JP5897164B2 - Composition for external use - Google Patents
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- JP5897164B2 JP5897164B2 JP2015009513A JP2015009513A JP5897164B2 JP 5897164 B2 JP5897164 B2 JP 5897164B2 JP 2015009513 A JP2015009513 A JP 2015009513A JP 2015009513 A JP2015009513 A JP 2015009513A JP 5897164 B2 JP5897164 B2 JP 5897164B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Description
本発明は、肥厚性瘢痕及び／又はケロイドの予防又は治療剤に関する。また、本発明は、肉芽組織の形成を抑制する形成抑制剤に関する。更に、本発明は、肥厚性瘢痕及び／又はケロイドの予防又は治療効果や肉芽形成抑制作用に優れた外用組成物に関する。 The present invention relates to a prophylactic or therapeutic agent for hypertrophic scar and / or keloid. The present invention also relates to a formation inhibitor that suppresses the formation of granulation tissue. Furthermore, the present invention relates to a composition for external use which is excellent in the effect of preventing or treating hypertrophic scar and / or keloid and the effect of suppressing granulation formation.
肥厚性瘢痕及びケロイドは、創傷後に肉芽細胞の増殖と細胞外基質の蓄積が過剰になって、過度の組織修復反応が生じることにより、創面の盛り上がり（隆起）、赤み、つっぱり、しこり等の赤色隆起性病変が認められる皮膚組織の異常である。肥厚性瘢痕は、創傷部分を越えて病変が広がり難く、時間経過と共に色調の退色や盛り上がりの減少が認められるという特徴がある一方、ケロイドは、創傷部分を越えて病変が広がることがあり、時間経過によって色調の退色や盛り上がりの減少が認められ難いという特徴がある。但し、肥厚性瘢痕及びケロイドは、いずれも肉芽細胞の増殖と細胞外基質の蓄積が過剰になることに起因して生じる皮膚の赤色化を伴う隆起性病変である点で共通しており、その予防又は治療方策は、肉芽細胞の過剰な増殖の抑制、細胞外基質の過剰な蓄積の抑制、病変部の消炎等が有効であることが知られている。 Hypertrophic scars and keloids are red, such as bulges (bumps), redness, tightness, and lump, due to excessive tissue repair after excessive wound granulation and extracellular matrix accumulation after wounding. Abnormal skin tissue with elevated lesions. While hypertrophic scars are difficult to spread beyond the wound area and are characterized by fading of color tone and a decrease in swell over time, keloids can spread lesions beyond the wound area. There is a feature that it is difficult to recognize the fading of the color tone or the decrease of the climax with the passage of time. However, both hypertrophic scars and keloids are common in that they are raised lesions with reddening of the skin caused by excessive proliferation of granulation cells and accumulation of extracellular matrix. As a preventive or therapeutic strategy, it is known that suppression of excessive proliferation of granulation cells, suppression of excessive accumulation of extracellular matrix, anti-inflammation of lesions, etc. are effective.
肥厚性瘢痕及びケロイドの治療には、従来、ステロイド剤やヘパリン類似物質等が使用されている。しかしながら、ステロイド剤では、治療効果自体は優れているものの、皮膚萎縮や毛細血管拡張、易感染性等の副作用をもたらす可能性があり、使用量や使用期間等に注意が必要とされている。一方、ヘパリン類似物質は、肥厚性瘢痕及びケロイドの治療目的で汎用されているが、その治療効果は十分に満足できるものではない。但し、ヘパリン類似物質には、ステロイド剤のような副作用を伴うことないため、ヘパリン類似物質による肥厚性瘢痕及び／又はケロイドの予防又は治療効果を向上できる製剤処方を開発できれば、肥厚性瘢痕及び／又はケロイドで悩まされている患者に福音をもたらすことが期待される。 For the treatment of hypertrophic scars and keloids, steroids and heparin-like substances have been used conventionally. However, although the steroid agent is excellent in therapeutic effect itself, it may cause side effects such as skin atrophy, capillary vasodilation, and infectivity, and attention is required for the amount used and the period of use. On the other hand, heparin-like substances are widely used for the treatment of hypertrophic scars and keloids, but their therapeutic effects are not fully satisfactory. However, since heparin-like substances do not have side effects like steroids, if a pharmaceutical formulation that can improve the prevention or treatment effect of hypertrophic scars and / or keloids by heparin-like substances can be developed, hypertrophic scars and / or Or it is expected to bring the gospel to patients suffering from keloids.
従来、ヘパリン類似物質の薬効を向上させる製剤処方については種々検討されている。例えば、特許文献１には、ヘパリン類似物質とベタイン類を併用することにより、乾燥性皮膚疾患や炎症性皮膚疾患に伴う肌荒れに対して優れた治療効果が奏され得ることが開示されている。また、特許文献２には、ヘパリン類似物質と非ステロイド性抗炎症剤を併用することにより、乾燥性皮膚疾患や炎症性皮膚疾患に対して優れた治療効果が奏され得ることが開示されている。更に、特許文献３には、ヘパリン類似物質、アラントイン又はその誘導体、及びパントテン酸又はその誘導体を組み合わせることによって、表皮角化細胞の角層細胞への正常な分化を促進できることが開示されている。しかしながら、肥厚性瘢痕及びケロイドは、真皮層における肉芽組織の再生異常が要因となっているため、特許文献１〜３が示す薬理効果（即ち、皮膚表皮で生じる皮膚症状に対する薬理効果）では、肥厚性瘢痕及び／又はケロイドに対する十分な治療効果は期待できない。 Conventionally, various investigations have been made on pharmaceutical formulations for improving the efficacy of heparin-like substances. For example, Patent Document 1 discloses that by using a heparin-like substance and betaines in combination, an excellent therapeutic effect can be achieved for rough skin associated with dry skin diseases and inflammatory skin diseases. Patent Document 2 discloses that a combination of a heparin-like substance and a non-steroidal anti-inflammatory agent can provide an excellent therapeutic effect for dry skin diseases and inflammatory skin diseases. . Furthermore, Patent Document 3 discloses that normal differentiation of epidermal keratinocytes into horny cells can be promoted by combining a heparin-like substance, allantoin or a derivative thereof, and pantothenic acid or a derivative thereof. However, since hypertrophic scars and keloids are caused by abnormal regeneration of granulation tissue in the dermis layer, the pharmacological effects shown in Patent Documents 1 to 3 (that is, pharmacological effects on skin symptoms occurring in the skin epidermis) are thickened. Sufficient therapeutic effect on sexual scars and / or keloids cannot be expected.
このような従来技術を背景として、ヘパリン類似物質による肥厚性瘢痕及び／又はケロイドの予防又は治療効果を向上できる製剤処方の開発が望まれている。 Against the background of such conventional technology, it is desired to develop a pharmaceutical formulation that can improve the preventive or therapeutic effect of hypertrophic scars and / or keloids due to heparin-like substances.
本発明は、ヘパリン類似物質による肥厚性瘢痕及び／又はケロイドの予防又は治療効果、或いはヘパリン類似物質による肉芽組織の形成抑制作用を向上できる製剤処方を提供することを目的とする。 An object of the present invention is to provide a pharmaceutical formulation that can improve the effect of preventing or treating hypertrophic scars and / or keloids with a heparin-like substance, or the granulation tissue formation-inhibiting action with a heparin-like substance.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、(A)ヘパリン類似物質と、(B)アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及び／又はそれらの塩とを併用することによって、ヘパリン類似物質を単独で使用する場合に比べて、肉芽組織の形成抑制作用が高く、肥厚性瘢痕及び／又はケロイドを効果的に予防又は治療できることを見出した。特に、(A)ヘパリン類似物質と、(B-1)アラントイン、及び／又はそれらの誘導体と、(B-2)グリチルリチン酸、グリチルレチン酸、それらの誘導体、及び／又はそれらの塩とを組み合わせることによって、肉芽組織の形成抑制作用が著しく向上し、肥厚性瘢痕及び／又はケロイドに対して格段に優れた予防又は治療効果を奏し得ることをも見出した。本発明は、これらの知見に基づいて更に検討を重ねることにより完成したものである。 The present inventor made extensive studies to solve the above problems, and combined use of (A) heparin-like substance and (B) allantoin, glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and / or salts thereof As a result, it has been found that compared with the case where a heparin-like substance is used alone, the granulation tissue formation inhibitory action is high, and hypertrophic scars and / or keloids can be effectively prevented or treated. In particular, combining (A) heparin analogues, (B-1) allantoin and / or their derivatives with (B-2) glycyrrhizic acid, glycyrrhetinic acid, their derivatives and / or their salts It has also been found that the granulation tissue formation inhibitory action is remarkably improved, and a markedly superior preventive or therapeutic effect can be obtained for hypertrophic scars and / or keloids. The present invention has been completed by further studies based on these findings.
即ち、本発明は、以下に掲げる態様の発明を提供する。
項１． (A)ヘパリン類似物質、並びに(B)アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有することを特徴とする、肥厚性瘢痕及び／又はケロイドの予防又は治療剤。
項２． 前記(B)成分として、少なくとも(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種を含有する、項１に記載の予防又は治療剤。
項３． 前記(B)成分として、(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種、並びに(B-2)グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有する、項１又は２に記載の予防又は治療剤。
項４．前記(A)成分１００重量部当たり、前記(B)成分を総量で１０〜２００００重量部含む、項１〜３のいずれかに記載の予防又は治療剤。
項５． 前記(A)成分１００重量部当たり、前記(B-1)成分を５〜１００００重量部、及び前記(B-2)成分を５〜１００００重量部含む、項３又は４に記載の予防又は治療剤。
項６． 前記(A)成分を０．０１〜５重量％含む、項１〜５のいずれかに記載の予防又は治療剤。
項７． 前記(B)成分を総量で０．０１〜１５重量％含む、項１〜６のいずれかに記載の予防又は治療剤。
項８． 前記(B-1)成分を０．０１〜５重量％、及び前記(B-2)成分を０．０１〜１０重量％含む、項３〜７のいずれかに記載の予防又は治療剤。
項９． きず又はやけどのあとの皮ふのしこり、或いはきず又はやけどのあとの皮ふのつっぱりの改善のために使用される、請求項１〜８のいずれかに記載の予防又は治療剤。
項１０． (A)ヘパリン類似物質、並びに(B)アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有することを特徴とする、肉芽組織の形成抑制剤。
項１１． 前記(B)成分として、少なくとも(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種を含有する、項１０に記載の肉芽組織の形成抑制剤。
項１２． 前記(B)成分として、(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種、並びに(B-2)グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有する、項１０又は１１に記載の肉芽組織の形成抑制剤。
項１３． 前記(A)成分１００重量部当たり、前記(B)成分を総量で１０〜２００００重量部含む、項１０〜１２のいずれかに記載の肉芽組織の形成抑制剤。
項１４． 前記(A)成分１００重量部当たり、前記(B-1)成分を５〜１００００重量部、及び前記(B-2)成分を５〜１００００重量部含む、項１２又は１３に記載の形成抑制剤。
項１５． 前記(A)成分を０．０１〜５重量％含む、項１０〜１４のいずれかに記載の肉芽組織の形成抑制剤。
項１６． 前記(B)成分を総量で０．０１〜１５重量％含む、項１０〜１５のいずれかに記載の肉芽組織の形成抑制剤。
項１７． 前記(B-1)成分を０．０１〜５重量％、及び前記(B-2)成分を０．０１〜１０重量％含む、請求項１２〜１６のいずれかに記載の肉芽組織の形成抑制剤。
項１８． きず又はやけどのあとの皮ふのしこり、或いはきず又はやけどのあとの皮ふのつっぱりの改善のために使用される、項１０〜１７のいずれかに記載の肉芽組織の形成抑制剤。
項１９． (A)ヘパリン類似物質、(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種、並びに(B-2)グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有することを特徴とする、外用組成物。
項２０． 前記(A)成分１００重量部当たり、前記(B-1)成分を５〜１００００重量部、及び前記(B-2)成分を５〜１００００重量部含む、項１９に記載の外用組成物。
項２１． 前記(A)成分を０．０１〜５重量％含む、項１９又は２０に記載の外用組成物。
項２２． 前記(B-1)成分を０．０１〜５重量％含む、項１９〜２１のいずれかに記載の外用組成物。
項２３． 前記(B-2)成分を０．０１〜１０重量％含む、項１９〜２２のいずれかに記載の外用組成物。
項２４． 肥厚性瘢痕及び／又はケロイドの予防又は治療に使用される、項１９〜２３のいずれかに記載の外用組成物。
項２５． 肉芽組織の形成を抑制するために使用される、項１９〜２４のいずれかに記載の外用組成物。
項２６． きず又はやけどのあとの皮ふのしこり、或いはきず又はやけどのあとの皮ふのつっぱりの改善のために使用される、項１９〜２５のいずれかに記載の外用組成物。
That is, this invention provides the invention of the aspect hung up below.
Item 1. (A) a heparin-like substance, and (B) at least one selected from the group consisting of allantoin, glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and hypertrophic scar and An agent for preventing or treating keloid.
Item 2. Item 2. The prophylactic or therapeutic agent according to Item 1, comprising at least one selected from the group consisting of (B-1) allantoin and derivatives thereof as the component (B).
Item 3. As the component (B), at least one selected from the group consisting of (B-1) allantoin and derivatives thereof, and (B-2) a group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof Item 3. The preventive or therapeutic agent according to Item 1 or 2, comprising at least one selected from the group consisting of:
Item 4. Item 4. The preventive or therapeutic agent according to any one of Items 1 to 3, comprising 10 to 20000 parts by weight of the total amount of the component (B) per 100 parts by weight of the component (A).
Item 5. The prevention or treatment according to Item 3 or 4, comprising 5 to 10,000 parts by weight of the component (B-1) and 5 to 10,000 parts by weight of the component (B-2) per 100 parts by weight of the component (A). Agent.
Item 6. Item 6. The preventive or therapeutic agent according to any one of Items 1 to 5, comprising 0.01 to 5% by weight of the component (A).
Item 7. Item 7. The preventive or therapeutic agent according to any one of Items 1 to 6, comprising 0.01 to 15% by weight of the total amount of the component (B).
Item 8. Item 8. The preventive or therapeutic agent according to any one of Items 3 to 7, comprising 0.01 to 5% by weight of the component (B-1) and 0.01 to 10% by weight of the component (B-2).
Item 9. The preventive or therapeutic agent according to any one of claims 1 to 8, which is used for improving the lump of the skin after a wound or burn or the firmness of the skin after a wound or burn.
Item 10. Granulation tissue formation comprising (A) a heparin-like substance and (B) at least one selected from the group consisting of allantoin, glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof Inhibitor.
Item 11. Item 11. The granulation tissue formation inhibitor according to Item 10, containing at least one selected from the group consisting of (B-1) allantoin and derivatives thereof as the component (B).
Item 12. As the component (B), at least one selected from the group consisting of (B-1) allantoin and derivatives thereof, and (B-2) a group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof Item 12. The granulation tissue formation inhibitor according to Item 10 or 11, comprising at least one selected from the group consisting of:
Item 13. Item 13. The granulation tissue formation inhibitor according to any one of Items 10 to 12, comprising 10 to 20000 parts by weight of the component (B) in total per 100 parts by weight of the component (A).
Item 14. The formation inhibitor according to Item 12 or 13, comprising 5 to 10,000 parts by weight of the component (B-1) and 5 to 10,000 parts by weight of the component (B-2) per 100 parts by weight of the component (A). .
Item 15. Item 15. The granulation tissue formation inhibitor according to any one of Items 10 to 14, comprising 0.01 to 5% by weight of the component (A).
Item 16. Item 16. The granulation tissue formation inhibitor according to any one of Items 10 to 15, comprising the component (B) in a total amount of 0.01 to 15% by weight.
Item 17. The granulation tissue formation suppression according to any one of claims 12 to 16, comprising 0.01 to 5% by weight of the component (B-1) and 0.01 to 10% by weight of the component (B-2). Agent.
Item 18. Item 18. The granulation tissue formation inhibitor according to any one of Items 10 to 17, which is used for improving the lump of the skin after a scratch or burn or the firmness of the skin after a scratch or burn.
Item 19. (A) at least one selected from the group consisting of heparin analogues, (B-1) allantoin and derivatives thereof, and (B-2) a group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof The composition for external use characterized by containing at least 1 sort (s) selected from these.
Item 20. Item 20. The external composition according to Item 19, comprising 5 to 10,000 parts by weight of the component (B-1) and 5 to 10,000 parts by weight of the component (B-2) per 100 parts by weight of the component (A).
Item 21. Item 21. The external composition according to Item 19 or 20, comprising 0.01 to 5% by weight of the component (A).
Item 22. Item 22. The topical composition according to any one of Items 19 to 21, comprising 0.01 to 5% by weight of the component (B-1).
Item 23. Item 23. The external composition according to any one of Items 19 to 22, comprising 0.01 to 10% by weight of the component (B-2).
Item 24. Item 24. The composition for external use according to any one of Items 19 to 23, which is used for prevention or treatment of hypertrophic scar and / or keloid.
Item 25. Item 25. The composition for external use according to any one of Items 19 to 24, which is used for suppressing formation of granulation tissue.
Item 26. Item 26. The composition for external use according to any one of Items 19 to 25, which is used for improving the lump of the skin after scratches or burns, or for improving the firmness of the skin after scratches or burns.
本発明によれば、ヘパリン類似物質を単独で使用する場合に比べて、格段に優れた肥厚性瘢痕及び／又はケロイドの予防又は治療効果を奏することができる。また、本発明によれば、肉芽組織が過剰に形成されるのを抑制できるので、皮膚の盛り上がり、赤み、つっぱり、しこり等の、肉芽組織の過剰な形成によって生じる皮膚疾患や皮膚症状を効果的に予防又は治療することができる。 According to the present invention, the prophylactic or therapeutic effect of hypertrophic scars and / or keloids can be significantly improved as compared with the case where a heparin-like substance is used alone. In addition, according to the present invention, since excessive formation of granulation tissue can be suppressed, skin diseases and skin symptoms caused by excessive formation of granulation tissue such as skin swell, redness, tension, and lump can be effectively prevented. Can be prevented or treated.
１．肥厚性瘢痕及び／又はケロイドの予防又は治療剤
本発明の予防又は治療剤は、ヘパリン類似物質（以下、(A)成分と表記することもある）と、アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種（以下、(B)成分と表記することもある）を含有し、肥厚性瘢痕及び／又はケロイドの予防又は治療に使用されることを特徴とする。以下、本発明の予防／又は治療剤について詳述する。
1. Preventive or therapeutic agent for hypertrophic scar and / or keloid The preventive or therapeutic agent of the present invention comprises a heparin-like substance (hereinafter also referred to as component (A)), allantoin, glycyrrhizic acid, glycyrrhetinic acid, their It contains at least one selected from the group consisting of derivatives and salts thereof (hereinafter also referred to as component (B)) and is used for the prevention or treatment of hypertrophic scars and / or keloids. It is characterized by. Hereinafter, the preventive / therapeutic agent of the present invention will be described in detail.
(A)成分
本発明の予防又は治療剤は、(A)成分としてヘパリン類似物質を含有する。ヘパリン類似物質とは、コンドロイチン多硫酸等の多硫酸化ムコ多糖であり、保湿作用や血流量増加作用等を有することが知られている公知の薬剤である。
(A) Component The preventive or therapeutic agent of the present invention contains a heparin-like substance as the component (A). A heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing action, a blood flow increasing action, and the like.
本発明で使用されるヘパリン類似物質の由来については、特に制限されないが、例えば、ムコ多糖類を多硫酸化することにより得られたもの、食用獣の組織（例えば、ウシやブタ等の気管軟骨を含む肺臓）から抽出したもの等が挙げられる。本発明の予防又は治療剤では、ヘパリン類似物質として、日本薬局方外医薬品規格に収戴されているヘパリン類似物質が好適に使用される。 The origin of the heparin-like substance used in the present invention is not particularly limited. For example, it is obtained by polysulfating mucopolysaccharides, tissues of edible animals (for example, tracheal cartilage such as cattle and pigs) And the like extracted from the lung including In the preventive or therapeutic agent of the present invention, as the heparin-like substance, a heparin-like substance included in the Japanese Pharmacopoeia Pharmaceutical Standards is preferably used.
本発明の予防又は治療剤における(A)成分の配合量については、該予防又は治療剤の製剤形態等に応じて適宜設定すればよいが、例えば０．０１〜５重量％、好ましくは０．０５〜３重量％、更に好ましくは０．１〜１重量％が挙げられる。 The blending amount of the component (A) in the preventive or therapeutic agent of the present invention may be appropriately set according to the form of preparation of the prophylactic or therapeutic agent, for example, 0.01 to 5% by weight, preferably 0. 05 to 3% by weight, more preferably 0.1 to 1% by weight.
(B)成分
本発明の予防又は治療剤は、(B)成分として、アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有する。このように、ヘパリン類似物質と前記(B)成分を組み合わせて使用することによって、ヘパリン類似物質が単独で有する肥厚性瘢痕及び／又はケロイドの予防又は治療効果を飛躍的に向上させることが可能になる。
(B) Component The preventive or therapeutic agent of the present invention contains, as component (B), at least one selected from the group consisting of allantoin, glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. Thus, by using a combination of the heparin analog and the component (B), it is possible to dramatically improve the preventive or therapeutic effect of hypertrophic scar and / or keloid possessed by the heparin analog alone. Become.
アラントインは、５−ウレイドヒダントインとも称される化合物であり、抗炎症作用や鎮痒作用等を有することが知られている公知の薬剤である。 Allantoin is a compound also called 5-ureidohydantoin, and is a known drug known to have anti-inflammatory action, antipruritic action and the like.
アラントインの誘導体としては、薬学的に許容できることを限度として特に制限されないが、具体的には、アラントインクロルヒドロキシアルミニウム、アラントインヒドロキシアルミニウム等が挙げられる。これらのアラントインの誘導体は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The allantoin derivative is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include allantoin chlorohydroxyaluminum and allantoinhydroxyaluminum. These allantoin derivatives may be used alone or in combination of two or more.
グリチルリチン酸は、抗炎症作用や抗アレルギー作用等を有することが知られている公知の薬剤である。 Glycyrrhizic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, and the like.
グリチルリチン酸の誘導体としては、薬学的に許容できることを限度として特に制限されないが、具体的には、グリチルリチン酸メチル、グリチルリチン酸ステアリル等が挙げられる。これらのグリチルリチン酸の誘導体は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The derivative of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include methyl glycyrrhizinate and stearyl glycyrrhizinate. These glycyrrhizic acid derivatives may be used alone or in combination of two or more.
グリチルリチン酸及びその誘導体の塩としては、薬理学上許容されるものである限り特に制限されないが、具体的には、ナトリウム塩、カリウム塩、二カリウム塩等のアルカリ金属塩；アンモニウム塩等が挙げられる。これらのグリチルリチン酸及びその誘導体の塩は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The salt of glycyrrhizic acid and its derivative is not particularly limited as long as it is pharmacologically acceptable, and specific examples include alkali metal salts such as sodium salt, potassium salt, dipotassium salt; ammonium salt and the like. It is done. These salts of glycyrrhizic acid and its derivatives may be used alone or in combination of two or more.
グリチルレチン酸は、抗炎症作用や抗アレルギー作用等を有することが知られている公知の薬剤である。 Glycyrrhetinic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, and the like.
グリチルレチン酸の誘導体としては、薬学的に許容できることを限度として特に制限されないが、具体的には、グリチルレチン酸ピリドキシン、グリチルレチン酸ステアリル、グリチルレチン酸グリセリル、グリチルレチン酸モノグルクロニド等が挙げられる。これらのグリチルレチン酸の誘導体は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The derivative of glycyrrhetinic acid is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate, and the like. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.
グリチルレチン酸及びその誘導体の塩としては、薬理学上許容されるものである限り特に制限されないが、具体的には、ナトリウム塩、カリウム塩等のアルカリ金属塩；アンモニウム塩等が挙げられる。これらのグリチルレチン酸及びその誘導体の塩は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The salt of glycyrrhetinic acid and its derivative is not particularly limited as long as it is pharmacologically acceptable, and specific examples include alkali metal salts such as sodium salt and potassium salt; ammonium salt and the like. These salts of glycyrrhetinic acid and its derivatives may be used alone or in combination of two or more.
本発明の予防又は治療剤において、(B)成分として、アラントイン、アラントインの誘導体、グリチルリチン酸、グリチルリチン酸の塩、グリチルリチン酸の誘導体、グリチルリチン酸の誘導体の塩、グリチルレチン酸、グリチルレチン酸の塩、グリチルレチン酸の誘導体、及びグリチルレチン酸の誘導体の塩の中から、１種を選択して使用してもよく、２種以上を組み合わせて使用してもよい。 In the preventive or therapeutic agent of the present invention, as component (B), allantoin, allantoin derivative, glycyrrhizic acid, glycyrrhizic acid salt, glycyrrhizic acid derivative, glycyrrhizic acid derivative salt, glycyrrhetinic acid, glycyrrhetinic acid salt, glycyrrhetin One type may be selected from among acid derivatives and glycyrrhetinic acid derivative salts, or two or more types may be used in combination.
これらの(B)成分の内、アラントイン及びその誘導体よりなる群から選択される少なくとも１種（以下、(B-1)成分と表記することもある）を使用する場合であれば、肥厚性瘢痕及び／又はケロイドの予防又は治療効果をより一層向上させるという観点から、好ましくはアラントインが挙げられる。 Among these (B) components, when using at least one selected from the group consisting of allantoin and its derivatives (hereinafter also referred to as (B-1) component), hypertrophic scar From the viewpoint of further improving the effect of preventing or treating keloid, allantoin is preferable.
また、これらの(B)成分の内、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種（以下、(B-2)成分と表記することもある）を使用する場合であれば、肥厚性瘢痕及び／又はケロイドの予防又は治療効果をより一層向上させるという観点から、好ましくはグリチルリチン酸、その誘導体、及び／又はそれらの塩、より好ましくはグリチルリチン酸及び／又はその塩、更に好ましくはグリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム、特に好ましくはグリチルリチン酸二カリウムが挙げられる。 Of these components (B), at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof (hereinafter sometimes referred to as component (B-2)) ), Preferably glycyrrhizic acid, a derivative thereof, and / or a salt thereof, more preferably glycyrrhizic acid, from the viewpoint of further improving the effect of preventing or treating hypertrophic scars and / or keloids. And / or a salt thereof, more preferably dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, particularly preferably dipotassium glycyrrhizinate.
これらの、(B)成分の中でも、より一層卓越した肥厚性瘢痕及び／又はケロイドの予防又は治療効果を奏させるという観点から、好ましく(B-1)成分、更に好ましくは(B-1)成分と(B-2)成分の組み合わせが挙げられる。 Among these (B) components, from the viewpoint of achieving a more prominent hypertrophic scar and / or keloid prevention or treatment effect, preferably (B-1) component, more preferably (B-1) component And a combination of components (B-2).
本発明の予防又は治療剤において、(A)成分と(B)成分の比率については、特に制限されないが、肥厚性瘢痕及び／又はケロイドの予防又は治療効果をより一層向上させるという観点から、(A)成分１００重量部当たり、(B)成分が総量で１０〜２００００重量部、好ましくは３０〜７０００重量部、更に好ましくは３０〜５０００重量部、より一層好ましくは３０〜１６００重量部、特に好ましくは５０〜７００重量部が挙げられる。 In the preventive or therapeutic agent of the present invention, the ratio of the component (A) and the component (B) is not particularly limited, but from the viewpoint of further improving the preventive or therapeutic effect of hypertrophic scar and / or keloid ( The total amount of component (B) is 10 to 20000 parts by weight, preferably 30 to 7000 parts by weight, more preferably 30 to 5000 parts by weight, and even more preferably 30 to 1600 parts by weight per 100 parts by weight of component A). Is 50 to 700 parts by weight.
より具体的には、(B)成分として(B-1)成分を単独で使用する場合であれば、(A)成分１００重量部当たり、(B-1)成分が５〜１００００重量部、好ましくは５０〜２０００重量部、更に好ましくは３０〜７００重量部、より一層好ましくは６０〜３５０重量部が挙げられる。(B)成分として(B-2)成分を単独で使用する場合であれば、(A)成分１００重量部当たり、(B-2)成分が５〜１００００重量部、好ましくは５０〜５０００重量部、更に好ましくは１０〜３０００重量部、より一層好ましくは３０〜１０００重量部、特に好ましくは６０〜３５０重量部が挙げられる。また、(B)成分として(B-1)成分及び(B-2)成分を組み合わせて使用する場合であれば、(A)成分１００重量部当たり、(B-1)成分が５〜１００００重量部、好ましくは５０〜５０００重量部、更に好ましくは５０〜２０００重量部、更に好ましくは３０〜７００重量部、より一層好ましくは６０〜３５０重量部、(B-2)成分が５〜１００００重量部、好ましくは５０〜５０００重量部、更に好ましくは１０〜３０００重量部、より一層好ましくは３０〜１０００重量部、特に好ましくは６０〜３５０重量部が挙げられる。 More specifically, when the component (B-1) is used alone as the component (B), the component (B-1) is preferably 5 to 10,000 parts by weight per 100 parts by weight of the component (A). Is 50 to 2000 parts by weight, more preferably 30 to 700 parts by weight, and still more preferably 60 to 350 parts by weight. When the component (B-2) is used alone as the component (B), the component (B-2) is 5 to 10,000 parts by weight, preferably 50 to 5000 parts by weight per 100 parts by weight of the component (A). More preferably, it is 10 to 3000 parts by weight, still more preferably 30 to 1000 parts by weight, and particularly preferably 60 to 350 parts by weight. In the case of using a combination of the component (B-1) and the component (B-2) as the component (B), the component (B-1) is 5 to 10,000 weights per 100 parts by weight of the component (A). Parts, preferably 50 to 5000 parts by weight, more preferably 50 to 2000 parts by weight, still more preferably 30 to 700 parts by weight, still more preferably 60 to 350 parts by weight, and the component (B-2) is 5 to 10,000 parts by weight. 50 to 5000 parts by weight, preferably 10 to 3000 parts by weight, more preferably 30 to 1000 parts by weight, and particularly preferably 60 to 350 parts by weight.
また、本発明の予防又は治療剤における(B)成分の配合量については、該予防又は治療剤の製剤形態、前述する(A)成分と(B)成分の比率等に応じて適宜設定すればよいが、例えば０．０１〜１５重量％、好ましくは０．０５〜８重量％、更に好ましくは０．１〜５重量％が挙げられる。 In addition, the blending amount of the component (B) in the preventive or therapeutic agent of the present invention may be appropriately set according to the preparation form of the preventive or therapeutic agent, the ratio of the component (A) and the component (B) described above, etc. For example, 0.01 to 15% by weight, preferably 0.05 to 8% by weight, and more preferably 0.1 to 5% by weight.
より具体的には、(B)成分として(B-1)成分を単独で使用する場合であれば、(B-1)成分の配合量として、例えば０．０１〜５重量％、好ましくは０．０５〜３重量％、更に好ましくは０．０５〜２重量％、より一層好ましくは０．１〜２重量％が挙げられる。(B)成分として(B-2)成分を単独で使用する場合であれば、(B-2)成分の配合量として、例えば０．０１〜１０重量％、好ましくは０．０５〜５重量％、更に好ましくは０．０５〜３重量％、より一層好ましくは０．１〜３量％が挙げられる。また、(B)成分として(B-1)成分及び(B-2)成分を組み合わせて使用する場合であれば、(B-1)成分の配合量として、例えば０．０１〜５重量％、好ましくは０．０５〜３重量％、更に好ましくは０．０５〜２重量％、より一層好ましくは０．１〜２重量％、(B-2)成分の配合量として、例えば０．０１〜１０重量％、好ましくは０．０５〜５重量％、更に好ましくは０．０５〜３重量％、より一層好ましくは０．１〜３量％が挙げられる。 More specifically, when the component (B-1) is used alone as the component (B), the blending amount of the component (B-1) is, for example, 0.01 to 5% by weight, preferably 0. 0.05 to 3% by weight, more preferably 0.05 to 2% by weight, and still more preferably 0.1 to 2% by weight. When the component (B-2) is used alone as the component (B), the amount of the component (B-2) is, for example, 0.01 to 10% by weight, preferably 0.05 to 5% by weight. More preferred is 0.05 to 3% by weight, and still more preferred is 0.1 to 3% by weight. In addition, when the combination of the component (B-1) and the component (B-2) is used as the component (B), the blending amount of the component (B-1) is, for example, 0.01 to 5% by weight, Preferably it is 0.05 to 3 weight%, More preferably, it is 0.05 to 2 weight%, More preferably, it is 0.1 to 2 weight%, As a compounding quantity of (B-2) component, it is 0.01-10, for example. % By weight, preferably 0.05 to 5% by weight, more preferably 0.05 to 3% by weight, and still more preferably 0.1 to 3% by weight.
その他の成分
本発明の予防又は治療剤は、前記(A)成分及び(B)成分の他に、必要に応じて、他の薬理成分を含有していてもよい。このような薬理成分としては、例えば、抗ヒスタミン剤（ジフェンヒドラミン、塩酸ジフェンヒドラミン等）、局所麻酔剤（プロカイン、テトラカイン、ブピパカイン、メピパカイン、クロロプロカイン、プロパラカイン、メプリルカイン又はこれらの塩、オルソカイン、オキセサゼイン、オキシポリエントキシデカン、ロートエキス、ペルカミンパーゼ、テシットデシチン等）、抗炎症剤（インドメタシン、フェルビナク、ジクロフェナクナトリウム、ロキソプロフェンナトリウム等）、皮膚保護剤（コロジオン、ヒマシ油等）、血行促進成分（ノニル酸ワニリルアミド、ニコチン酸ベンジルエステル、カプサイシン、トウガラシエキス等）、清涼化剤（メントール、カンフル等）、ビタミン類（ビタミンＡ等）、ムコ多糖類（コンドロイチン硫酸ナトリウム、グルコサミン等）等が挙げられる。
Other Components The preventive or therapeutic agent of the present invention may contain other pharmacological components as necessary in addition to the components (A) and (B). Examples of such pharmacological components include antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, propalacaine, meprilucaine or salts thereof, orthocaine, oxesasein, oxypolyentoxy Decane, funnel extract, percaminpase, tesit decite, etc.), anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting components (nonyl acid vanillylamide, nicotinic acid benzyl ester) , Capsaicin, pepper extract, etc.), refreshing agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (chondroy) Sodium emission sulfate, glucosamine, etc.) and the like.
また、本発明の予防又は治療剤は、所望の製剤形態にするために、必要に応じて、基材や添加剤が含まれていてもよい。このような基剤や添加剤については、薬学的に許容されることを限度として特に制限されないが、例えば、水、低級アルコール（エタノール、イソプロパノール等）、多価アルコール（グリセリン、プロピレングリコール、ジプロピレングリコール、１，３−ブチレングリコール等）等の水性基剤；油類（オリーブ油、サフラワー油、大豆油、つばき油、とうもろこし油、なたね油、ひまわり油、綿実油、落花生油、ラード、スクワラン、魚油等）、鉱物油（流動パラフィン、パラフィン、ゲル化炭化水素、ワセリン等）、ワックス類・ロウ類（ミツロウ、カルナウバロウ、キャンデリラロウ、セレシン、ライスワックス、マイクロクリスタリンワックス等）、エステル油（ミリスチン酸イソプロピル、アジピン酸イソプロピル、セバシン酸ジエチル、セバシン酸イソプロピル、パルミチン酸イソプロピル、パルミチン酸セチル、オレイン酸エチル等）、脂肪酸アルキルエステル、脂肪酸（ステアリン酸、オレイン酸、パルミチン酸、ベヘン酸、リノール酸、ラノリン等）、脂肪酸エステル（パルミチン酸セチル、パルミチン酸イソプロピル、リノール酸エチル等）、高級アルコール（ステアリルアルコール、セタノール、ベヘニルアルコール、ミリスチルアルコール、オレイルアルコール、ヘキサデシルアルコール、ラノリンアルコール等）、コレステロール、トリ２−エチルヘキサン酸グリセリル、２−エチルヘキサン酸セチル、シリコーンオイル（ジメチルポリシロキサン、環状シリコーン等）等の油性基剤；ＰＯＥ（１０〜５０モル）フィトステロールエーテル、ＰＯＥ（１０〜５０モル）ジヒドロコレステロールエーテル、ＰＯＥ（１０〜５０モル）２−オクチルドデシルエーテル、ＰＯＥ（１０〜５０モル）デシルテトラデシルエーテル、ＰＯＥ（１０〜５０モル）オレイルエーテル、ＰＯＥ（２〜５０モル）セチルエーテル、ＰＯＥ（５〜５０モル）ベヘニルエーテル、ＰＯＥ（５〜３０モル）ポリオキシプロピレン（５〜３０モル）２−デシルテトラデシルエーテル、ＰＯＥ（１０〜５０モル）ポリオキシプロピレン（２〜３０モル）セチルエーテルなどのポリオキシエチレンアルキルエーテル、これらのリン酸・リン酸塩（ＰＯＥセチルエーテルリン酸ナトリウムなど）、ＰＯＥ（２０〜６０モル）ソルビタンモノオレート、ＰＯＥ（１０〜６０モル）ソルビタンモノイソステアレート、ＰＯＥ（１０〜８０モル）グリセリルモノイソステアレート、ＰＯＥ（１０〜３０モル）グリセリルモノステアレート、ＰＯＥ（２０〜１００モル）・ポリオキシプロピレン変性シリコーン、ＰＯＥ・アルキル変性シリコーン、モノラウリン酸ポリエチレングリコール、モノパルミチン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、ジラウリン酸ポリエチレングリコール、ジパルミチン酸ポリエチレングリコール、ジステアリン酸ポリエチレングリコール、ジオレイン酸ポリエチレングリコール、ジリシノレイン酸ポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油（５〜１００）、ポリソルベート（２０〜８５）、グリセリン脂肪酸エステル（モノステアリン酸グリセリン等）、水素添加大豆リン脂質、水素添加ラノリンアルコール等の界面活性剤；清涼化剤（メントール、カンフル、ボルネオール、ハッカ水、ハッカ油等）、防腐剤（メチルパラベン、プロピルパラベン、安息香酸、安息香酸ナトリウム、ソルビン酸等）、着香剤（シトラール、１，８−シオネール、シトロネラール、ファルネソール等）、着色剤（タール色素（褐色２０１号、青色２０１号、黄色４号、黄色４０３号等）、カカオ色素、クロロフィル、酸化アルミニウム等）、粘稠剤（カルボキシビニルポリマー、ヒプロメロース、ポリビニルピロリドン、アルギン酸ナトリウム、エチルセルロース、カルボキシメチルセルロースナトリウム、キサンタンガム、カラギーナン等）、ｐＨ調整剤（リン酸、塩酸、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン、トリイソプロパノールアミン等）、湿潤剤（ｄｌ−ピロリドンカルボン酸ナトリウム液、Ｄ−ソルビトール液、マクロゴール等）、安定化剤（ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エデト酸ナトリウム、メタリン酸ナトリウム、Ｌ−アルギニン、Ｌ−アスパラギン酸、ＤＬ−アラニン、グリシン、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム、二酸化硫黄、クロロゲン酸、カテキン、ローズマリー抽出物等）、酸化防止剤、紫外線吸収剤、キレート剤、粘着剤、緩衝剤、溶解補助剤、可溶化剤、保存剤等の添加剤が挙げられる。 Moreover, in order to make the preventive or therapeutic agent of this invention into a desired formulation form, the base material and the additive may be contained as needed. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene) Aqueous bases such as glycol and 1,3-butylene glycol; oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc. ), Mineral oil (liquid paraffin, paraffin, gelled hydrocarbon, petroleum jelly, etc.), waxes and waxes (honey bees, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , Isopropyl adipate, sebacic acid Ethyl, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc., fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (palmitic acid) Cetyl, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, 2-ethyl Oily bases such as cetyl hexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE ( 0-50 mol) Dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) ) Cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2- 30 mol) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acid / phosphate thereof (such as POE cetyl ether sodium phosphate), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan Monoisostearate, POE (10 80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol) polyoxypropylene-modified silicone, POE alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene monopalmitate Glycol, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20 -85), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanoli Surfactants such as alcohol; refreshing agents (menthol, camphor, borneol, mint water, mint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral) , 1,8-shioner, citronellal, farnesol, etc.), coloring agent (tar pigment (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickener (Carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, Hydroxy Potassium, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate, D-sorbitol, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, metalin) Acid sodium, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidant, UV absorption Additives such as agents, chelating agents, pressure-sensitive adhesives, buffers, solubilizers, solubilizers, preservatives and the like.
製剤形態・用途
本発明の予防又は治療剤は、外用剤として、肥厚性瘢痕及び／又はケロイドの予防が求められる皮膚部位、又は肥厚性瘢痕及び／又はケロイドの病変部に適用して使用される。また、本発明の予防又は治療剤は、肥厚性瘢痕及び／又はケロイドを効果的に予防又は治療できるので、例えば、傷・火傷の後の皮膚の変色（赤み、くすみ）、引きつれ（つっぱり）、しこり、弾力の低下等の改善目的で使用することができる。
Formulation Form / Use The preventive or therapeutic agent of the present invention is used as an external preparation applied to a skin site where hypertrophic scar and / or keloid prevention is required, or a hypertrophic scar and / or keloid lesion. . In addition, since the preventive or therapeutic agent of the present invention can effectively prevent or treat hypertrophic scars and / or keloids, for example, skin discoloration (redness, dullness) after a wound / burn, pulling (slipping) It can be used for the purpose of improving, such as lumping, lowering elasticity.
本発明の予防又は治療剤は、経皮適用できる剤型である限り、その製剤形態については、特に制限されず、液状、固形状、半固形状（ゲル状、軟膏状、ペースト状）等のいずれであってもよい。 As long as the preventive or therapeutic agent of the present invention is a dosage form that can be applied transdermally, the formulation form is not particularly limited, and it may be liquid, solid, semi-solid (gel, ointment, paste), etc. Either may be sufficient.
また、本発明の予防又は治療剤は、皮膚に適用されるものである限り、皮膚外用医薬品、化粧料、皮膚洗浄料等のいずれの製剤形態であってもよい。本発明の予防又は治療剤の製剤形態として、具体的には、クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等の皮膚外用医薬品；軟膏、クリーム、乳液、化粧水、ローション、パック、ゲル等の化粧料；ボディーシャンプー、ヘアシャンプー、リンス等の皮膚洗浄料等が挙げられる。これらの製剤形態の中でも、好ましくは皮膚外用医薬品、更に好ましくはクリーム剤、ローション剤、ジェル剤、乳液剤、パック剤が挙げられる。 Further, the prophylactic or therapeutic agent of the present invention may be in any form of pharmaceutical preparation for external use for skin, cosmetics, skin cleansing agents and the like as long as it is applied to the skin. Specific examples of the preparation form of the preventive or therapeutic agent of the present invention include creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, and other external skin drugs; ointments, Cosmetics such as creams, emulsions, lotions, lotions, packs and gels; skin cleansing agents such as body shampoos, hair shampoos and rinses. Among these preparation forms, preferably a skin external medicine, more preferably a cream, a lotion, a gel, an emulsion, or a pack.
また、本発明の予防又は治療剤の用量については、製剤形態、適用する症状の程度等に応じて適宜設定すればよい。本発明の予防又は治療剤の用量の一例として、１回当たり、皮膚１ｃｍ2当たり、前記(A)成分の適用量換算で０．１〜３ｍｇ程度となる量で、1日１〜数回程度の頻度が挙げられるが、かかる範囲に限定されるものではない。 Moreover, what is necessary is just to set suitably about the dosage of the preventive or therapeutic agent of this invention according to a formulation form, the grade of the symptom to apply, etc. As an example of the dose of the preventive or therapeutic agent of the present invention, per dose, about 1 to several times a day, in an amount of about 0.1 to 3 mg per 1 cm 2 of skin, in terms of the applied amount of the component (A) However, it is not limited to such a range.
２．肉芽組織の形成抑制剤
本発明の肉芽組織の形成抑制剤は、(A)ヘパリン類似物質と、(B)アラントイン、グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種を含有し、肉芽組織の形成を抑制するために使用されることを特徴とする。
2. Granulation tissue formation inhibitor The granulation tissue formation inhibitor of the present invention is selected from the group consisting of (A) heparin-like substances and (B) allantoin, glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. It is characterized by being used for suppressing the formation of granulation tissue.
本発明の肉芽組織の形成抑制剤において、(A)成分及び(B)成分の種類、(B)成分の好ましいもの、(B)成分の好ましい組み合わせ態様、(A)成分及び(B)成分の配合量や比率等については、前記「１．肥厚性瘢痕及び／又はケロイドの予防又は治療剤」の場合と同様である。 In the granulation tissue formation inhibitor of the present invention, the types of the components (A) and (B), the preferred components (B), the preferred combinations of the components (B), the components (A) and (B) The blending amount and ratio are the same as in the case of “1. Preventive or therapeutic agent for hypertrophic scar and / or keloid”.
また、本発明の肉芽組織の形成抑制剤において、(A)成分及び(B)成分以外に配合できる他の成分、製剤形態、用量等についても、前記「１．肥厚性瘢痕及び／又はケロイドの予防又は治療剤」の場合と同様である。 In addition, in the granulation tissue formation inhibitor of the present invention, other components that can be blended in addition to the component (A) and the component (B), formulation forms, doses, etc., are also described in “1. Hypertrophic scar and / or keloid. This is the same as in the case of the “prophylactic or therapeutic agent”.
本発明の肉芽組織の形成抑制剤は、肉芽組織の形成を抑制できるので、肥厚性瘢痕、ケロイド、皮膚の盛り上がり、変色（赤み、くすみ）、つっぱり、しこり、弾力低下等の、肉芽組織の過剰な形成によって生じる皮膚疾患や皮膚症状の予防又は治療目的で使用できる。 Since the granulation tissue formation inhibitor of the present invention can suppress the formation of granulation tissue, excessive granulation tissue such as hypertrophic scar, keloid, skin swell, discoloration (redness, dullness), tension, lump, reduced elasticity, etc. It can be used for the purpose of preventing or treating skin diseases and skin symptoms caused by natural formation.
３．外用組成物
本発明の外用組成物は、(A)ヘパリン類似物質と、(B-1)アラントイン及びその誘導体よりなる群から選択される少なくとも１種と、(B-2)グリチルリチン酸、グリチルレチン酸、それらの誘導体、及びそれらの塩よりなる群から選択される少なくとも１種とを含有することを特徴とする。
3. Composition for External Use The composition for external use of the present invention comprises (A) a heparin-like substance, (B-1) at least one selected from the group consisting of allantoin and its derivatives, and (B-2) glycyrrhizic acid and glycyrrhetinic acid. , Derivatives thereof, and at least one selected from the group consisting of salts thereof.
本発明の外用組成物において、(A)成分、(B-1)成分、及び(B-2)成分の種類、これらの好ましいもの、これらの配合量や比率等については、前記「１．肥厚性瘢痕及び／又はケロイドの予防又は治療剤」の場合と同様である。 In the composition for external use of the present invention, the types of component (A), component (B-1), and component (B-2), preferred ones thereof, blending amount and ratio thereof, etc. are described in “1. Thickening”. It is the same as in the case of the “prophylaxis or / and keloid preventive or therapeutic agent”.
また、本発明の外用組成物において、(A)成分、(B-1)成分、及び(B-2)成分以外に配合できる他の成分、製剤形態、用量等についても、前記「１．肥厚性瘢痕及び／又はケロイドの予防又は治療剤」の場合と同様である。 In addition, in the composition for external use of the present invention, other components that can be blended in addition to the component (A), the component (B-1), and the component (B-2), the preparation form, the dosage, etc. It is the same as in the case of the “prophylaxis or / and keloid preventive or therapeutic agent”.
本発明の外用組成物は、肥厚性瘢痕及び／又はケロイドの予防又は治療効果や、肉芽組織の形成抑制作用が卓越しており、肥厚性瘢痕、ケロイド、皮膚の盛り上がり、赤み、つっぱり、しこり等の皮膚疾患や皮膚症状の予防又は治療目的で好適に使用できる。 The composition for external use of the present invention has a prophylactic or therapeutic effect on hypertrophic scars and / or keloids and an excellent inhibitory action on granulation tissue formation, such as hypertrophic scars, keloids, skin swelling, redness, tension, lump, etc. Can be suitably used for the purpose of preventing or treating skin diseases and skin symptoms.
以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.
試験例１：肉芽組織の形成抑制作用の評価
７週齢（馴化期間１週間を含む）のＳｌｃ：Ｗｉｓｔａｒラットの背部正中線上に小切開を加え、約３０ｍｇとなるように調整した滅菌済みコットンペレット（「リッチモンドコットンペレット」、株式会社アグサジャパン製）を１個挿入した後に、切開部を縫合した。縫合から６時間後、コットンペレット埋植部位の皮膚上に表１に示すジェル剤約１ｇを塗布（初回塗布）した。初回塗布から２４時間間隔で、１日１回、合計６日間、コットンペレット埋植部位に表１に示すジェル剤約１ｇを塗布した。最終塗布の翌日に、ラット背部から、コットンペレットを取り巻いて形成された肉芽をコットンペレットと共に摘出した。摘出した肉芽を乾燥した後に重量を測定し、これを肉芽乾燥重量とした。また、コントロールとして、ジェル剤の塗布を行わないこと以外は、前記と同様の方法で、肉芽乾燥重量を求めた。肉芽乾燥重量から埋植したコットンペレットの重量を差し引いた値を肉芽重量とした。なお、本試験では、１群当たり１０匹のラットを使用して肉芽重量の平均値を算出した。また、得られた肉芽重量から、以下の式に従って、肉芽形成抑制率（％）を算出した。
各ジェル剤の塗布によって認められた肉芽形成抑制率を表１に示す。この結果から、ヘパリン類似物質及びアラントインを併用した場合（実施例１及び２）では、ヘパリン類似物質単独の場合（比較例１）に比して、肉芽形成抑制率が１．７倍以上にまで向上していることが確認された。更に、ヘパリン類似物質、アラントイン、及びグリチルリチン酸二カリウムを組み合わせた場合（実施例３）には、肉芽形成抑制率の飛躍的な向上が認められた。以上の結果から、ヘパリン類似物質及びアラントインの併用、並びにヘパリン類似物質、アラントイン及びグリチルリチン酸二カリウムの併用は、肉芽組織の形成抑制作用が高く、肥厚性瘢痕及び／又はケロイドの予防又は治療に有効であることが明らかとなった。 Table 1 shows granulation formation inhibition rates observed by application of each gel agent. From this result, when the heparin-like substance and allantoin are used in combination (Examples 1 and 2), the granulation formation inhibition rate is 1.7 times or more compared to the case of the heparin-like substance alone (Comparative Example 1). It was confirmed that there was an improvement. Furthermore, when heparin-like substances, allantoin, and dipotassium glycyrrhizinate were combined (Example 3), a dramatic improvement in granulation formation inhibition rate was observed. From the above results, the combined use of heparin-like substances and allantoin, and the combined use of heparin-like substances, allantoin and dipotassium glycyrrhizinate have high inhibitory action on granulation tissue formation and are effective in the prevention or treatment of hypertrophic scars and / or keloids. It became clear that.
試験例２：傷あとの治療効果の評価
皮膚の傷あと（擦り傷や切り傷のあと）に、盛り上がり、つっぱり、変色（赤み、くすみ）等が認められ、ケロイドや肥厚性瘢痕の症状がある被験者１０名によって、表２に示すクリーム剤の治療効果を評価した。具体的な試験方法及び試験結果は、以下の通りである。
Test Example 2: Evaluation of the therapeutic effect after wounding After skin wounds (after abrasions and cuts), swell, tension, discoloration (redness, dullness), etc. were observed, and 10 subjects with symptoms of keloid or hypertrophic scar The therapeutic effects of the creams shown in Table 2 were evaluated. Specific test methods and test results are as follows.
１．試験方法
投与方法
具体的には、被験者を５名ずつの２群に分け、一方の群では表２に示す実施例４のクリーム剤を患部に塗布し、他方の群では表２に示す比較例２のクリーム剤を患部に塗布した。なお、両群とも、クリーム剤の塗布は０．２ｇを１日１回の頻度で１カ月間行った。
1. Test method
Method of administration Specifically, the subjects were divided into 2 groups of 5 each, and the cream of Example 4 shown in Table 2 was applied to the affected area in one group, and Table 2 was shown in the other group. The cream of Comparative Example 2 was applied to the affected area. In both groups, the cream was applied 0.2 g once a day for one month.
患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）の目視評価
各クリーム剤の塗布１ヶ月後に、患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）のそれぞれについて目視にて観察し、下記判定基準に従って治療効果を評点化し、各群の評点の平均値を求めた。なお、患部の盛り上がりの評価については、症状の認められた被験者についてのみ評価を行い、比較例のクリーム剤を塗布した群では２名、実施例のクリーム剤を塗布した群では１名の被験者について評価を行った。
＜判定基準＞
評点
３：クリーム剤の塗布前に比べて、著しく改善した
２：クリーム剤の塗布前に比べて、改善した。
１：クリーム剤の塗布前に比べて、僅かに改善した。
０：クリーム剤の塗布前に比べて、殆ど改善が認められなかった。
Visual evaluation of swell, squeeze, and discoloration (redness, dullness) of affected area 1 month after application of each cream, each swell, squeeze, and discoloration (redness, dimness) of the affected area was visually observed, and the following criteria The treatment effect was scored according to the above, and the average score of each group was determined. In addition, about evaluation of the swell of an affected part, it evaluates only about the test subject who recognized the symptom, and it is about one test subject in the group which applied the cream preparation of the Example, and 2 persons in the group which applied the cream preparation of the comparative example Evaluation was performed.
<Criteria>
Score 3: Remarkably improved compared to before applying cream 2: Improved compared to before applying cream.
1: Improved slightly compared to before applying the cream.
0: Almost no improvement was observed compared to before application of the cream.
皮膚弾力の評価
各クリーム剤の塗布前及び塗布１ヶ月後に、患部の弾力性指標（Ｒ７、純弾性）をキュートメーター（Cutometer MPA 580、株式会社インテグラル製）によって求めることにより、皮膚弾力の測定を行った。また、健常な皮膚部位についても同様に皮膚弾力の測定を行い、健常な皮膚部位における皮膚弾力を１とした場合の患部の皮膚弾力の相対値を求めた。なお、皮膚弾力の評価は、実施例４のクリーム剤を塗布した群の中から、無作為に抽出した３名の被験者に対して行った。
Evaluation of skin elasticity Measurement of skin elasticity by determining the elasticity index (R7, pure elasticity) of the affected area with a cutometer (Cutometer MPA 580, manufactured by Integral Co., Ltd.) before and 1 month after application of each cream. Went. In addition, the skin elasticity was measured in the same manner for a healthy skin site, and the relative value of the skin elasticity of the affected area when the skin elasticity in the healthy skin site was set to 1 was obtained. In addition, evaluation of skin elasticity was performed with respect to three test subjects randomly extracted from the group to which the cream of Example 4 was applied.
皮膚の色の評価
各クリーム剤の塗布前及び塗布１ヶ月後に、患部の色相（Ｈｕｅ）と明度（Ｖａｌｕｅ）を、分光測色計（分光測色計CM-700d、コニカミノルタ株式会社製）を用いて測定した。また、比較として、健常な皮膚部位における色相と明度についても測定した。本試験では、患部及び健常皮膚部の複数個所に対して測定を行った。なお、皮膚の色の評価は、１群当たり、無作為に抽出した４名の被験者に対して行った。
Evaluation of skin color Before and 1 month after application of each cream, the hue (Hue) and lightness (Value) of the affected area were measured using a spectrocolorimeter (spectral colorimeter CM-700d, manufactured by Konica Minolta Co., Ltd.). And measured. For comparison, the hue and brightness of a healthy skin site were also measured. In this test, measurements were performed on a plurality of locations on the affected area and the healthy skin area. The skin color was evaluated for 4 subjects randomly extracted per group.
２．試験結果
患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）を目視評価した結果を表３に示す。この結果から、ヘパリン類似物質、アラントイン及びグリチルリチン酸二カリウムを組み合わせて使用した場合（実施例４）には、ヘパリン類似物質単独（比較例２）に比べて、患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）の治療効果が高いことが確認された。特に、実施例４のクリーム剤による患部の盛り上がりの治療効果は、比較例２のクリーム剤の場合に比して格段に向上していた。
2. Test results Table 3 shows the results of visual evaluation of the swell, tension and discoloration (redness, dullness) of the affected area. From this result, when heparin-like substance, allantoin and dipotassium glycyrrhizinate were used in combination (Example 4), compared to the heparin-like substance alone (Comparative Example 2), the swelled, stiffened, and discolored ( It was confirmed that the therapeutic effect of redness and dullness was high. In particular, the therapeutic effect of the swell of the affected area by the cream of Example 4 was significantly improved as compared with the cream of Comparative Example 2.
また、皮膚弾力をキュートメーターで測定した結果を表４に示す。なお、健常皮膚における皮膚弾力を１とした場合の患部の皮膚弾力の相対値は、低い値になる程、弾力が小さくなり、高い値になる程、弾力が高くなる。表４から明らかなように、実施例４のクリーム剤の塗布前の患部は、健常皮膚に比べて弾力が低かったが、実施例４のクリーム剤の塗布後は、健常皮膚と同等又はそれ以上に弾力が高くなっており、患部の症状が効果的に改善していた。 Table 4 shows the results of skin elasticity measured with a cut meter. Note that the relative value of the skin elasticity of the affected area when the skin elasticity in healthy skin is 1, the lower the elasticity, the lower the elasticity, and the higher the elasticity, the higher the elasticity. As is clear from Table 4, the affected area before application of the cream of Example 4 was less elastic than that of healthy skin, but after application of the cream of Example 4, it was equal to or greater than that of healthy skin. The symptom of the affected area was effectively improved.
更に、皮膚の色を分光測色計で測定した結果を図１及び２に示す。図１には、実施例４のクリーム剤の塗布した群の内、４名の被験者の結果を示し、図２には、比較例２のクリーム剤の塗布した群の内、３名の被験者の結果を示す。なお、図１及び２において、横軸は色相（Ｈｕｅ）を示しており、右に進むにつれて黄色に近くなり、左に進むにつれて赤色に近くなることを示している。また、図１及び２において、縦軸は、明度（Ｖａｌｕｅ）を示しており、値が大きくなるほど明るいことを示している。 Furthermore, the results of measuring the skin color with a spectrocolorimeter are shown in FIGS. FIG. 1 shows the results of 4 subjects in the group to which the cream of Example 4 was applied. FIG. 2 shows the results of 3 subjects in the group to which the cream of Comparative Example 2 was applied. Results are shown. In FIGS. 1 and 2, the horizontal axis indicates the hue (Hue), and the closer to the right, the closer to yellow, and the further to the left, the closer to red. In FIGS. 1 and 2, the vertical axis indicates lightness (Value), and the higher the value, the brighter the value.
図１に示されるように、実施例４のクリーム剤を塗布した場合には、患部の赤みが減少して明度も増しており、健常皮膚に近い色になっていた。一方、図２に示されているように、比較例２のクリーム剤を塗布した場合には、塗布前に比べて患部の色の変化は殆ど認められなかった。 As shown in FIG. 1, when the cream of Example 4 was applied, the redness of the affected area decreased and the brightness increased, and the color was close to that of healthy skin. On the other hand, as shown in FIG. 2, when the cream of Comparative Example 2 was applied, almost no change in the color of the affected area was observed compared to before application.
以上の結果から、ヘパリン類似物質、アラントイン及びグリチルリチン酸二カリウムを組み合わせた場合には、患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）の治療効果が格段に優れており、ケロイドや肥厚性瘢痕を効果的に治療できることが明らかとなった。 From the above results, when heparin-like substance, allantoin and dipotassium glycyrrhizinate were combined, the treatment of swelling, stretching and discoloration (redness, dullness) of the affected area was remarkably excellent, and keloid and hypertrophic scar It was revealed that can be effectively treated.
製剤例
表５〜７に示す組成のクリーム剤（実施例５〜１９）、表８に示すローション剤（実施例２０〜２５）、表９に示すジェル剤（実施例２６〜３０）、及び表１０〜１２に示す乳液剤（実施例３１〜４８）を調製した。これらの製剤は、いずれも、前記試験例２の場合と同様に、患部の盛り上がり、つっぱり、及び変色（赤み、くすみ）の治療効果が格段に優れており、ケロイドや肥厚性瘢痕を効果的に治療できることが確認された。
Formulation Examples Creams ( Examples 5 to 19) having the compositions shown in Tables 5 to 7, Lotions (Examples 20 to 25) shown in Table 8, Gels (Examples 26 to 30) shown in Table 9, and Tables The emulsion (Examples 31-48) shown in 10-12 was prepared. As in the case of Test Example 2, all of these preparations are remarkably excellent in the treatment of swelling, stretching, and discoloration (redness, dullness) of the affected area, and effectively prevent keloids and hypertrophic scars. It was confirmed that it could be treated.
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| JP7197349B2 (en) * | 2018-12-27 | 2022-12-27 | 小林製薬株式会社 | External emulsion composition |
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