JP2007308403A - Skin care preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a skin care preparation based on a new mechanism of action. <P>SOLUTION: The skin care preparation comprises a medicine having a muscle relaxant action as an active ingredient. Dantrolene sodium is preferably used as the medicine having a muscle relaxant action being the active ingredient. Since by the skin care preparation, a muscular defense is controlled by the medicine having a muscle relaxant action and circulatory failure of topical tissue is ameliorated, inflammations of the skin and subcutaneous tissue are prevented and treated. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an external preparation for skin. More specifically, the present invention relates to an external preparation for skin useful for preventing and treating various diseases by suppressing muscle defense based on a novel mechanism of action.

In recent years, an increasing number of people suffer from various skin diseases including inflammatory skin diseases such as eczema and atopic dermatitis due to various factors such as changes in eating habits, environmental changes, and increased stress. Many skin external preparations have already been proposed as such various skin disease therapeutic agents (for example, Patent Documents 1 to 3).
JP 2005-247732 A JP 2005-325098 A JP 2006008584 A

So far, inflammation that occurs in the skin, whether it is an allergic reaction or a bacterial infection, has been addressed with treatments based on suppressing the excessive immune response and bacterial growth that cause it. . More specifically, anti-inflammatory treatments using anti-inflammatory analgesics such as corticosteroids and NSAIDS (non-steroidal anti-inflammatory drugs), or bacteriostatic / bactericidal treatments using antibiotics and antibacterial agents fall under this category. However, as the inflammation on the skin prolongs, all of these treatments not only tend to diminish their effectiveness, but side effects become a serious problem.
For example, long-term continuous use of topical corticosteroids leads to local skin atrophy, subcutaneous capillary dilation, and induction of infections such as fungal diseases. Furthermore, discontinuing topical corticosteroids often causes a rebound phenomenon, often leading to exacerbation of the underlying disease. In addition, as is well known, long-term use of antibiotics has led to fungal substituting phenomena and emergence of resistant bacteria, which have already developed into social problems.

In view of the problems of such conventional external preparations for skin, the present inventor examined external preparations for skin based on a novel mechanism of action. As a result, various strains were prepared by relaxing the tension of muscle tissue causing muscular defense. It has been found that the symptoms of skin diseases can be improved and the effect is also observed in diseases other than skin diseases.
That is, when the tissue is damaged in various ways, various chemical mediators are released from the local tissue and cause inflammation. These inflammation-inducing substances not only cause inflammation, but also cause contraction and tension of skeletal muscle and cause muscular defense (also called muscular defense) in the inflamed area. For example, when inflammation occurs in various tissues or organs for some reason, the muscular defense continuously increases the tension of skeletal muscles in the vicinity, preventing the inflammation from spreading to surrounding tissues and organs. Yes. In addition, when injured from the outer surface of the skin due to trauma, burn, etc., the muscle tissue existing in the skin and subcutaneous tissue contracts and works to prevent bleeding and infection as much as possible.
In addition, long-term continuous use of a topical corticosteroid used for the purpose of suppressing inflammation results in skeletal muscle tension, which strongly impairs local circulation in combination with muscular defense. The local side effects of various external preparations of corticosteroids known so far are caused by such a mechanism.

Muscle defense is a purposeful biological response that is supposed to occur to protect the surrounding tissues from the various adverse effects of inflammation. However, the long-lasting tension (muscle defense) of local muscle tissue that accompanies inflammation of acute or chronic skin or subcutaneous tissue causes insufficiency of fluid such as blood in the local tissue, causing inflammation in response. Not only will it help, but rather it will result in preventing recovery from inflammation of the skin and subcutaneous tissue.
From such a point of view, the present inventor contains a drug capable of relaxing muscle tissue against excessive muscular defense that accompanies inflammation in the acute phase and muscular defense that accompanies chronic inflammation. It has been found that effective local anti-inflammation can be achieved by suppressing muscular defense directly and locally using an external preparation.
The present invention is based on such a new anti-inflammatory mechanism, and contains an agent having a muscle relaxant action as an active ingredient, and suppresses muscular defense, thereby causing inflammation of acute or refractory chronic skin or subcutaneous tissue. It provides a skin external preparation having an extremely high therapeutic effect on the skin.

  The external preparation for skin of the present invention contains a drug having a muscle relaxing action as an active ingredient. As the drug having the muscle relaxing action, a skeletal muscle relaxant and / or an anticholinergic is preferably used, and dantrolene sodium is particularly preferably used.

  According to the external preparation for skin of the present invention, muscular defense is suppressed by a drug having a muscle relaxing action, and circulatory failure of a local tissue is improved. As a result, it is possible to prevent or treat inflammation of acute or refractory chronic skin and subcutaneous tissue.

The external preparation for skin of the present invention contains a drug having a muscle relaxing action as an active ingredient. As the drug having the muscle relaxing action, any drug can be used as long as it can relieve strain of muscle tissue.
As the drug having such a muscle relaxing action, a skeletal muscle relaxant and an anticholinergic are preferably used. Examples of skeletal muscle relaxants include dantrolene sodium, baclofen, afloqualone, botulinum toxin, and the like. Similarly, an anticholinergic agent having a muscle relaxing action can also be used, and examples thereof include atropine and trihexyphenidyl hydrochloride.

As described above, drugs having various muscle relaxing effects can be used to relieve muscle tissue tension based on muscular defense, but drugs that have an effect only on skeletal muscle and hardly affect smooth muscle are preferred. From this point of view, dantrolene sodium, which has an action mechanism that suppresses Ca ⁺⁺ release from the sarcoplasmic reticulum of skeletal muscle, inhibits Ca ⁺⁺ binding to topolonin, and suppresses skeletal muscle contraction, relieves skeletal muscle tension. It is considered as the most preferable drug as a drug used for the purpose of suppressing muscular defense.

  The external preparation for skin of the present invention can be produced by mixing the above-mentioned drug having muscle relaxing action with a conventional pharmaceutical carrier and preparing it in an appropriate dosage form. Examples of such dosage forms include ointments, liquids, emulsions, creams, sprays, gels, poultices, etc., but since the effects are fast and simple, the ointment is used. Is preferred. The above preparation can be prepared according to a conventional preparation method.

  The content of the active ingredient in the external preparation for skin of the present invention can be appropriately adjusted depending on the dosage form, application symptoms, and the like. For example, in the case of an ointment preparation, usually 0.001% to 2.0% (w / w, the same applies hereinafter) , Preferably 0.01% to 1.0%, more preferably 0.05% to 0.5%, and still more preferably about 0.1%. In addition, when muscular defense has occurred over a wide range, such as a wide range of burns and trauma, in addition to the external preparation for skin of the present invention, in order to suppress a muscular defense reaction over a wide range of injured sites, The drug possessed can also be administered orally or parenterally.

  In the preparation of the skin external preparation of the present invention, various additives commonly used in this field can be added, such as purified water, ointment base (hydrophilic ointment base and hydrophobic ointment base), animals and plants. Examples include fats and oils, higher alcohols such as cetanol and oleyl alcohol, polyhydric alcohols such as glycerin and propylene glycol, petrolatum, lanolin, surfactants, preservatives, antioxidants, and refreshing agents.

  The external preparation for skin of the present invention can be administered by an appropriate administration route according to the dosage form, and the dose can also be adjusted as appropriate. For example, in the case of an ointment preparation, its dosage and usage can be adjusted as appropriate depending on the patient's symptoms, body weight, age, etc., and usually an appropriate amount may be applied to the affected area 1 to 5 times a day.

  The external preparation for skin of the present invention is not only effective for the prevention and treatment of various skin diseases such as atopic dermatitis, but also the prevention and treatment of various diseases whose symptoms are alleviated and cured by suppressing muscular defense. Useful for. Hereinafter, although the example of an applicable disease is demonstrated concretely, an applicable disease is not limited to the following example.

Dermatitis (eczema, atopic dermatitis, urticaria, dry dermatitis, etc.)
In order to calm inflammation in the acute phase and chronic phase of the skin and subcutaneous tissue, it is important to remove excessive tension and contraction of skeletal muscle such as muscular defense, which occurs at and around the site of inflammation. By administering the external preparation for skin of the present invention, it is possible to relieve the tension of skeletal muscles and eliminate local circulatory disturbance, so that inflammation of the skin and subcutaneous tissue can be effectively calmed down.

Wound trauma wounds, inflammation appearing due to wounds such surgical wounds, like the mechanism causing excessive muscle guarding, impair local circulation, not only result in delaying wound healing, a strong pain May cause. By administering the external preparation for skin of the present invention, the same mechanism as described above can provide an excellent therapeutic effect on the skin and inflammation around the skin that appear due to trauma, and can alleviate pain. In this case, not only the local anti-inflammatory effect but also the effect of promoting wound healing by restoring the local circulation.

In tissue disorders such as burns and burns, subcutaneous tissue such as skin and muscle directly suffers large damage, and local skeletal muscle contraction (muscle defense) is maximized. In particular, wound healing of moderate or more burns is often intractable. This is thought to be due to the fact that the local skeletal muscle contraction (muscular defense) becomes extremely strong and the local circulation almost stops because the skin and muscle tissue are significantly damaged by the burn. In addition, it is known that the acetylcholine receptor increases in burned muscle tissue. For this reason, the contraction of the local skeletal muscle occurs very strongly during the burn and strongly inhibits local circulation. As a result, more than moderate burns are often refractory and pain often occurs. By administering the topical skin preparation of the present invention, skeletal muscle contraction and muscular defense can be eased and local circulatory insufficiency can be eliminated, so that recovery from moderate burns or more can be accelerated. At the same time, and the accompanying intense pain can be alleviated. In addition, radiation burns that appear as a side effect of radiation therapy for cancer treatment are similarly effective.

Reducing side effects of topical corticosteroids Long-term continuous use of topical corticosteroids causes various side effects caused by the topical corticosteroids themselves to increase local skeletal muscle tone. Conceivable. In other words, the skeletal muscle response to corticosteroids, combined with the muscular defense of the biological response to inflammation, significantly inhibits local circulation. This serious circulatory disorder is thought to have appeared as a side effect of topical corticosteroids. By administering the external preparation for skin of the present invention, it becomes possible to directly relieve the continuous tension of local skeletal muscle, and the local side effects of the external preparation for corticosteroids can be greatly relieved.

Spastic Paralysis Symptoms The topical skin preparation of the present invention is a skeletal muscle that causes spastic paralysis for spastic paralysis symptoms such as spastic paralysis associated with myasthenia gravis and amyotrophic lateral sclerosis, spastic paralysis after cerebral infarction. Administration to the site can effectively relieve paralytic symptoms and improve QOL.

Stiff neck, muscular back pain, shoulder stiffness elicited by tension disc herniation excessive muscle tissue, muscular back pain, to such disc herniation, by administering the external preparation for skin of the present invention to the affected area, effective mitigation of the symptoms Can be achieved.

When chronic skeletal muscle tone persists due to various rheumatoid arthritis, it often has a significant adverse effect on local lymph flow. This causes edema and inflammation in the local joint tissue. When the topical skin preparation of the present invention is administered, rheumatoid arthritis is achieved by removing the local skeletal muscle tone that is the root cause and restoring the local circulation without using anti-inflammatory analgesics or immunosuppressants. Can be cured.

One of the causes of hair growth agent hair loss is said to be due to the excessive tension of the scalp impairing blood circulation to the hair root. When the external preparation for skin of the present invention is administered, excessive tension of the scalp can be relieved, blood circulation to the hair root can be improved, and hair growth can be promoted.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example etc., this invention is not limited to the example which concerns.

Example 1
Preparation of Ointment Formulation An ointment formulation having an active ingredient content of 0.1% was prepared according to a conventional method using dantrolene sodium (Dantorium injection, trade name, manufactured by Astellas Pharma Inc.) and a hydrophilic ointment base. This ointment was used in the following clinical trials.

The following trials were conducted with prior consent from the subjects.
Clinical trial example 1
A 12-year-old boy, atopic dermatitis suffered from atopic dermatitis shortly after birth, and used oral and external preparations such as antihistamines and steroids over a long period of time, but there was no decisive effect, gradually redness of the skin It was thinning and no further medication was possible. Therefore, the use of the ointment of the present invention was started. The ointment was used twice a day in the morning and evening, and it was prescribed to be used in the area where dermatitis was caused and used at the time of pruritus. Soon after the start of use of the ointment, strong itching disappeared completely, and after 1 month, skin inflammation and thinning improved. Since then, atopic dermatitis has been completely controlled only by the ointment.

Clinical trial example 2
34 year old female, chronic eczema
From the age of 20, eczema began to form throughout the body. At that time, it appeared seasonal at the turn of the season, but eczema has appeared throughout the body for the past two years. In addition to topical steroids and oral antihistamines, they were unable to achieve stable effects and were not regularly treated for fear of side effects of steroids over long periods of time. Therefore, the use of the ointment of the present invention was started. The ointment was used twice a day in the morning and evening. In addition, it was instructed to use it locally when itching sensation appeared and used it locally. The eczema that had appeared throughout the body soon after the start of use of the ointment was cured, leaving a part. Occasionally, it is now possible to control the symptoms of eczema that appears by simply applying it as needed.

Case 3
36-year-old woman, refractory face
Beginning at the age of 18, he began making comedones, then gradually worsened with age. After 30 years of age, there was a comedy in the face, and going out was exacerbated. Therefore, the use of the ointment of the present invention was started. The ointment was used twice a day in the morning and evening. The redness of the face started to disappear soon after the start of the use of the ointment, and the comedones almost disappeared after one month.

Clinical trial example 4
Rheumatoid arthritis, 48-year-old woman About half a year ago, edema and pain appeared in the second index finger joint and both knee joints of both hands. When I visited a local orthopedic surgeon, I was diagnosed with rheumatoid arthritis and was prescribed antirheumatic drugs. While taking this, the pain disappeared, but when the drug expired, the pain recurred and the amount of the drug gradually increased, so I felt anxious. Therefore, the use of the ointment of the present invention was started. It was recommended that the ointment be used twice a day in the morning and evening in the pain area, and used as needed when pain appears. Soon after the start of use of the ointment, the pain became very mild, and after 3 months, the administration of antirheumatic drugs is unnecessary and controlled. Finger edema has disappeared completely.

Clinical trial example 5
A 50-year-old man burned with hot water on his right index finger and became a second burn. After having been sufficiently cooled with tap water as soon as possible, he visited our hospital. Since the pain was so strong that it could not be controlled by taking NSAID alone, use of the ointment of the present invention was started. It was recommended that the ointment be used twice a day, morning and evening at the site of injury, and used as needed when pain appeared. The pain disappeared completely immediately after the use of the ointment, and the patient himself was greatly surprised. The healing speed of the burned skin surface was extremely fast, and blistering occurred after 3 days, a thin skin surface was formed after 1 week, and the wound was completely cured without leaving a scar after 2 weeks.

Formulation Example 25 g white petrolatum, 20 g stearyl alcohol, 12 g propylene glycol, 4 g polyoxyethylene hydrogenated castor oil, 1 g monoglyceride glyceride, 0.1 g ethyl paraoxybenzoate, 0.1 g dantrolene sodium and 37.8 g purified water are used as raw materials. According to a conventional method, an O / W type hydrophilic ointment was prepared.

Claims (3)

  An external preparation for skin containing a drug having a muscle relaxing action as an active ingredient.   The skin external preparation according to claim 1, wherein the drug having a muscle relaxing action is a skeletal muscle relaxant and / or an anticholinergic agent.   The skin external preparation according to claim 2, wherein the active ingredient is dantrolene sodium.