JPH08310948A - Antialopecic agent - Google Patents

Abstract

PURPOSE: To obtain an antialopecic agent, having excellent antialopecic actions, hardly causing adverse effects and capable of remarkably suppressing the progress of alopecia due to the use of especially an anticancer agent. CONSTITUTION: This antialopecic agent contains 1-100wt.%, preferably 10-100wt.% n-3-based highly unsaturated fatty acid (e.g. docosahexaenoic acid) as an active ingredient. The fatty acid is preferably >=90% purity in aspects of reduction, etc., in adverse effects. The active ingredient is formulated into a solid pharmaceutical preparation such as a powder, a granule, a capsule or a tablet or a liquid pharmaceutical preparation such as a syrup or an elixir or further a parenteral injection, a suppository, etc., by, as necessary, suitably blending a usually used ingredient therewith. The daily dose is about 0.1-2g/ human expressed in terms of the n-3-based unsaturated fatty acid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-alopecia agent effective for preventing and ameliorating alopecia, and more specifically, an anti-hair loss characterized by containing an n-3 polyunsaturated fatty acid as an active ingredient. It is related to anti-inflammatory drugs.

[0002]

Anticancer agents are widely used alone or in conjunction with surgical removal and radiation therapy for the treatment of cancer. However, while the use of an appropriate anti-cancer agent is effective for treating cancer or prolonging life, it is unavoidable that some side effects are brought about.

Alopecia also occurs as a side effect with a fairly high frequency. Alopecia has a direct impact on life,
Although it does not cause physical pain, it has a great influence on the psychological state of the patient, and its reduction is strongly desired in clinical settings.

N- which is the active ingredient of the anti-alopecia agent of the present invention
Polyunsaturated fatty acids of type 3 are known to have some useful physiological effects such as an effect of inhibiting the arachidonic acid cascade. For example, formulations for the prevention and treatment of thrombotic symptoms (JP-A-55-15444, JP-A-57-35512), drugs acting on the heart and cardiovascular system, and methods for producing the same (JP-A-64-27). ), A composition with selenium which acts on the thromboembolic state of the cardiovascular system (JP-A-2-22228), a lipid metabolism improving agent (JP-A-3-24018), and a brain function improving agent (JP-A-3-589).
26) or an angiogenesis inhibitor (JP-A-3-86819),
Functional food having brain function improving effect (Japanese Patent Laid-Open No. 2-49723)
No.) etc.

Further, fish oil containing a large amount of icosapentaenoic acid and docosahexaenoic acid also suppresses the activity of macrophages [Dustin LB, et al., J. IMMUNOL. 144, 48].
8-4897 (1990)], LTB ₄ and LTC ₄ production inhibition [Lokes
h BR, et al., Biochim. Biophys. Acta, 958,99-10
7, (1988)], a report that the production of TNF is suppressed [End
res S., et al., N. Enl. J. Med., 320,265-271, (198
9)] However, it is not known at all that n-3 polyunsaturated fatty acids have an action as an anti-alopecia agent.

[0006]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a new type of anti-alopecia agent having few side effects and excellent anti-alopecia activity.

[0007]

Means for Solving the Problems The present inventors have conducted extensive studies on reducing alopecia, particularly alopecia associated with administration of anticancer agents, and as a result, administration of n-3 polyunsaturated fatty acids suppresses alopecia. The present invention has been completed based on the new finding. That is, the present invention provides an anti-alopecia agent, which comprises an n-3 polyunsaturated fatty acid as an active ingredient.

The n-3 polyunsaturated fatty acid used in the present invention may be a free acid, a salt thereof, an ester, a glyceride or the like. Examples of the salt include sodium salt, potassium salt, calcium salt and the like, and examples of the ester include linear or branched alkyl esters having 1 to 6 carbon atoms, such as methyl ester, ethyl ester, propyl ester. , I-propyl ester, butyl ester, hexyl ester and the like. The glyceride may be any of monoglyceride, diglyceride and triglyceride. For example, monoglyceride of higher unsaturated higher fatty acid and a method for producing the same (JP-A-62-226947).
), A glyceride of eicosapentaenoic acid, a method for producing the same, an oil and fat product containing the same (JP-A-62-153249), and a method for producing a highly unsaturated fatty acid glyceride (JP-A-62-91188).
No.), a method for producing a glycerin ester of eicosapentaenoic acid (Japanese Patent Publication No. 5-82197), and the like. As the oil containing the n-3 polyunsaturated fatty acid, the proportion of the n-3 polyunsaturated fatty acid (as a free acid) in the total fatty acids is 10% or more, preferably 20% or more. Examples of such things are sardines, mackerel, horse mackerel, salmon, fish oil extracted from blue-backed fish such as saury, fish oil derived from orbital fat of large marine fish such as tuna and bonito, oil and fat derived from microorganisms, krill oil, cod Preferred examples include those obtained by refining marine product-derived fats and oils extracted from squid liver.

In the present invention, as the n-3 polyunsaturated fatty acid, icosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), especially the latter is preferable in that the hair loss suppressing effect is remarkable. Further, n-3 used in the present invention
The polyunsaturated fatty acid having a purity of 90% or higher, more preferably 95% or higher, is preferable in terms of reducing side effects.

The anti-alopecia agent of the present invention can be administered orally or parenterally. As the orally-administered agent, solid preparations such as powder, granules, capsules and tablets, or liquid preparations such as syrups and elixirs can be used. In addition, parenteral administration agents such as injections and suppositories can be used.

These preparations are manufactured according to a conventional method by adding pharmacologically and pharmaceutically acceptable manufacturing aids to the active ingredient. Further, it is also possible to prepare a sustained-release preparation by a known technique. When the manufacturing aid is used, the amount of the n-3 polyunsaturated fatty acid in the anti-alopecia agent of the present invention is usually 1 to 100% by weight, preferably 10 to 100%.
% By weight.

In order to produce a solid preparation for oral administration, the active ingredient and excipients such as lactose, starch, crystalline cellulose, calcium lactose, magnesium aluminometasilicate, and silicic acid anhydride are mixed to prepare a powder. Alternatively, if necessary, a binder such as sucrose, hydroxypropylcellulose, polyvinylpyrrolidone, etc., a disintegrating agent such as carboxymethylcellulose, carboxymethylcellulose calcium, etc. are added to wet or dry granulate to obtain granules. To manufacture tablets, these powders and granules may be tableted as they are or by adding a lubricant such as magnesium stearate and talc. These granules or tablets are coated with an enteric base such as hydroxypropylmethyl cellulose phthalate, methacrylic acid, and methyl methacrylate copolymer to form an enteric preparation, or coated with ethyl cellulose, carnauba wax, hardened oil, etc. to form a sustained-release preparation. You can also do it. To manufacture capsules, powders or granules should be filled in hard capsules, or the active ingredient should be dissolved as it is or in glycerin, polyethylene glycol, sesame oil, olive oil, etc. and then coated with a gelatin film to give soft capsules. You can

To prepare a liquid preparation for oral administration, an active ingredient and a sweetener such as sucrose, sorbitol and glycerin are dissolved in water to prepare a transparent syrup, and essential oil, ethanol and the like are added to form an elixir. Alternatively, gum arabic, tragacanth, polysorbate 80, sodium carboxymethyl cellulose, etc. may be added to prepare an emulsion or suspension. If desired, a flavoring agent may be added to these liquid formulations.
Coloring agents, preservatives and the like may be added.

In order to produce an injection, the active ingredient is optionally added with hydrochloric acid, sodium hydroxide, lactose, sodium lactate,
Dissolve in distilled water for injection together with pH adjusting agents such as sodium monohydrogen phosphate and sodium dihydrogen phosphate, isotonic agents such as sodium chloride and glucose, and sterilize and filter into ampoules, or mannitol and dextrin. Alternatively, cyclodextrin, gelatin, etc. may be added and freeze-dried under vacuum to prepare a solution-type injection before use. Further, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to give an emulsion for injection.

For the preparation of a rectal preparation, is the active ingredient and a suppository base such as cacao butter, tri-, di- and monoglycerides of fatty acids, polyethylene glycol, etc. moistened and melted and poured into a mold to cool? The active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then coated with a gelatin film.

To prepare an external preparation for skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to prepare an ointment, or rosin, an alkyl acrylate ester. After kneading with an adhesive such as a polymer, it is spread on a non-woven fabric such as polyethylene to obtain a tape.

The anti-alopecia agent of the present invention having the above constitution is
It can be produced by a known production method, for example, the method described in the Japanese Pharmacopoeia 10th Edition General Rules for Preparation or a method with appropriate modification.

The dose depends on the type of target disease, the age of the patient,
Depending on sex, weight, symptoms, or mode of administration,
Generally, the amount of the n-3 polyunsaturated fatty acid is about 0.1 to 2 g / person per day, and it can be used once or several times. Hereinafter, the present invention will be described in detail with reference to Examples.

[0019]

【Example】

[Example 1] Male Wistar rats aged 8 days were used in the experiment. This sample was divided into the following four groups A to D. One mother was attached to each group and allowed to freely feed. The mother was allowed to freely ingest solid food CE2 manufactured by CLEA Japan and had free access to water. The drug is administered once a day from 11 am to 11 pm
I went during the time.

A) Ara-C [Kirocide Injection (trade name) manufactured by Nippon Shinyaku Co., Ltd.) single administration group (7 animals) Ara-C is 20 mg / ml of injection solution in 0.9% physiological saline at 2 mg / ml. Dilute to 0.1ml / 10g
The body weight was administered intraperitoneally for 7 consecutive days. B) Ara-C and DHA combined administration group (3 animals) Similarly, Ara-C was intraperitoneally administered at the same dose as above for 7 consecutive days, and DHA (ethyl ester, purity 97).
%, Containing Vitamin E 0.3%) was orally administered in an amount of 0.1 ml / animal simultaneously for 7 days using an oral sonde specially processed for infants. C) Ara-C and EPA combined administration group (7 animals) Similarly, Ara-C was intraperitoneally administered at the same dose as above for 7 consecutive days, and EPA (ethyl ester, purity 97).
%, Containing Vitamin E 0.3%) was orally administered in an amount of 0.1 ml / animal simultaneously for 7 days using an oral sonde specially processed for infants. D) Control group (2 animals) Only physiological saline was intraperitoneally administered.

The hair loss was determined by macroscopic observation at 17 days of age for the samples administered in the above 4 groups. The degree of hair loss was determined according to the following criteria. Table 1 shows the test results.

Criteria for Degree of Hair Loss Score 0: 0 to 25% Hair Loss 1:26 to 50% Hair Loss 2:51 to 75% Hair Loss 3:76 to 100% Hair Loss

[0023]

[Table 1] * Displays the number of rats corresponding to each score

From the above results, the DHA combination administration group and E
In the PA-administered group, suppression of hair loss was observed.

[Example 2] SD male rats aged 8 days were used for the experiment. This sample was divided into the following three groups A to C. One mother was attached to each group and allowed to freely feed. The mother was allowed to freely ingest solid food CE2 manufactured by CLEA Japan and had free access to water. The drug was administered once a day between 10 am and 11 am.

A) Ara-C single administration group (6 animals) For Ara-C, 20 mg / ml injection solution was diluted to 5 mg / ml with 0.9% physiological saline to give 0.1 ml / 10 g.
The body weight was administered intraperitoneally for 7 consecutive days. B) Ara-C and DHA combined administration group (9 animals) Similarly, Ara-C was intraperitoneally administered at the same dose as above for 7 consecutive days, and DHA (ethyl ester, purity 97) was used.
%, Containing Vitamin E 0.3%) was orally administered in an amount of 0.1 ml / animal simultaneously for 7 days using an oral sonde specially processed for infants. C) Control group (2 animals) Only physiological saline was intraperitoneally administered.

The hair loss of the administered samples of the above 3 groups was evaluated by visual observation from 13 to 17 days of age.
The degree of hair loss was determined according to the above criteria. The test results are shown in Table 2.

[0028]

[Table 2] * Displays the number of rats corresponding to each score

From the above results, it is clear that the progression of hair loss is significantly suppressed in the DHA combined administration group.

[0030]

INDUSTRIAL APPLICABILITY The anti-alopecia agent containing the n-3 polyunsaturated fatty acid of the present invention as an active ingredient remarkably suppresses alopecia, particularly the progression of alopecia associated with the use of anti-cancer agents. The n-3 polyunsaturated fatty acid, which is an active ingredient, is a substance with extremely low toxicity, and thus the anti-alopecia agent of the present invention is highly useful.

Claims (2)

[Claims] 1. An anti-alopecia agent comprising an n-3 polyunsaturated fatty acid as an active ingredient. 2. The anti-alopecia agent according to claim 1, wherein the n-3 polyunsaturated fatty acid is icosapentaenoic acid or docosahexaenoic acid.