric alcohol (alkanediol, erythritol, glycerin, xylitol, diglycerin, dipropylene glycol, 1,3-butylene glycol, propylene glycol, hexane as a humectant in the solubilizer of claim 1. Diol, polyglycerin, D-mannitol, etc.), sericin, urea, uric acid, hyaluronic acid, hydrolyzed collagen gel, DMAE (dimethylaminoethanol), lecithin, soybean lecithin, egg yolk lecithin, chitin / chitosan, The film preparation for forming a film on the skin according to claim 1, which improves the moisture retention of the skin after film formation. By containing this moisturizing agent, it also has an effect of keeping moisturizing effectively for a long time in combination with the sealing action of the film.

According to the film preparation for forming a film on the skin of the present invention, a group obtained by dissolving nitrocellulose in a solubilizer of 3-methylbutyl acetate, isobutyl acetate, acetone, or a mixture thereof, and further adding ethyl alcohol. Since various medicinal drugs were added to the agent in addition to anti-inflammatory drugs, the solvent was volatilized after application to the skin, and a transparent or translucent film on the skin required a film close to the skin tissue (especially the stratum corneum) It can be formed on the skin, seals and protects the affected area, enhances the effect and durability of the contained drug by sterilizing the affected area and promoting percutaneous absorption of the drug by the ODT effect and the bactericidal effect of the affected area, Prevents infection and transfer of dirt to third parties due to outflow of body fluids and diffusion of contaminants such as bacteria. In addition, it is possible to prevent the occurrence of inflammation caused by scratching the affected part due to itching. Even a base that does not contain a drug alone protects the skin itself by forming a film on the skin where the plaster is thinly applied, and protects the skin from physical irritation. In other words, there is an effect of having an action that can also be a second artificial stratum corneum.

[Table 2] diagram of anti-inflammatory action test of Example 1 and Comparative Example 1 of the present invention [Table 3] diagram of blood flow measurement test of Example 1 and Comparative Example 1 of the present invention [Table 4] chart of contamination degree of wearing clothes of Example 1 and Comparative Example 1 of the present invention It is a figure of [Table 6] of the antitussive test result of Example 2 of this invention, and Comparative Examples 2 and 3. FIG.

Hereinafter, preferred examples of the film preparation for forming a film on the skin of the present invention will be described.
[Example 1]
[Composition ratio]
A preferred example 1 having an anti-inflammatory action of a film preparation for forming a film on the skin of the present invention will be described. First, the blending ratio of this example is shown in the following [Table 1].
[Table 1] [Composition ratio (wt%)]
Nitrocellulose ... 6.0%
Ethyl alcohol ... 72.9%
3-methylbutyl acetate 6.0%
Acetone 10.0%
Indomethacin: 0.5%
Crotamiton: 0.5%
Sericin 1.0%
l-Menthol: 0.1%
Sesame oil ... 3.0%

[Preparation method]
The film preparation for forming a film on the skin of Example 1 is prepared by the following procedure so as to achieve the above composition ratio.
First, 5 to 10% by weight, preferably 6.0% by weight of nitrocellulose is dissolved in 3 to 8% by weight, preferably 6.0% by weight of 3-methylbutyl acetate, and then further acetone 12 to 8%. Add wt%, preferably 10.0 wt% and stir well at a liquid temperature of 30 ° C. Next, 80 to 60% by weight, preferably 72.9% by weight, of ethyl alcohol is added to the solution and stirred well, and then indomethacin, crotamiton, l-menthol, and sesame oil are added in small amounts while stirring. After stirring and kneading for 3 hours, the mixture is allowed to stand at room temperature for 24 hours for production.
That is, the above-mentioned nitrocellulose, 3-methylbutyl acetate, and acetone are film-forming materials, and ethyl alcohol is a solvent that volatilizes, and in 30 seconds to 1 minute after application, ethyl alcohol volatilizes and a film is formed on the surface of the preparation. To be.
In the above composition, 0.5% of indomethacin is added as a non-steroidal anti-inflammatory agent for external use whose main effect is to treat painful and swollen skin diseases and inflammation of muscles and joints. If it is too much, side effects and costs increase, so 1 to 0.2% by weight is good, and 1 to 0.2% by weight of crotamiton as an indomethacin solubilizing agent / antifungal agent, preferably 0.5% by weight, film formation Sericin 1.0 was attached as a moisturizing agent for improving the moisturizing properties of the later skin, but it is preferably 0.2 to 5.0% by weight, preferably 1.0 to 3.0% by weight, If it is less than 0.2% by weight, there is no effect, and if it exceeds 5% by weight, sericin precipitates and does not dissolve. As a bactericidal disinfectant / cooling agent, 0.05% to 0.3% by weight of l-menthol, preferably 0.1% by weight, and sesame oil is added to increase the strength, flexibility and ODT effect of the film during film formation. Although the weight percent is added, even if the amount is too small, there is no medicinal effect.

[Anti-inflammatory test with bathing]
The effect | action and effect of the film preparation for baths which forms a film on the skin of Example 1 manufactured by said composition and the adjustment method were verified on the following conditions.
(1) Subject: This film preparation (hereinafter: Example 1)
Control product: Usually commercially available anti-inflammatory gel preparation containing indomethacin (hereinafter referred to as Comparative Example 1) (B company indomethacin-containing gel preparation)
(2) Subjects: 5 adult volunteers with low back pain x 2 groups, 10 people in total (men 43 to 58 years old)
(3) Test method: Dosage / administration method and administration period A predetermined amount of the example product or comparative product was uniformly applied to the subject's waist 12 hours before bathing (1 hour after waking up). This action was carried out for 6 consecutive days every day.
(4) Symptom Evaluation Judgment Symptoms of low back pain were evaluated according to the following criteria.
3 points: Severely symptom 2 points: Severe symptom 1 point: Slight symptom 0 point: No symptom (5) Judgment of improvement of symptom Judged.
Significant improvement (++): 3 → 0, 2 → 0
Moderate improvement (++): 3 → 1, 1 → 0
Minor improvement (+): 3 → 2, 2 → 1
Unchangeable (±): Symptoms do not change
Deterioration (-): Deterioration of symptoms (6) Evaluation of feeling of use Evaluation after use was determined according to the following criteria.
1 point: very preferable, 2 points: preferable, 3 points: normal, 4 points: bad,
5 points: Very bad, 6 points: Cannot be used (7) Dirt of bath (hot water) when bathing 1 point: Very, 2 points: Yes, 3 points: A little, 4 points: Almost no,
5 points: Not at all

(8) Test results The test results are shown in Table 2 of FIG. As shown in [Table 2], Example 1 was determined on the 7th day, and in the determination of the degree of improvement of symptoms, there were 4 cases of marked improvement, 1 case of moderate improvement, and 5 cases out of 5 cases. More than moderate improvement. On the other hand, in the improvement degree of the symptom in the comparative example 1, the moderate improvement was 1 case and the mild improvement was 4 cases.
Moreover, in the determination of the feeling of use in Example 1, it was very preferable, but 4 examples were preferable, but 1 example was preferable, and 5 examples out of 5 were more than preferable. On the other hand, in the judgment of the feeling of use in Comparative Example 1, there were 2 cases that were bad, 1 case that was very bad, and 2 cases that were normal.
There was no stain on the bathtub and hot water at the time of bathing in Example 1, but there were 5 cases, and it was considered that there was no bathtub contamination due to the preparation. On the other hand, in Comparative Example 1, there were 2 cases of bathing and hot water stains when taking a bath, and all 3 cases were answered very much.
From the above results, the Example product is superior to the Comparative Example product in all aspects of improvement in symptoms, feeling of use, and evaluation of bath stains when taking a bath. Proved to be
In this way, it is possible to maintain a certain amount applied since the paste is not soiled after application and the paste is not wiped off by clothes etc., and the paste is washed by washing the body such as bathing and showering. Since it is not washed away, the drug effect on the affected area can be maintained, and bathing does not contaminate the hot water in the bathtub.

[Blood flow measurement test]
The effect on the blood flow of the film preparation for forming a film on the skin of Example 1 produced by the above composition and preparation method was verified under the following conditions.
(1) Subject: Film formulation for bath (formulation of Example 1 above)
Control product: Ordinary commercially available anti-inflammatory analgesic indomethacin-containing gel preparation (hereinafter: Comparative Example 1) (B company indomethacin-containing gel preparation)
(2) Subject: Adult male volunteer (57 years old)
(3) Test method:
After confirming that the subject was in a certain resting state, a probe was applied to the subject's right waist, and the maximum blood flow (PK), average blood flow (MN), and pulse were measured. Thereafter, a certain amount of the comparative product was uniformly applied to the right waist, and after 60 minutes, the shoulder was immersed in a 40 ° C. bath for 10 minutes, and PK, MN and pulse of the left shoulder were measured again after 1 hour from the bath.
Seven days later, the same test subject was also measured for the comparative example product. The following measuring instruments were used for measurement throughout all tests.
Measuring instrument: Ultrasonic blood flow meter ES-1000SP2
Probe: MODEL / T8MO5S8C

(4) Test results:
The test results are shown in [Table 3] in FIG. As can be seen from [Table 3], before application of the preparation of Example 1, the maximum blood flow was 5.8 (no relative unit because of relative velocity: the same applies hereinafter), the average blood flow was 1.8, and the pulse was 60. However, in the measurement after bathing in which the example product was applied, the maximum blood flow was 20.1, the average blood flow was 5.6, and the pulse stay was 60. When Example 1 was applied and bathed, an increase in blood flow of about 3.5 times at the maximum blood flow and about 3.1 times of the average blood flow was observed, but the pulse rate remained almost unchanged.
On the other hand, Comparative Example 1 had a maximum blood flow of 6.1, an average blood flow of 1.8, and a pulse of 61 (several / minute) before application. The maximum blood flow was 8.6, the average blood flow was 2.2, and the pulse was 61 (several / minute). By application and bathing in Comparative Example 1, a slight increase of about 40% (1.4 times) in the maximum blood flow and about 20% (1.2 times) in the average blood flow was observed, but there was almost no change in the pulse.
From the above results, it is considered that the synergistic effect of the bath and the preparation of the example product is much more efficient with respect to the blood flow than the comparative example product.

[Contamination test for worn clothes]
(1) Test method The degree of contamination of clothes (especially underwear) worn on the day at the same time in the anti-inflammatory test with bathing was determined for 6 days every day according to the following criteria for the underwear taken off during bathing.
Very dirty: 1 point, dirty: 2 points, slightly dirty: 3 points,
Almost no dirt: 4 points, no dirt: 5 points (2) Test results The test results are shown in Table 4 in FIG. As can be seen from [Table 4], in Example 1, all five subjects replied that the stain on the underwear due to the drug was not soiled at all during the test period of 6 days. On the other hand, the comparative example product gave more answers than all five people including the test subject who answered that it was very dirty. This trend was almost the same during the test period.
From the above results, the product of the example did not contaminate the clothes (especially the underwear) compared to the product of the comparative example, which gave a good impression to the subject, and this was reflected in the persistence of the treatment and its therapeutic effect. It was thought to be an important factor.

Next, a second embodiment of the present invention will be described.
[Example 2]
In the film preparation for forming a film on the skin of the present invention, a preferred Example 2 having an antipruritic (suppressing itching) action will be described.
First, the mixing ratio of Example 2 is shown in the following [Table 5].
[Table 5] [Composition ratio:% by weight]
Nitrocellulose ... 8.0
Polyvinyl alcohol ... 1.0
Ethyl alcohol ... 68.9
Isobutyl acetate ... 5.0
Acetone ... 10.0
Diphenhydramine ... 1.0
l-menthol ... 3.0
dl-Camphor ... 1.0
Glycyrrhetinic acid ... 0.1
Chitin and chitosan ... 1.0
Castor oil ... 1.0

[Adjustment method]
The film preparation for forming a film on the skin of Example 2 is adjusted by the following procedure so as to achieve the above composition ratio.
First, 5-10% by weight of nitrocellulose, preferably 8.0% by weight and 0.5-2% by weight, preferably 1.0% by weight of polyvinyl alcohol, and 3-7% by weight of isobutyl acetate, preferably 5%. After dissolving in 0.0% by weight with stirring, 8 to 12% by weight, preferably 10.0% by weight of acetone is further added and stirred well at a liquid temperature of about 30 ° C. Next, 50 to 80% by weight, preferably 68.9% by weight, of ethyl alcohol is added to this stirring liquid and stirred for about 30 minutes, and then diphenhydramine, l-menthol, dl-camphor, glycyrrhetinic acid and castor oil are sequentially stirred. Add little by little and stir 3 hours after adding the last component. Thereafter, it is allowed to stand at room temperature for 24 hours for production.
That is, the above-mentioned nitrocellulose, polyvinyl alcohol, isobutyl acetate, and acetone are film-forming materials. Ethyl alcohol is a solvent that volatilizes, and the ethyl alcohol volatilizes within about 30 seconds to 1 minute after application, and a film is formed on the surface of the preparation. To be formed.
In the above composition, 0.5% of diphenhydramine is added as an antiallergic external preparation. However, if it is too little, there is no medicinal effect, and if it is too much, side effects and costs increase, so 02 to 1.2% by weight is good. 1.0-5.0% by weight of l-menthol as a refreshing agent, preferably 3.0% by weight, and 1.0% of dl-camphor as an antidepressant were added, but 0.5-10.0% by weight 1.0 to 5% by weight, preferably 0.5 to 3.0% by weight, preferably 1.0% by weight of glycyrrhetinic acid as an anti-inflammatory agent, moisturizing to improve the skin's moisture retention after film formation Chitin / chitosan 1.0 is attached as an agent, but 0.2 to 3% by weight is preferable, preferably 1.0% by weight, and castor oil for enhancing the strength and flexibility of the film during film formation and the ODT effect. 1.0% by weight is added, but if it is too little, there is no medicinal effect, too much Since the film formation is inhibited, 0.5 to 10% by weight is preferable.

[Antipruritic examination]
The effect | action and effect of the antipruritic film formulation which forms a film on the skin of Example 2 manufactured by said composition and the adjustment method were verified on the following conditions.
(1) Subject: film preparation (formulation of Example 2 above)
Control product: A commercially available itching-preventing ointment (Diphenhydramine manufactured by Company D,
ointment formulation containing l-menthol, dl-camphor, etc .: hereinafter referred to as Comparative Example 2)
(2) Subjects: 3 male volunteers aged 55 to 58 (3) Test method:
One captured mosquito was placed in a transparent polyethylene bag (30 cm × 50 cm), inflated with air, and the subject's right hand was placed in the bag. After confirming that the mosquito stabbed a part of the hand, the Example product was applied, and the time from the occurrence of itchiness to the disappearance and the disappearance time of the edema that occurred at the stabbed site were measured. Further, the degree of redness after 1 hour of intentionally scratching the stabbed portion 10 times was evaluated according to the following evaluation criteria.
At the same time, the degree of skin damage at the scratched site was recorded according to the following criteria.
As a control (Comparative Example 3), no drug treatment was recorded. However, the part of the hand that mosquito sucks is not limited, and the part of the hand that has been stung first is selected as the evaluation target.
Evaluation criteria for redness: very strong (++), strong (++),
Slightly strong (+), cannot be judged (±), no response (-)
Evaluation criteria for skin damage: very strong (++), strong (++), slightly strong (+),
Mild (±), None (-)

(4) Test results:
The test results are shown in [Table 6] in FIG.
In Example 2, itching disappeared in 43 seconds on average after drug application, and edema took 13.7 minutes, whereas in Comparative Example 2, it took 156 seconds on average to disappear, and 31 in edema disappearance. It took 3 minutes.
In Comparative Example 2, it took about 3.6 times as long as the stagnation disappeared and about 2.3 times as long as the edema disappeared. In the untreated control (Comparative Example 3), the itch disappearance time averaged 328 seconds, and the edema disappearance time was 86.7 minutes. In addition, the skin reaction 1 hour after intentionally scratching the affected area was strong redness in 1 case and no strong treatment in 2 cases in 3 cases. In Comparative Example 2, there were 2 cases of strong redness, which could not be judged, but 1 case. However, in Example 2, it was not possible to judge, but other than 1 case had no reaction.
At the same time, the degree of skin damage evaluated in the non-treated comparative example 3 was strong but 1 case, slightly strong but 2 cases, comparative example 2 was slightly strong but 2 cases, and the mildness was 1 case. There was no skin damage.
From the above results, both Example 2 and Comparative Example 2 exhibited an effective antipruritic effect compared to no treatment for inflammation such as itch caused by mosquito bites, but the former far exceeded the latter. From the above results, it is considered that Example 2 can be a useful preparation more than the conventional Comparative Example 2.
Moreover, in Example 2, in order to seal the affected part without any burden, it does not cause skin damage such as rash of the affected part, and the plaster is not wiped off with clothes, etc. The applied amount can be maintained, and the medicinal effect acts reliably.

As described above, the embodiment of the film preparation for forming a film on the skin of the present invention improves the transdermal absorbability of the contained drug to the affected area, enhances the local therapeutic effect, and further protects the affected area with a film. In order to prevent physical and chemical irritation and bacterial infection from the outside, the solvent is volatilized after being applied to the skin, and the affected part is formed on the affected part of the skin by applying a transparent or translucent film. It seals, enhances the transdermal absorbability of the drug, prevents the direct contact between the affected area and moisture, and at the same time prevents the side effect (rash, redness, blistering, etc.) of the affected area.
Moreover, by preventing the outflow of the drug by bathing or showering by covering the drug applied to the affected area with a film as in Example 1, the effect can be expected to be sustained, and further, the third through water. Eliminate infection and discomfort to the elderly. In addition, since it is non-aqueous, the contained drug has high stability, and there is no need to use a preservative or surfactant that has a risk of adversely affecting the skin. Further, as in Example 2, it is extremely effective against stagnation, and stagnation disappears immediately.
In addition, as a drug-free preparation, the role of the stratum corneum of the skin (protection against physical and chemical invasion from the outside), sweating control, and body odor (by sterilization and disinfection by base components (such as ethyl alcohol)) It is also possible to prevent sweat odor), and one or more moisturizing agents may be included to improve the moisture retention of the skin after the film formation.
Thus, it goes without saying that the present invention is not limited to the above-described embodiments as long as the features of the present invention are not impaired.

The film preparation according to the present invention solves the above-mentioned problems, and the invention according to claim 1 is characterized in that nitrocellulose is dissolved in a mixture of 3-methylbutyl acetate or isobutyl acetate and acetone, and ethyl alcohol is further added. In order to improve the strength, flexibility and ODT effect of the film during film formation, it contains one or more natural oils such as perilla oil, sesame oil, sesame oil , olive oil, horse oil, hinoki oil and castor oil. and, by incorporating a topical non-steroid anti-inflammatory drugs or topical corticosteroids as an anti-inflammatory agent, and characterized in that so as to seal the affected area by forming a transparent or semi-transparent film on the skin of the application site The film preparation forms a film on the skin.

Further, the invention of claim 1, containing as a drug that dissolves in the dissolution agent, the topical adrenocortical hormone whose main efficacy to suppress the external non-steroid anti-inflammatory drugs or affected area of inflammation as anti-inflammatory agents However, the topical corticosteroids for external use include amcinonide, prednisolone valerate acetate, dexamethasone valerate, betamethasone valerate, diflorazone acetate, hydrocortisone acetate, difluprednate, betamethasone dipropionate, dexamethasone, triamcinolone acetonide, halcinonide, Hydrocortisone, flumetasone pivalate, pudesonide, mometasone furoate, fluocinonide, fluocinolone acetonide, fludroxycortide, prednisolone, alcromethasone propionate, clobetasol propionate, propionate Dexamethasone, there deprodone propionate, beclomethasone propionate, betamethasone, clobetasone butyrate, hydrocortisone butyrate, butyrate propionate, hydrocortisone, is betamethasone butyrate propionate.
The non-steroidal anti-inflammatory drugs for external use include indomethacin, ufenamate, glycyrrhetinic acid, ketoprofen, diclofenac sodium, suprofen, piroxicam, felbinac, bufexamac, flurbiprofen, bendazac, methyl salicylate, and salicylic acid.
Furthermore, the invention of claim 1 contains at least one of natural oils such as perilla oil, sesame oil, sesame oil, olive oil, horse oil, hinoki oil and castor oil as a drug dissolved in the solubilizing agent. characterized in the strength and flexibility of the film and this was to enhance the ODT effect.

The invention of claim 2 includes a polyhydric alcohol (alkanediol, erythritol, glycerin, xylitol, diglycerin, dipropylene glycol, 1,3-butylene glycol, propylene glycol, hexane as a humectant in the solubilizer of claim 1. Diol, polyglycerin, D-mannitol, etc.), sericin, urea, uric acid, hyaluronic acid, hydrolyzed collagen gel, DMAE (dimethylaminoethanol), lecithin, soybean lecithin, egg yolk lecithin, chitin / chitosan, The film preparation for forming a film on the skin according to claim 1, which improves the moisture retention of the skin after film formation. By containing this moisturizing agent, it also has an effect of keeping moisturizing effectively for a long time in combination with the sealing action of the film.

According to the film preparation to form a film on the skin of the present invention, based on nitrocellulose, acetic acid 3-methylbutyl or isobutyl acetate, and the dissolved in a solubilizer acetone, or a mixture thereof, and further added ethyl alcohol since the addition of efficacy in addition to anti-inflammatory drug agent, solvent is volatilized after application to the skin, a transparent or translucent film skin tissue on the skin (especially the stratum corneum) on the skin need to close film To seal and protect the affected area, enhance the effect and durability of the contained drug by disinfecting the affected area and promoting percutaneous absorption of the drug by the ODT effect and the bactericidal effect of the affected area. Prevent infection and transfer of dirt to third parties due to spills and diffusion of contaminants such as bacteria. In addition, it is possible to prevent the occurrence of inflammation caused by scratching the affected part due to itching. Even a base that does not contain a drug alone protects the skin itself by forming a film on the skin where the plaster is thinly applied, and protects the skin from physical irritation. In other words, there is an effect of having an action that can also be a second artificial stratum corneum.
Further, Shisooiru, sesame oil, perilla oil, olive oil, horse oil, cypress oil, among natural oils castor oil, because it increases the strength and flexibility and ODT effect of film during to film containing one or more kinds, the affected area to be able to seal without burden without causing skin disorders such as diseased rash, further, as a drug dissolved in the dissolution agent, topical non-steroidal anti-inflammatory drugs some have as anti-inflammatory agents of the affected area because contain a topical corticosteroid whose main efficacy to suppress inflammation, without soiling the clothes or the like after the application of topical corticosteroids, since it is not also plaster is wipe off by clothes The applied amount can be maintained , and since the plaster is not washed away by washing the body such as bathing or showering , the drug effect of the affected area can be maintained, and bathing does not contaminate the hot water in the bathtub .

Claims (4)

  Nitrocellulose is dissolved in 3-methylbutyl acetate, isobutyl acetate, acetone, or a mixture thereof, and a drug for the purpose of medicinal effect is added to a solubilizing agent to which ethyl alcohol is added. Or the film formulation which forms a film on the skin characterized by sealing the affected part by forming a translucent film.   2. The film preparation for forming a film on the skin according to claim 1, further comprising an external non-steroidal anti-inflammatory drug as an anti-inflammatory agent or an external corticosteroid as an anti-inflammatory agent as the drug dissolved in the dissolution agent. .   As a drug dissolved in the solubilizer, it contains at least one of natural oils such as perilla oil, sesame oil, sesame oil, olive oil, horse oil, cypress oil, and castor oil. The film preparation for forming a film on the skin according to claim 1, wherein the ODT effect is enhanced.   Polyhydric alcohol (alkanediol, erythritol, glycerin, xylitol, diglycerin, dipropylene glycol, 1,3-butylene glycol, propylene glycol, hexanediol, polyglycerin, D-mannitol, etc.) as a humectant in the solubilizer Contains at least one of sericin, urea, uric acid, hyaluronic acid, hydrolyzed collagen gel, DMAE (dimethylaminoethanol), lecithin, soy lecithin, egg yolk lecithin, chitin / chitosan, and improves skin moisture retention after film formation The film preparation for forming a film on the skin according to claim 1.

Images