JP5051471B2 - Resting phase alopecia treatment - Google Patents
Resting phase alopecia treatment Download PDFInfo
- Publication number
- JP5051471B2 JP5051471B2 JP2008531975A JP2008531975A JP5051471B2 JP 5051471 B2 JP5051471 B2 JP 5051471B2 JP 2008531975 A JP2008531975 A JP 2008531975A JP 2008531975 A JP2008531975 A JP 2008531975A JP 5051471 B2 JP5051471 B2 JP 5051471B2
- Authority
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- Prior art keywords
- leptin
- alopecia
- therapeutic agent
- resting
- hair
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Description
本発明は、休止期脱毛症治療剤に関し、さらに詳しくは、レプチンまたはその部分ペプチドを有効成分として含有する休止期脱毛症治療剤に関する。 The present invention relates to a therapeutic agent for resting alopecia, and more specifically to a therapeutic agent for resting alopecia containing leptin or a partial peptide thereof as an active ingredient.
毛髪はその部位により、頭髪、眉毛、睫毛、ヒゲ、腋毛、陰毛、体毛などと区別される。しかし、その構造は共通で、一本の毛髪は包根部の毛母において細胞分裂により新しい毛髪成分としての角質が新生されて成長し、それを包む固有の上皮性の毛包で支持、固定される。 Hair is distinguished from head hair, eyebrows, eyelashes, beards, eyelashes, pubic hairs, body hairs, etc., depending on the site. However, the structure is common, and a single hair grows and grows as a new hair component by cell division in the hair matrix of the root of the root, and is supported and fixed by the intrinsic epithelial hair follicle that encloses it. The
頭皮における発毛は連続して起こるものではなく、発育と休止の期間を交互に繰り返す活性サイクルにより起こるものである。このサイクルは主に、成長期、退行期、および休止期という３つの段階に分けられ、これを毛周期と呼ぶ。成長期はサイクルの発育段階であり、毛包が真皮に深く浸透し、細胞が急速に増殖し、分化して毛髪を形成することを特徴とする。次の段階は退行期であり、これは細胞分裂が停止し、この間に毛包が真皮において退行し、発毛が停止することを特徴とする推移段階である。次の段階の休止期は休止段階として特徴づけられ、この間に退行した毛包は真皮乳頭細胞群と近接した毛根を有する。その後、毛根中で急速に細胞が増殖し、真皮乳頭が膨張し、基底膜成分が同化して、新たな成長期が始まる。ところで、充分な成長期が維持されず、休止期へ移行し、休止期が延期するといわゆる休止期脱毛症が生じる。 Hair growth in the scalp does not occur continuously, but occurs by an active cycle that alternates between the period of development and rest. This cycle is mainly divided into three stages, a growth period, a regression period, and a rest period, and this is called a hair cycle. Growth is the developmental stage of the cycle, characterized by deep penetration of hair follicles into the dermis, rapid proliferation and differentiation of cells to form hair. The next stage is the regression phase, which is a transitional stage characterized by the termination of cell division, during which the hair follicles regress in the dermis and the hair growth stops. The next quiescent phase is characterized as a quiescent phase, during which the regressed hair follicle has a hair root in close proximity to the dermal papillary cell population. Thereafter, cells rapidly proliferate in the hair root, the dermal papilla expands, the basement membrane components become assimilated, and a new growth phase begins. By the way, when a sufficient growth period is not maintained, the period shifts to a rest period and the rest period is postponed, so-called rest period alopecia occurs.
現在では、このような休止期脱毛症の治療剤として、休止期脱毛症の一種である男性型脱毛症の治療のために、局所用ミノキシジル（ＲＯＧＡＩＮＥ（登録商標）としてＰｈａｒｍａｃｉａ＆Ｕｐｊｏｈｎから市販されている）および経口用フィナステライド（ＰＲＯＰＥＣＩＡ（登録商標）として Ｍｅｒｃｋ ＆ Ｃｏ．，Ｉｎｃ．から市販されている）が知られている。
なお、特許文献１には、ニコチン酸エステルを投与するとレプチンレベルが増加し、皮膚腫瘍の退化、皮膚のホモオスタシスおよび再構築、創傷治癒、毛髪の成長をもたらすことが記載されている。しかしながら、この文献には、レプチンを投与することにより毛周期の休止期から成長期を誘導して、休止期脱毛症を治療しうることにつては記載されていない。Currently, as a therapeutic agent for such resting alopecia, topical minoxidil (commercially available from Pharmacia & Upjohn as ROGAINE®) for the treatment of male pattern alopecia, which is a type of resting alopecia. And oral finasteride (commercially available from Merck & Co., Inc. as PROPECIA®).
Patent Document 1 describes that administration of nicotinic acid ester increases leptin levels, leading to skin tumor degeneration, skin homoostasis and reconstruction, wound healing, and hair growth. However, this document does not describe that leptin can be administered to induce the growth phase from the resting phase of the hair cycle to treat resting alopecia.
本発明は、毛周期の休止期から成長期を誘導して休止期脱毛症（特に、男性型脱毛症）を治療するのに有用な薬剤を提供することを目的とする。 An object of the present invention is to provide a drug useful for treating resting alopecia (particularly male pattern alopecia) by inducing a growth period from a resting period of the hair cycle.
本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、レプチンまたはその部分ペプチドが、毛周期の休止期から成長期を誘導し、休止期脱毛症の治療に優れた効果を有することを見出し、この知見に基づいてさらに研究を進め、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that leptin or a partial peptide thereof induces the growth phase from the resting phase of the hair cycle and has an excellent effect on the treatment of resting alopecia. Based on this finding, the present inventors have further studied and completed the present invention.
すなわち、本発明は、
［１］ レプチンまたはその部分ペプチドを有効成分として含有することを特徴とする休止期脱毛症の治療剤、
［２］ 有効成分がレプチンである上記［１］に記載の治療剤、
［３］ 有効成分がレプチンの部分ペプチドである上記［１］に記載の治療剤、
［４］ レプチンがヒトレプチンである上記［２］に記載の治療剤、
［５］ ヒトレプチンがヒトリコンビナントレプチンである上記［４］に記載の治療剤、
［６］ 部分ペプチドが配列番号４で示される上記［３］に記載の治療剤、
［７］ 休止期脱毛症が男性型脱毛症である上記［１］〜［６］のいずれかに記載の治療剤、
［８］ 製剤型が皮下投与用注射剤である上記［１］〜［７］のいずれかに記載の治療剤、
［９］ 製剤型が局所塗布用製剤である上記［１］〜［７］のいずれかに記載の治療剤、
［１０］ 有効成分がリポソーム化されている上記［９］に記載の治療剤、
［１１］ 休止期脱毛症の治療剤を製造するためのレプチンまたはその部分ペプチドの使用、および
［１２］ 休止期脱毛症の患者に、治療有効量のレプチンまたはその部分ペプチドを投与することを特徴とする休止期脱毛症の治療方法、
に関する。That is, the present invention
[1] A therapeutic agent for resting alopecia comprising leptin or a partial peptide thereof as an active ingredient,
[2] The therapeutic agent according to the above [1], wherein the active ingredient is leptin,
[3] The therapeutic agent according to the above [1], wherein the active ingredient is a partial peptide of leptin,
[4] The therapeutic agent according to the above [2], wherein the leptin is human leptin,
[5] The therapeutic agent according to the above [4], wherein the human leptin is human recombinant leptin,
[6] The therapeutic agent according to the above [3], wherein the partial peptide is represented by SEQ ID NO: 4,
[7] The therapeutic agent according to any one of the above [1] to [6], wherein the resting alopecia is androgenetic alopecia,
[8] The therapeutic agent according to any one of [1] to [7] above, wherein the formulation type is an injection for subcutaneous administration,
[9] The therapeutic agent according to any one of the above [1] to [7], wherein the formulation type is a formulation for topical application,
[10] The therapeutic agent according to the above [9], wherein the active ingredient is made into a liposome.
[11] Use of leptin or a partial peptide thereof for producing a therapeutic agent for resting alopecia, and [12] A therapeutically effective amount of leptin or a partial peptide thereof is administered to a patient with resting alopecia A method for treating resting alopecia,
About.
本発明に係る休止期脱毛症治療剤は、これをヒトに投与することにより、毛周期の休止期から成長期へと誘導し、休止期脱毛症を治療することができる。 The therapeutic agent for alopecia alopecia according to the present invention can be administered to humans to induce the hair cycle from the resting phase to the growing phase to treat resting alopecia.
図１は、毛周期（Ａ）の図およびｄｂ／ｄｂマウスまたは正常マウスの生後３５日（成長期）の毛包状態を示す写真である。Ｂは正常マウス、Ｃはｄｂ／ｄｂマウスを示す。
図２は、生後７週齢（第２休止期）のｏｂ／ｏｂマウスもしくは正常マウスの背部抜毛後１４日目の写真およびｏｂ／ｏｂマウスもしくは正常マウスの毛包状態を示す図である。Ａ、Ｂは正常マウス、Ｃ、Ｄはｏｂ／ｏｂマウスを示す。
図３は、生理食塩水またはレプチンを投与したｏｂ／ｏｂマウスの１６日目の背部の写真である。Ａは生理食塩水投与マウス、Ｂはレプチン投与マウスを示す。
図４は、生後７週齢の正常マウスに生理食塩水もしくはレプチンを投与した２１日目の毛包状態を示す写真、およびレプチンまたは生理食塩水を投与した正常マウスの２１日目の背部の写真である。Ａは生理食塩水投与マウス、Ｂはレプチン投与マウスを示す。Ｃの上はレプチン投与マウス、Ｃの下は生理食塩水投与マウスを示す。
図５は、生後７週齢の正常マウスに生理食塩水もしくはレプチンの部分ペプチド（配列番号４）を投与した正常マウスの２１日目の背部の写真である。FIG. 1 is a diagram showing a hair cycle (A) and a photograph showing a hair follicle state at 35 days after birth (growth stage) of a db / db mouse or a normal mouse. B shows a normal mouse and C shows a db / db mouse.
FIG. 2 shows photographs of the 14th day after dorsal hair removal of ob / ob mice or normal mice at 7 weeks of age (second rest period) and the follicular state of ob / ob mice or normal mice. A and B are normal mice, and C and D are ob / ob mice.
FIG. 3 is a photograph of the dorsal region on the 16th day of an ob / ob mouse administered with physiological saline or leptin. A shows a physiological saline-administered mouse, and B shows a leptin-administered mouse.
FIG. 4 is a photograph showing the hair follicle state on the 21st day after administration of physiological saline or leptin to a 7-week-old normal mouse, and a photograph of the back of the normal mouse on day 21 after administration of leptin or physiological saline. It is. A shows a physiological saline-administered mouse, and B shows a leptin-administered mouse. Above C shows leptin-administered mice, and below C shows physiological saline-administered mice.
FIG. 5 is a photograph of the dorsal region on the 21st day of normal mice in which normal saline or leptin partial peptide (SEQ ID NO: 4) was administered to 7-week-old normal mice.
本発明に係る脱毛症治療剤の有効成分は、レプチンまたはその部分ペプチドである。本発明に係るレプチンとしては、マウスレプチンでもよく、ヒトレプチンでもよいが、好ましくはヒトレプチンである。シグナルペプチド（２１アミノ酸）を含めたヒトレプチンのアミノ酸配列は、配列番号１で示され、マウスのそれは、配列番号２で示される。 The active ingredient of the therapeutic agent for alopecia according to the present invention is leptin or a partial peptide thereof. The leptin according to the present invention may be mouse leptin or human leptin, preferably human leptin. The amino acid sequence of human leptin including the signal peptide (21 amino acids) is shown in SEQ ID NO: 1, and that of mouse is shown in SEQ ID NO: 2.
また、本発明に係るレプチンは、レプチン機能が維持されていれば、数アミノ酸が欠失してもよく、付加してもよく、置換されていてもよい。 Further, the leptin according to the present invention may be deleted, added, or substituted as long as the leptin function is maintained.
一方、本発明に係るレプチンの部分ペプチドとしては、前記レプチンの活性部位を含む部分ペプチド、すなわち低分子機能性ペプチドが挙げられる。部分ペプチドとしては、レプチンの起源となる動物（特にヒト）が本来有している酵素により切断されて生じる部分ペプチドが、抗原性が低いという点で好ましく、具体的には例えば配列番号４で示されるペプチドが挙げられる。 On the other hand, the leptin partial peptide according to the present invention includes a partial peptide containing the leptin active site, that is, a low molecular weight functional peptide. As the partial peptide, a partial peptide generated by cleavage by an enzyme originally possessed by an animal (particularly human) that is the origin of leptin is preferable in that it has low antigenicity. Peptides.
本発明に係るレプチンおよびレプチンの部分ペプチドは、常法により作製することができ、ヒトリコンビナントレプチン（Ｒ＆Ｄ システムズ社製）またはヒトレプチンの部分ペプチド（ＢＲＡＣＨＥＭ社製）などの市販品を用いることもできる。作製する場合、遺伝子工学的手法により常法に従って製造することができる。例えば、レプチンを例に挙げて説明すると次のとおりであるが、部分ペプチドの場合も、これに準じて製造することができる。まず、レプチンをコードする遺伝子（レプチン遺伝子）を、通常の遺伝子工学的方法（例えば、Ｓａｍｂｒｏｏｋ Ｊ．，Ｆｒｉｓｃｈ Ｅ．Ｆ．，Ｍａｎｉａｔｉｓ Ｔ．著、モレキュラークローニング第２版（Ｍｏｌｅｃｕｌａｒ Ｃｌｏｎｉｎｇ ２ｎｄ ｅｄｉｔｉｏｎ）、コールド スプリング ハーバー ラボラトリー発行（Ｃｏｌｄ Ｓｐｒｉｎｇ Ｈａｒｂｏｒ Ｌａｂｏｒａｔｏｒｙ ｐｒｅｓｓ）などに記載されている方法）に準じて取得する。レプチン遺伝子は、ヒトレプチン遺伝子が好ましく、シグナルペプチドをコードした配列を含むそのＤＮＡ配列は配列番号３のとおりである。次いで、得られたレプチン遺伝子を用い、通常の遺伝子工学的方法に準じてレプチンを製造することができる。 The leptin and the leptin partial peptide according to the present invention can be prepared by a conventional method, and commercially available products such as human recombinant leptin (R & D Systems) or human leptin partial peptide (BRACHEM) can also be used. When producing, it can be produced according to a conventional method by genetic engineering techniques. For example, leptin is described below as an example, but partial peptides can also be produced according to this. First, a gene encoding leptin (leptin gene) is obtained by a conventional genetic engineering method (for example, Sambrook J., Frisch EF, Maniatis T., Molecular Cloning 2nd edition), Cold Acquired in accordance with Spring Harbor Laboratory publication (method described in Cold Spring Harbor Laboratory Press). The leptin gene is preferably a human leptin gene, and its DNA sequence including a sequence encoding a signal peptide is as shown in SEQ ID NO: 3. Next, using the obtained leptin gene, leptin can be produced according to an ordinary genetic engineering method.
例えば、レプチン遺伝子が宿主細胞中で発現できるようなプラスミドを作製し、これを宿主細胞に導入して形質転換し、さらに形質転換された宿主細胞（形質転換体）を培養することで得られる培養物からレプチンを取得すればよい。 For example, a culture obtained by preparing a plasmid capable of expressing the leptin gene in a host cell, introducing the plasmid into the host cell, transforming it, and further culturing the transformed host cell (transformant). Leptin can be obtained from the object.
上記プラスミドとしては、例えば、宿主細胞中で複製可能な遺伝情報を含み、自立的に増殖できるものであって、宿主細胞からの単離・精製が容易であり、宿主細胞中で機能可能なプロモーターを有し、検出可能なマーカーをもつ発現ベクターに、レプチンをコードする遺伝子が導入されたものを好ましく挙げることができる。例えば、大腸菌での発現に使用される発現ベクターは、ｌａｃ、ｔｒｐ、ｔａｃなどのプロモーターを含む発現ベクターであって、これらはファルマシア社、宝酒造などから市販されている。さらなる高発現を導くことが必要な場合には、レプチンをコードする遺伝子の上流にリボゾーム結合領域を連結してもよい。用いられるリボゾーム結合領域としては、Ｇｕａｒｅｎｔｅ Ｌ．ら（Ｃｅｌｌ ２０，ｐ５４３）や谷口ら（Ｇｅｎｅｔｉｃｓ ｏｆ Ｉｎｄｕｓｔｒｉａｌ Ｍｉｃｒｏｏｒｇａｎｉｓｍｓ，ｐ２０２，講談社）による報告に記載されたものを挙げることができる。 Examples of the plasmid include a promoter that contains genetic information that can be replicated in a host cell, can be propagated autonomously, can be easily isolated and purified from the host cell, and can function in the host cell. Preferred examples include those in which a gene encoding leptin is introduced into an expression vector having a detectable marker. For example, an expression vector used for expression in E. coli is an expression vector containing a promoter such as lac, trp, tac, etc., and these are commercially available from Pharmacia, Takara Shuzo. If it is necessary to induce higher expression, a ribosome binding region may be linked upstream of the gene encoding leptin. Examples of the ribosome binding region used include Guarente L. et al. (Cell 20, p543) and Taniguchi et al. (Genetics of Industrial Microorganisms, p202, Kodansha).
宿主細胞としては、原核生物もしくは真核生物である微生物細胞、昆虫細胞または哺乳動物細胞などを挙げることができる。例えば、レプチンの大量調製が容易になるという観点では、大腸菌などを好ましく挙げることができる。 Examples of host cells include prokaryotic or eukaryotic microbial cells, insect cells, or mammalian cells. For example, from the viewpoint of facilitating mass preparation of leptin, preferred is E. coli.
本発明の治療剤は、休止期脱毛症の治療に優れた効果を発揮する。本発明の治療剤が適用できる休止期脱毛症としては、男性型脱毛症、分娩後（出産後）脱毛症、ピル服用後脱毛症、ダイエット・飢餓性脱毛症、圧迫性脱毛症、甲状腺機能低下による脱毛症、下垂体機能低下による脱毛症、副甲状腺機能低下による脱毛症、薬物性脱毛症、脂漏性脱毛症、牽引性脱毛症、粃糠性脱毛症、内分泌疾患に伴う脱毛症、接触性皮膚炎による脱毛症などが挙げられ、とりわけ男性型脱毛症が好ましい。本発明の休止期脱毛症治療剤は、局所的に外用投与されたときには、局所に塗布するかあるいは皮下注射するのが好ましい。有効成分であるレプチンまたはその部分ペプチドの投与量は、対象者の性別、年齢、体重、状態（症状）によっても異なるが、局所に塗布する場合、投与する皮膚面積に応じて、適宜選択することができるが、通常、適用部位の面積約１０ｃｍ２に対して、１日につき、約１０〜１０００mｇ、好ましくは約１０〜５００mｇであるのがよい。前記の投与用量を、１日あたり、１回または数回に分けて適用すると良い。また、皮下注射する場合、レプチンまたはその部分ペプチドの投与量は、投与する皮膚面積に応じて、適宜選択することができるが、通常、適用部位の面積約１０ｃｍ２に対して、約１〜１０００mｇ、好ましくは約１０〜１００mｇであるのがよい。投与回数は特に限定するものではないが、１日１回ないし数週間に１回投与が好ましい。The therapeutic agent of the present invention exhibits an excellent effect in the treatment of resting alopecia. Resting alopecia to which the therapeutic agent of the present invention can be applied includes androgenetic alopecia, postpartum (postpartum) alopecia, post-pill alopecia, diet / starvation alopecia, pressure alopecia, hypothyroidism Alopecia due to pituitary hypofunction, alopecia due to hypoparathyroidism, drug alopecia, seborrheic alopecia, traction alopecia, alopecia areata, alopecia associated with endocrine disease, contact Alopecia due to atopic dermatitis is mentioned, and male pattern alopecia is particularly preferable. When the therapeutic agent for resting alopecia of the present invention is locally applied externally, it is preferably applied locally or injected subcutaneously. The dose of leptin, which is an active ingredient, or its partial peptide varies depending on the subject's gender, age, weight, and condition (symptoms), but when applied locally, it should be selected appropriately according to the area of skin to be administered. However, it is usually about 10 to 1000 mg, preferably about 10 to 500 mg per day for the area of the application site of about 10 cm 2 . The administration dose may be applied once or several times per day. In the case of subcutaneous injection, the dose of leptin or a partial peptide thereof can be appropriately selected depending on the skin area to be administered, but is usually about 1 to 1000 mg with respect to the area of the application site of about 10 cm 2 . , Preferably about 10-100 mg. The frequency of administration is not particularly limited, but administration once a day to once every several weeks is preferable.
本発明の脱毛症治療剤は局所的に投与される。その投与剤型としては、局所に塗布する場合は、軟膏、クリームなどの半固形剤、シャンプー、リンス、ローションなどの液剤、あるいはテープ剤などが挙げられ、局所に皮下投与する場合は、注射剤が挙げられる。これらの剤型への製剤化方法については、原則として通常の方法に従うものであるが、これらの製剤を製造する場合には、その製剤形態に応じた適当量の担体もしくは添加剤を使用することができる。
例えば、注射剤とする場合、溶媒（例えば、精製水）のほかに、分散剤（例、ツイーン（Ｔｗｅｅｎ）８０（アトラスパウダー社製、米国）、ＨＣＯ６０（日光ケミカルズ製）、ポリエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウムなど）、保存剤（メチルパラベン、プロピルパラベン、ベンジルアルコールなど）、等張化剤（塩化ナトリウム、マンニトール、ソルビトール、ブドウ糖など）などの添加物を適宜使用することができる。
一方、局所に塗布するのに適した製剤（例えば、軟膏、クリーム、ローションなど）とする場合には、レプチンまたはその部分ペプチドをリポソーム化するなどして経皮吸収を容易にして、レプチンまたはその部分ペプチドが毛包組織に到達しやすくなるようにしておくことが好ましい。The therapeutic agent for alopecia of the present invention is locally administered. Examples of dosage forms include semi-solid preparations such as ointments and creams, liquid preparations such as shampoos, rinses and lotions, and tapes when applied topically, and injections when administered subcutaneously locally. Is mentioned. The formulation method for these dosage forms is in accordance with the usual method in principle. However, when manufacturing these formulations, use appropriate amounts of carriers or additives according to the formulation form. Can do.
For example, in the case of an injection, in addition to a solvent (for example, purified water), a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose , Sodium alginate, etc.), preservatives (methyl paraben, propyl paraben, benzyl alcohol, etc.), and isotonic agents (sodium chloride, mannitol, sorbitol, glucose, etc.) can be appropriately used.
On the other hand, when the preparation is suitable for topical application (eg, ointment, cream, lotion, etc.), leptin or a partial peptide thereof is made into a liposome to facilitate percutaneous absorption, and leptin or its It is preferable to make the partial peptide easy to reach the hair follicle tissue.
リポソーム化とは、リポソーム（すなわち、膜状に集合した脂質および内部の水相から構成される閉鎖小胞）の内部に薬物を包含させることを意味し、レプチンまたはその部分ペプチドはリポソームを構成する膜状に集合した脂質層に包含されていてもよくリポソーム内部の水相に包含されてもよい。 Liposomeization means inclusion of a drug inside a liposome (that is, a closed vesicle composed of lipids assembled in a membrane and an internal aqueous phase), and leptin or a partial peptide thereof constitutes the liposome. It may be included in a lipid layer assembled in a film form or in an aqueous phase inside the liposome.
本発明に係るリポソームには、脂質膜中および内水相中にそれぞれ親油性もしくは親水性の種々の成分を内包させることができる。 In the liposome according to the present invention, various lipophilic or hydrophilic components can be encapsulated in the lipid membrane and the inner aqueous phase, respectively.
レプチンまたはその部分ペプチドのリポソーム化は、常法によって実施することができる。例えば、レプチンまたはその部分ペプチドの膜構成脂質成分への溶解、膜構成脂質成分とともに水溶性の非揮発性有機溶媒に混合、水性溶液への溶解もしくは懸濁などにより、レプチンまたはその部分ペプチドを脂質膜もしくは内水相へ内包させることができる。上記により調製したリポソーム化レプチンまたはその部分ペプチドを治療剤基剤に分散させて、休止期脱毛症の治療剤を得る。 Leptin or its partial peptide can be made into a liposome by a conventional method. For example, leptin or its partial peptide is dissolved in a lipid component of the membrane, mixed with a water-soluble non-volatile organic solvent together with the lipid component of the membrane, dissolved or suspended in an aqueous solution, etc. It can be included in a membrane or an inner aqueous phase. Liposomal leptin prepared as described above or a partial peptide thereof is dispersed in a therapeutic agent base to obtain a therapeutic agent for resting alopecia.
リポソーム化に用いられる脂質としては、グリセロリン脂質、グリセロ糖脂質、スフィンゴリン脂質、スフィンゴ糖脂質、ステロール類などが挙げられる。前記グリセロリン脂質としては、ホスファチジルコリン、ホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルセリンなどが挙げられ、グリセロ糖脂質としては、ジガラクトシルジグリセリド、ガラクトシルジグリセリドなどが挙げられ、スフィンゴリン脂質としては、スフィンゴミエリンなどが挙げられ、スフィンゴ糖脂質としては、セレブロシド、ガングリオシドなどが挙げられ、ステロール類としては、コレステロール、コレステロールヘミサクシネートなどが挙げられる。ここで、ホスファチジルコリン、ホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルセリン、スフィンゴミエリン、ガングリオシドなどは各々二本ずつ飽和または不飽和の脂肪酸エステル鎖を有するが、その脂肪酸（アルカノイルまたはアルケノイル基）部分の炭素数が１０〜１８である脂質をリポソーム構成成分として使用することができる。炭素数が１０〜１８であるアルカノイルまたはアルケノイル基としては、例えば、デシリル、ウンデシリル、ラウロイル、トリデシリル、ミリストイル、ペンタデシリル、パルミトイル、ヘプタデシリル、ステアロイル、オレオイル基などを挙げることができるが、好ましくはラウロイル、ミリストイル、パルミトイル及びステアロイル基である。リポソーム内部を構成する水相には、通常、塩化ナトリウム水溶液、緩衝液（リン酸緩衝液、酢酸緩衝液など）、単糖類もしくは二糖類の水溶液（グルコース水溶液、トレハロース水溶液など）を使用することができる。
上記のようにして得られるリポソーム化レプチンまたはその部分ペプチドを用いて、前記した局所塗布に適した製剤とするには、この分野で採用されている方法に準じて行えばよい。Examples of lipids used for liposome formation include glycerophospholipid, glyceroglycolipid, sphingophospholipid, glycosphingolipid, and sterols. Examples of the glycerophospholipid include phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine. Examples of the glyceroglycolipid include digalactosyldiglyceride and galactosyldiglyceride. Examples of the sphingophospholipid include sphingomyelin. Examples of the glycosphingolipid include cerebroside and ganglioside, and examples of the sterols include cholesterol and cholesterol hemisuccinate. Here, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sphingomyelin, ganglioside each have two saturated or unsaturated fatty acid ester chains, but the fatty acid (alkanoyl or alkenoyl group) moiety has 10 carbon atoms. Lipids that are ˜18 can be used as liposome constituents. Examples of the alkanoyl or alkenoyl group having 10 to 18 carbon atoms include desilyl, undesilyl, lauroyl, tridesilyl, myristoyl, pentadesilyl, palmitoyl, heptadesilyl, stearoyl, oleoyl group, preferably lauroyl, Myristoyl, palmitoyl and stearoyl groups. For the aqueous phase constituting the interior of the liposome, an aqueous sodium chloride solution, buffer solution (phosphate buffer solution, acetate buffer solution, etc.), monosaccharide or disaccharide solution (glucose aqueous solution, trehalose aqueous solution, etc.) is usually used. it can.
In order to obtain a preparation suitable for topical application using the liposomal leptin or its partial peptide obtained as described above, it may be carried out according to a method employed in this field.
以下に試験例を用いて本発明を説明するが、本発明はこれに限定されるものではない。 Hereinafter, the present invention will be described using test examples, but the present invention is not limited thereto.
[試験例１]
（１）ｄｂ／ｄｂ（レプチン受容体欠損）マウスにおける毛周期の検討
日本クレア（株）より入手した生後３５日のＣ５７ＢＬ／ＫｓＪ−ｄｂ／ｄｂマウス（レプチン受容体欠損マウス）および同系統正常マウス（各ｎ＝３）の背部皮膚を切除し、ホルマリン固定後、公知の方法を用いてヘマトキシリン・エオジン染色標本を作製し、毛包の状態を観察した。その結果、全ての個体において正常マウスでは成長期毛包を認めた（図１のＢ）が、ｄｂ／ｄｂマウスでは休止期毛包のみが認められた（図１のＣ）。このことから、ｄｂ／ｄｂマウスは第２成長期へ移行できないことが検証された。なお、図１のＡにマウスの正常な毛周期を示す。[Test Example 1]
(1) Examination of hair cycle in db / db (leptin receptor-deficient) mice 35-day-old C57BL / KsJ-db / db mice (leptin receptor-deficient mice) obtained from Nippon Claire Co., Ltd. and normal mice of the same strain The back skin of each (n = 3) was excised, and after fixing with formalin, a hematoxylin-eosin stained specimen was prepared using a known method, and the state of the hair follicle was observed. As a result, in all the individuals, the growing hair follicle was observed in the normal mouse (B in FIG. 1), but only the resting hair follicle was observed in the db / db mouse (C in FIG. 1). From this, it was verified that db / db mice cannot enter the second growth phase. FIG. 1A shows the normal hair cycle of a mouse.
（２）ｏｂ／ｏｂ（レプチン欠損）マウスにおける抜毛による成長期誘導
日本クレア（株）より入手した生後７週齢（第２休止期）のＣ５７ＢＬ／６Ｊ−ｏｂ／ｏｂマウスレプチン欠損マウス）および同系統正常マウス（各ｎ＝３）の背部体毛を抜毛し、１４日後に背部皮膚を切除し、ホルマリン固定後ヘマトキシリン・エオジン染色標本を作製し、毛包の状態を観察した。その結果、全ての個体において正常マウスでは成長期毛包を認めたが（図２のＢ）、ｏｂ／ｏｂマウスでは休止期毛包のみが認められた（図２のＤ）。このことから、ｏｂ／ｏｂマウスは抜毛刺激による成長期誘導ができないことが検証された。なお、図２のＡ、Ｃは背部皮膚切除直前のマウス背部の写真である。(2) Growth phase induction by hair removal in ob / ob (leptin deficient) mice Seven-week-old (second resting phase C57BL / 6J-ob / ob mouse leptin-deficient mice) obtained from Nippon Claire Co., Ltd.) and the same The back body hairs of normal mice (n = 3 each) were removed, and the back skin was excised 14 days later. After fixing with formalin, hematoxylin / eosin stained specimens were prepared, and the state of the hair follicles was observed. As a result, in all the individuals, the growth follicle was observed in the normal mouse (B in FIG. 2), but only the resting follicle was observed in the ob / ob mouse (D in FIG. 2). From this, it was verified that ob / ob mice cannot induce the growth phase by hair removal stimulation. 2A and 2C are photographs of the back of the mouse immediately before the dorsal skin resection.
（３）ｏｂ／ｏｂ（レプチン欠損）マウスにおけるレプチンによる成長期誘導
上記生後７週齢（第２休止期）のｏｂ／ｏｂマウス（ｎ＝３）の背部体毛を抜毛し、マウスリコンビナントレプチン（Ｒ＆Ｄ システムズ社製）の生理食塩水溶液（１０μｇ／０．１ｍｌ）を単回皮下注射したところ、１６日目には背部皮膚は黒色に変化し、成長期が誘導されていることが確認された（図３のＢ）。なお、生理食塩水のみを投与したコントロール群では、背部皮膚はほとんど変化しなかった（図３のＡ）。このことから、レプチン欠損個体において、レプチンは休止期から成長期を誘導することが検証された。(3) Growth phase induction by leptin in ob / ob (leptin deficient) mice The dorsal body hair of the above-mentioned 7-week-old (second resting phase) ob / ob mice (n = 3) was removed, and mouse recombinant leptin (R & D) A single subcutaneous injection of a physiological saline solution (10 μg / 0.1 ml) manufactured by Systems, Inc. confirmed that the dorsal skin turned black on the 16th day and that the growth period was induced (FIG. 3 B). In the control group to which only physiological saline was administered, the back skin was hardly changed (A in FIG. 3). From this, it was verified that leptin induces the growth phase from the resting phase in leptin-deficient individuals.
（４）Ｃ５７ＢＬ／６Ｊマウス（正常マウス）におけるレプチンによる成長期誘導
上記生後７週齢（第２休止期）のＣ５７ＢＬ／６Ｊマウス（正常マウス，ｎ＝３）の背部体毛を剃毛し、上記マウスリコンビナントレプチンの生理食塩水溶液（１０μｇ／０．１ｍｌ）または生理食塩水のみを単回皮下注射したところ、レプチンを皮下注射したマウスでは２１日目には皮下注射部位に一致して発毛を認め（図４のＣ、矢印部分）、組織学的にも明らかに成長期毛包であることが確認されたが（図４のＢ、矢印部分）、生理食塩水を皮下注射したマウスでは発毛は認めず（図４のＣ、下部）、組織学的にも休止期のままであった（図４のＡ）。このことから、正常個体においても、レプチンは休止期から成長期を誘導することが検証された。(4) Growth period induction by leptin in C57BL / 6J mice (normal mice) The shaved back hairs of the above-mentioned 7-week-old (second rest period) C57BL / 6J mice (normal mice, n = 3) were shaved. A single subcutaneous injection of mouse recombinant leptin in physiological saline solution (10 μg / 0.1 ml) or saline alone, hair growth was observed in mice injected with leptin on the 21st day in line with the subcutaneous injection site. (C, arrow in FIG. 4) Histologically, the hair follicle was also confirmed (B, arrow in FIG. 4), but hair growth occurred in mice injected with saline subcutaneously. (C in FIG. 4, lower part) and histologically remained in a resting state (A in FIG. 4). From this, it was verified that leptin induces the growth phase from the resting phase even in normal individuals.
[試験例２]
Ｃ５７ＢＬ／６Ｊマウス（正常マウス）における部分ペプチドによる成長期誘導
上記生後７週齢（第２休止期）のＣ５７ＢＬ／６Ｊマウス（正常マウス，ｎ＝３）の背部体毛を剃毛し、ヒトレプチンの部分ペプチド（２２−５６残基、配列番号４、ＢＲＡＣＨＥＭ社製）の生理食塩水溶液（１０μｇ／０．１ｍｌ）または生理食塩水のみを単回皮下注射したところ、部分ペプチドを皮下注射したマウスでは２１日目には皮下注射部位に一致して発毛を認め（図５のＢ）、生理食塩水を皮下注射したマウスでは発毛は認めなかった（図５のＡ）。このことから、正常個体においても、部分ペプチドは休止期から成長期を誘導することが検証された。[Test Example 2]
Growth phase induction by partial peptides in C57BL / 6J mice (normal mice) The back body hairs of the above-mentioned 7-week-old (second resting) C57BL / 6J mice (normal mice, n = 3) were shaved, and a part of human leptin A single subcutaneous injection of a physiological saline solution (10 μg / 0.1 ml) of peptide (22-56 residues, SEQ ID NO: 4, manufactured by BRACHEM) or physiological saline alone, 21 days for mice subcutaneously injected with a partial peptide In the eyes, hair growth was observed in accordance with the site of subcutaneous injection (FIG. 5B), and no hair growth was observed in mice subcutaneously injected with physiological saline (A in FIG. 5). From this, it was verified that even in normal individuals, the partial peptide induces the growth phase from the resting phase.
（５）考察
以上の実験から、レプチンまたはその部分ペプチドは休止期脱毛症に対する治療効果を有することがわかった。(5) Discussion From the above experiment, it was found that leptin or its partial peptide has a therapeutic effect on resting alopecia.
本発明に係る休止期脱毛症の治療剤は、休止期脱毛症の治療のための医薬として利用し得る。 The therapeutic agent for resting alopecia according to the present invention can be used as a medicament for treating resting alopecia.
Claims (6)
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