JP2014108960A - Composition for mucosal application - Google Patents
Composition for mucosal application Download PDFInfo
- Publication number
- JP2014108960A JP2014108960A JP2012265842A JP2012265842A JP2014108960A JP 2014108960 A JP2014108960 A JP 2014108960A JP 2012265842 A JP2012265842 A JP 2012265842A JP 2012265842 A JP2012265842 A JP 2012265842A JP 2014108960 A JP2014108960 A JP 2014108960A
- Authority
- JP
- Japan
- Prior art keywords
- composition
- mucosa
- component
- present
- item
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 178
- -1 fatty acid ester Chemical class 0.000 claims abstract description 57
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- 210000004877 mucosa Anatomy 0.000 claims description 81
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 18
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- 239000003945 anionic surfactant Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
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- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
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- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
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- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
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- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 2
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- WXKPPMQZRGORPB-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;acetate Chemical compound [Na+].CC([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O WXKPPMQZRGORPB-UHFFFAOYSA-M 0.000 description 1
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011232 storage material Substances 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- WYXIGTJNYDDFFH-UHFFFAOYSA-Q triazanium;borate Chemical compound [NH4+].[NH4+].[NH4+].[O-]B([O-])[O-] WYXIGTJNYDDFFH-UHFFFAOYSA-Q 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
本発明は粘膜適用組成物に関する。更に詳しくは、本発明は、保存効力が増強された粘膜適用組成物に関する。 The present invention relates to a composition applied to mucosa. More particularly, the present invention relates to a mucosa-applied composition with enhanced storage efficacy.
眼科用組成物等の粘膜適用組成物は、使用時の微生物汚染等による製品の腐敗が防止されていることが望ましいため、その腐敗を防止して組成物に保存効力を付与する目的で、防腐剤が配合されている。しかし、防腐剤を多量に配合すると、細胞毒性等の悪影響が懸念されるため、十分な保存効力を保ちつつ、防腐剤の配合量を抑えることが望まれている。 It is desirable that the composition applied to mucous membranes such as an ophthalmic composition is prevented from being spoiled due to microbial contamination during use, and therefore, for the purpose of preventing the spoilage and imparting preservative effect to the composition. An agent is blended. However, when a large amount of the preservative is blended, there is a concern about adverse effects such as cytotoxicity. Therefore, it is desired to suppress the blending amount of the preservative while maintaining a sufficient preservation effect.
クロロブタノールは、局所麻酔剤の一種として、粘膜適用組成物に配合されることが知られており、また防腐力を有することも知られている。 Chlorobutanol is known as a kind of local anesthetic agent to be blended in a composition applied to mucosa, and is also known to have antiseptic power.
一方、粘膜適用組成物においては、溶解補助剤が多くの処方に配合されており、その一つとして界面活性剤が挙げられる。 On the other hand, in a composition applied to mucosa, a solubilizing agent is blended in many formulations, and one of them is a surfactant.
モノステアリン酸ポリエチレングリコールは、非イオン界面活性剤の一種であり、他の配合成分の溶解補助等を目的として、例えば、眼科用組成物等の粘膜適用組成物に配合されることが知られている（特許文献１）。 Polyethylene glycol monostearate is a kind of nonionic surfactant, and is known to be blended in mucosa-applied compositions such as ophthalmic compositions for the purpose of assisting dissolution of other blended components. (Patent Document 1).
また、ポリオキシエチレンソルビタン脂肪酸エステルも、非イオン界面活性剤の一種であり、他の配合成分の溶解補助等を目的として、眼科用組成物等の粘膜適用組成物に配合されることが知られている。 Polyoxyethylene sorbitan fatty acid ester is also a kind of nonionic surfactant, and is known to be blended in mucosa-applied compositions such as ophthalmic compositions for the purpose of assisting dissolution of other blended components. ing.
また、一般に、非イオン性界面活性剤は、防腐剤を不活性化し、保存効力を低下させる作用を有することが知られている。 In general, it is known that a nonionic surfactant has an action of inactivating a preservative and reducing the storage efficacy.
上記したように、粘膜適用組成物における保存安定性を確保するために、粘膜適用組成物において、保存効力を増強させることは重要な課題である。本発明は、このような従来技術の現状に鑑みてなされたものであり、粘膜適用組成物において、その保存効力を増強させることを課題とする。 As described above, in order to ensure the storage stability in the composition applied to mucosa, it is an important problem to enhance the storage efficacy in the composition applied to mucosa. This invention is made | formed in view of the present condition of such a prior art, and makes it a subject to enhance the preservation | save effect in a mucosa application composition.
本発明者等は、上記課題を解決すべく鋭意検討を行った結果、粘膜適用組成物においてクロロブタノール（以下、「(A)成分」と表記することもある）と、モノステアリン酸ポリエチレングリコール（以下、「(B)成分」又は「ステアリン酸ポリオキシル」と表記することもある）と、ポリオキシエチレンソルビタン脂肪酸エステル（以下、「(C)成分」とを共に配合することにより、意外にも粘膜適用組成物の保存効力が増強されることを見出した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that chlorobutanol (hereinafter sometimes referred to as “component (A)”) and polyethylene glycol monostearate ( In the following, it is surprising that the combination of “(B) component” or “polyoxyl stearate” and polyoxyethylene sorbitan fatty acid ester (hereinafter “(C) component”) It has been found that the storage efficacy of the applied composition is enhanced.
すなわち、本発明は、以下の新規な粘膜適用組成物を提供するものである。
項1-1．(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含有する、粘膜適用組成物。
項1-2．(B)成分が、酸化エチレンの平均付加モル数が2〜80モルのステアリン酸ポリオキシルである、項1-1に記載の粘膜適用組成物。
項1-3．(C)成分が、モノオレイン酸ポリオキシエチレン（20）ソルビタンである、項1-1又は項1-2に記載の粘膜適用組成物。
項1-4．粘膜適用組成物の総量を基準として、(A)成分の含有量が、0.01〜1w/v％である、項1-1乃至1-3のいずれかに記載の粘膜適用組成物。
項1-5．粘膜適用組成物の総量を基準として、(B)成分の含有量が、総量で0.01〜2.5w/v％である、項1-1乃至1-4のいずれかに記載の粘膜適用組成物。
項1-6．(A)成分の総含有量１質量部に対して、(B)成分の含有比率が、総含有量で0.01〜250質量部である、項1-1乃至1-5のいずれかに記載の粘膜適用組成物。
項1-7．(B)成分の総含有量１質量部に対して、(C)成分の含有比率が、総含有量で0.004〜100質量部である、項1-1乃至1-6のいずれかに記載の粘膜適用組成物。
項1-8. 更に、(D)緩衝剤を含有する、項1-1乃至1-7のいずれかに記載の粘膜適用組成物。
項1-9．粘膜適用組成物の総量を基準として、(D)成分の含有量が、総量で0.1〜5w/v％である、項1-8に記載の粘膜適用組成物。
項1-10．更に、(B)成分及び(C)成分以外の界面活性剤(E)を含有する、項1-1乃至1-9のいずれかに記載の粘膜適用組成物。
項1-11．(D)成分が、ホウ酸、リン酸、クエン酸及びそれらの塩からなる群より選択される少なくとも一種である、項1-10に記載の粘膜適用組成物。
項1-12．粘膜適用組成物の総量を基準として、(E)成分の含有量が、総量で0.1〜5w/v％である、項1-10又は1-11に記載の粘膜適用組成物。
項1-13．点眼剤である項1-1乃至1-12のいずれかに記載の粘膜適用組成物。
項1-14．洗眼剤である項1-1乃至1-12のいずれかに記載の粘膜適用組成物。
項1-15．コンタクトレンズ装着液である項1-1乃至1-12のいずれかに記載の粘膜適用組成物。
項1-16．コンタクトレンズケア用剤である項1-1乃至1-12のいずれかに記載の粘膜適用組成物。
項1-17．点鼻剤である項1-1乃至1-12のいずれかに記載の粘膜適用組成物。
That is, the present invention provides the following novel mucosa-applied composition.
Item 1-1. A mucosa-applied composition comprising (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester.
Item 1-2. Item (B) The mucosa-applied composition according to Item 1-1, wherein the component is polyoxyl stearate having an average added mole number of ethylene oxide of 2 to 80 moles.
Item 1-3. Item (C) The mucosa-applied composition according to Item 1-1 or Item 1-2, wherein the component is polyoxyethylene (20) sorbitan monooleate.
Item 1-4. The mucosa-applied composition according to any one of Items 1-1 to 1-3, wherein the content of the component (A) is 0.01 to 1 w / v% based on the total amount of the mucosa-applied composition.
Item 1-5. Item 5. The mucosa-applied composition according to any one of Items 1-1 to 1-4, wherein the total amount of the component (B) is 0.01 to 2.5 w / v% based on the total amount of the mucosa-applied composition.
Item 1-6. The content ratio of the component (B) is 0.01 to 250 parts by mass with respect to 1 part by mass of the total content of the component (A), or any one of items 1-1 to 1-5 Mucosal composition.
Item 1-7. The content ratio of component (C) is 0.004 to 100 parts by mass with respect to 1 part by mass of the total content of component (B), Mucosal composition.
Item 1-8. The mucosa-applied composition according to any one of Items 1-1 to 1-7, further comprising (D) a buffer.
Item 1-9. Item 9. The mucosa-applied composition according to Item 1-8, wherein the content of the component (D) is 0.1 to 5 w / v% in total based on the total amount of the mucosa-applied composition.
Item 1-10. Item 10. The composition for applying to mucosa according to any one of Items 1-1 to 1-9, further comprising a surfactant (E) other than the component (B) and the component (C).
Item 1-11. Item 11. The composition for applying to mucosa according to Item 1-10, wherein the component (D) is at least one selected from the group consisting of boric acid, phosphoric acid, citric acid and salts thereof.
Item 1-12. Item 11. The mucosa-applied composition according to item 1-10 or 1-11, wherein the content of the component (E) is 0.1 to 5 w / v% in total based on the total amount of the composition applied to mucosa.
Item 1-13. Item 13. The composition for applying to mucosa according to any one of Items 1-1 to 1-12, which is an eye drop.
Item 1-14. Item 13. The composition for applying to mucosa according to any one of Items 1-1 to 1-12, which is an eye wash.
Item 1-15. Item 13. The mucosa-applied composition according to any one of Items 1-1 to 1-12, which is a contact lens mounting liquid.
Item 1-16. Item 13. The mucosa-applied composition according to any one of Items 1-1 to 1-12, which is a contact lens care agent.
Item 1-17. Item 13. The composition for applying to mucosa according to any one of Items 1-1 to 1-12, which is a nasal drop.
また、本発明は、下記に掲げる態様の、粘膜適用組成物における保存効力を増強する方法を提供する。
項2-1．(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを、粘膜適用組成物に含有させることにより、該粘膜適用組成物における保存効力を増強する方法。
項2-2．(A)クロロブタノールを含有する粘膜適用組成物に、(B)モノステアリン酸ポリエチレングリコール及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含有させることにより、該粘膜適用組成物における保存効力を増強する方法。
In addition, the present invention provides a method for enhancing the storage efficacy of the composition applied to mucosa according to the following aspects.
Item 2-1. A method for enhancing the storage efficacy of a mucosa-applied composition by containing (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) a polyoxyethylene sorbitan fatty acid ester in the mucosa-applied composition.
Item 2-2. (A) A method for enhancing the storage efficacy of a composition applied to mucosa by containing (B) polyethylene glycol monostearate and (C) polyoxyethylene sorbitan fatty acid ester in the composition applied to mucosa containing chlorobutanol .
更に、本発明は、下記の掲げる態様の使用も提供する。
項3-1.粘膜適用組成物の製造のための、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルの使用。
項3-2．粘膜適用組成物が、上記項1-1乃至1-17のいずれかに記載の組成物である、項3-1に記載の使用。
Furthermore, the present invention also provides the use of the following aspects.
Item 3-1: Use of (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester for the production of a composition for application to mucosa.
Item 3-2. Item 3. The use according to Item 3-1, wherein the mucosa-applied composition is the composition according to any one of Items 1-1 to 1-17.
更に、本発明は、下記に掲げる態様の使用も提供する。
項4-1.粘膜適用組成物としての、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含む組成物の使用。
項4-2.組成物が、上記項1-1乃至1-17のいずれかに記載の組成物である、項4-1に記載の使用。
Furthermore, the present invention also provides the use of the embodiments listed below.
Item 4-1: Use of a composition comprising (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester as a composition applied to mucosa.
Item 4-2. The use according to Item 4-1, wherein the composition is the composition according to any one of Items 1-1 to 1-17.
更に、本発明は、下記に掲げる態様の組成物も提供する。
項5-1.粘膜適用組成物としての使用のための、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含む組成物。
項5-2.上記項1-1乃至1-17のいずれかに記載されたものである、項5-1に記載の組成物。
Furthermore, this invention also provides the composition of the aspect hung up below.
Item 5-1: A composition comprising (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester, for use as a composition for applying to mucosa.
Item 5-2. The composition according to Item 5-1, which is described in any one of Items 1-1 to 1-17.
更に、本発明は、下記に掲げる態様の粘膜適用組成物の製造方法も提供する。
項6-1.水と、(A)クロロブタノールと、(B)モノステアリン酸ポリエチレングリコールと、(C)ポリオキシエチレンソルビタン脂肪酸エステルとを混合する工程を含む、粘膜適用組成物の製造方法。
項6-2.粘膜適用組成物が、上記項1-1乃至1-17のいずれかに記載の組成物である、項6-1に記載の製造方法。
Furthermore, this invention also provides the manufacturing method of the mucosa applicable composition of the aspect hung up below.
Item 6-1. A method for producing a mucosa-applied composition comprising a step of mixing water, (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester.
Item 6-2. The method according to Item 6-1, wherein the composition applied to mucosa is the composition according to any one of Items 1-1 to 1-17.
本発明によれば、クロロブタノール、モノステアリン酸ポリエチレングリコール、及びポリオキシエチレンソルビタン脂肪酸エステルを、粘膜適用組成物において共に含有させることにより、粘膜適用組成物の保存効力を増強させることができる。 According to the present invention, by containing chlorobutanol, polyethylene glycol monostearate, and polyoxyethylene sorbitan fatty acid ester together in the mucosa-applied composition, the storage efficacy of the mucosa-applied composition can be enhanced.
粘膜適用組成物は、眼粘膜や鼻粘膜等に対して安全に適用できることが必要であり、刺激性の高い防腐剤を高濃度に配合することは望ましくないが、溶解補助剤としても配合可能なモノステアリン酸ポリエチレングリコール及びポリオキシエチレンソルビタン脂肪酸エステルを、クロロブタノールと併用することにより、防腐剤を高濃度に配合せずとも、高い保存効力を有する粘膜適用組成物を得ることが可能となる。 It is necessary that the composition applied to the mucosa can be safely applied to the ocular mucosa, the nasal mucosa, etc., and it is not desirable to add a highly irritating antiseptic at a high concentration, but it can also be added as a solubilizing agent. By using polyethylene glycol monostearate and polyoxyethylene sorbitan fatty acid ester in combination with chlorobutanol, it is possible to obtain a composition for applying to mucosa having a high preservative effect without blending a preservative at a high concentration.
また、粘膜適用組成物は、その容器が粘膜と接触した場合、粘液等による汚染を受け易いと考えられるが、本発明の粘膜適用組成物は保存効力が増強されているため、そのような汚染に対しても効果的に微生物を殺菌することが可能であり、粘膜適用組成物として極めて有用である。 In addition, the composition applied to mucosa is considered to be easily contaminated by mucus or the like when the container comes into contact with the mucous membrane. However, since the composition for applying mucosa of the present invention has enhanced preservation effect, Can effectively sterilize microorganisms and is extremely useful as a composition applied to mucosa.
［１．粘膜適用組成物］
本発明の粘膜適用組成物は、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含有する。
本明細書において配合割合の単位「％」は、「w/v％」を意味し、「g/100mL」と同義である。
[1. Mucosal composition]
The composition for applying to mucosa of the present invention contains (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester.
In this specification, the unit “%” of the blending ratio means “w / v%” and is synonymous with “g / 100 mL”.
本明細書中、特に記載のない限り、略号「ＰＯＥ」は、ポリオキシエチレンを意味する。 In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.
本明細書中、特に記載のない限り、略号「ＰＯＰ」は、ポリオキシプロピレンを意味する。 In the present specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.
本明細書中、特に記載のない限り、コンタクトレンズとは、ハード、酸素透過性ハード、ソフト（シリコーンハイドロゲルレンズを含む）、カラー等のあらゆるタイプのコンタクトレンズを包含する意味とする。 In the present specification, unless otherwise specified, the contact lens is meant to include all types of contact lenses such as hard, oxygen-permeable hard, soft (including silicone hydrogel lenses), and color.
以下、本発明について、具体的に説明する。
（１）クロロブタノール
本発明の粘膜適用組成物は、クロロブタノール（(A)成分）を含有する。
Hereinafter, the present invention will be specifically described.
(1) Chlorobutanol The composition applied to mucosa of the present invention contains chlorobutanol (component (A)).
本発明の粘膜適用組成物における、(A)成分の含有量は特に限定はなく、併用する(B)成分及び(C)成分の種類及びその含有量、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物の総量を基準として、(A)成分の含有量は、0.00001〜5w/v％、好ましくは0.0005〜3w/v％、より好ましくは0.001〜2w/v％、更に好ましくは0.005〜1w/v％、特に好ましくは0.01〜0.5w/v％である。 The content of the component (A) in the composition applied to the mucosa of the present invention is not particularly limited, and the types and contents of the components (B) and (C) to be used in combination, the use of the composition applied to the mucosa, the formulation form It is set as appropriate according to the method of use. For example, based on the total amount of the composition applied to mucosa of the present invention, the content of the component (A) is 0.00001 to 5 w / v%, preferably 0.0005 to 3 w / v%, more preferably 0.001 to 2 w / v%, More preferably, it is 0.005-1 w / v%, Most preferably, it is 0.01-0.5 w / v%.
上記(A)成分の含有量であれば、後述する保存効力増強作用が、より効果的に発揮される。 If it is content of the said (A) component, the preservation | save efficacy enhancement effect | action mentioned later is exhibited more effectively.
（２）モノステアリン酸ポリエチレングリコール（ステアリン酸ポリオキシル）
本発明の粘膜適用組成物は、モノステアリン酸ポリエチレングリコール（(B)成分）を含有する。モノステアリン酸ポリエチレングリコールは、ステアリン酸マクロゴール、ステアリン酸ポリエチレングリコール又はステアリン酸ポリオキシルとも称される公知の化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。
(2) Polyethylene glycol monostearate (polyoxyl stearate)
The composition for applying to mucosa of the present invention contains polyethylene glycol monostearate (component (B)). Polyethylene glycol monostearate is a known compound that is also referred to as macrogol stearate, polyethylene glycol stearate or polyoxyl stearate, and several types with different average added mole numbers of ethylene oxide are known.
本発明では、(B)成分として用いられるステアリン酸ポリオキシルにおける酸化エチレンの平均付加モル数は、２〜８０モル程度である。具体的には、酸化エチレンの平均付加モル数が５５であるステアリン酸ポリオキシル５５、酸化エチレンの平均付加モル数が４５であるステアリン酸ポリオキシル４５、酸化エチレンの平均付加モル数が４０であるステアリン酸ポリオキシル４０、酸化エチレンの平均付加モル数が３０であるステアリン酸ポリオキシル３０、酸化エチレンの平均付加モル数が２５であるステアリン酸ポリオキシル２５、酸化エチレンの平均付加モル数が１０であるステアリン酸ポリオキシル１０、酸化エチレンの平均付加モル数が４であるステアリン酸ポリオキシル４、酸化エチレンの平均付加モル数が２であるステアリン酸ポリオキシル２等が挙げられる。 In the present invention, the average added mole number of ethylene oxide in the polyoxyl stearate used as the component (B) is about 2 to 80 moles. Specifically, polyoxyl stearate 55 having an average addition mole number of ethylene oxide of 55, polyoxyl stearate 45 having an average addition mole number of ethylene oxide of 45, and stearic acid having an average addition mole number of ethylene oxide of 40 Polyoxyl 40, polyoxyl stearate 30 with an average addition mole number of ethylene oxide of 30, polyoxyl stearate 25 with an average addition mole number of ethylene oxide of 25, polyoxyl stearate with an average addition mole number of ethylene oxide of 10 And polyoxyl stearate 4 having an average added mole number of ethylene oxide of 4, polyoxyl stearate 2 having an average added mole number of ethylene oxide of 2, and the like.
これらの中で、本発明の効果を好適に発揮できるステアリン酸ポリオキシルの一例として、酸化エチレンの平均付加モル数が２〜８０、好ましくは１０〜７０、さらに好ましくは１０〜６０、特に好ましくは２０〜６０のステアリン酸ポリオキシルを挙げることができる。 Among these, as an example of polyoxyl stearate capable of suitably exhibiting the effects of the present invention, the average added mole number of ethylene oxide is 2 to 80, preferably 10 to 70, more preferably 10 to 60, and particularly preferably 20 Mention may be made of ˜60 polyoxyl stearates.
本発明の粘膜適用組成物における、(B)成分の含有量は特に限定はなく、(B)成分の種類、併用する(A)成分及び(C)成分の含有量、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物の総量を基準として、
(B)成分の含有量が、総量で0.0001〜10w/v％、好ましくは0.0005〜5w/v％、より好ましくは0.001〜4w/v％、さらに好ましくは0.005〜3w/v％、特に好ましくは0.01〜2.5w/v％である。
In the composition applied to mucosa of the present invention, the content of the component (B) is not particularly limited, the type of the component (B), the content of the components (A) and (C) to be used in combination, It is appropriately set according to the use, formulation form, method of use and the like. For example, based on the total amount of the composition applied to mucosa of the present invention,
The total content of component (B) is 0.0001 to 10 w / v%, preferably 0.0005 to 5 w / v%, more preferably 0.001 to 4 w / v%, still more preferably 0.005 to 3 w / v%, particularly preferably 0.01 to 2.5 w / v%.
上記(B)成分の含有量は、粘膜適用組成物において、保存効力の増強作用を一層高めるという観点から好適である。 The content of the component (B) is preferable from the viewpoint of further enhancing the effect of enhancing the preservation efficacy in the mucosa-applied composition.
本発明の粘膜適用組成物における、(A)成分に対する(B)成分の含有比率は、(A)成分及び(B)成分の種類、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物に含まれる(A)成分の総含有量１質量部に対して、(B)成分の含有比率が、総含有量で0.0001から10000質量部、好ましくは0.0003〜3000質量部、より好ましくは0.001〜1000質量部、更に好ましくは0.003〜300質量部、特に好ましくは0.01〜100質量部、最も好ましくは0.1〜30質量部である。 In the composition applied to mucosa of the present invention, the content ratio of the component (B) to the component (A) depends on the type of the component (A) and the component (B), the use of the composition applied to the mucosa, the formulation form, the usage method, It is set accordingly. For example, the content ratio of the component (B) is 0.0001 to 10000 parts by mass, preferably 0.0003 to 1 part by mass with respect to 1 part by mass of the total content of the component (A) contained in the mucosa-applied composition of the present invention. 3000 parts by mass, more preferably 0.001 to 1000 parts by mass, still more preferably 0.003 to 300 parts by mass, particularly preferably 0.01 to 100 parts by mass, and most preferably 0.1 to 30 parts by mass.
上記 (A)成分に対する(B)成分の含有比率は、本発明の効果をより一層高めるという観点から好適である。 The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further enhancing the effect of the present invention.
（３）ポリオキシエチレンソルビタン脂肪酸エステル
本発明の粘膜適用組成物は、ポリオキシエチレンソルビタン脂肪酸エステル（(C)成分）を含有する。
(3) Polyoxyethylene sorbitan fatty acid ester The composition applied to mucosa of the present invention contains polyoxyethylene sorbitan fatty acid ester (component (C)).
本発明に用いられるポリオキシエチレンソルビタン脂肪酸エステルとしては、モノヤシ油脂肪酸ポリオキシエチレンソルビタン、モノラウリン酸ポリオキシエチレンソルビタン、モノパルミチン酸ポリオキシエチレンソルビタン、モノステアリン酸ポリオキシエチレンソルビタン、モノイソステアリン酸ポリオキシエチレンソルビタン、トリステアリン酸ポリオキシエチレンソルビタン、モノオレイン酸ポリオキシエチレンソルビタン、トリオレイン酸ポリオキシエチレンソルビタン等を利用でき、これらは市販のものを利用することができる。好ましくは、モノラウリン酸POE(20)ソルビタン（ポリソルベート20）、モノパルミチン酸POE（20）ソルビタン（ポリソルベート40）、モノステアリン酸POE（20）ソルビタン（ポリソルベート60）、トリステアリン酸POE（20）ソルビタン（ポリソルベート65）、モノオレイン酸POE(20)ソルビタン(ポリソルベート80)であり、特に好ましくはモノオレイン酸POE(20)ソルビタン(ポリソルベート80)である。 Examples of the polyoxyethylene sorbitan fatty acid ester used in the present invention include mono coconut oil fatty acid polyoxyethylene sorbitan, monolauric acid polyoxyethylene sorbitan, monopalmitic acid polyoxyethylene sorbitan, monostearic acid polyoxyethylene sorbitan, monoisostearic acid polyoxy Ethylene sorbitan, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, and the like can be used, and commercially available ones can be used. Preferably, monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan ( Polysorbate 65) and monooleic acid POE (20) sorbitan (polysorbate 80), particularly preferably monooleic acid POE (20) sorbitan (polysorbate 80).
本発明の粘膜適用組成物における、(C)成分の含有量は特に限定はなく、(C)成分の種類、併用する(A)成分及び(B)成分の種類及び含有量、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物の総量を基準として、(C)成分の含有量が、総量で0.0001〜5w/v％、好ましくは0.001〜3w/v％、更に好ましくは0.005〜2w/v％、特に好ましくは0.01〜1w/v％である。 The content of the component (C) in the composition applied to the mucosa of the present invention is not particularly limited, the type of the component (C), the types and contents of the components (A) and (B) to be used together, the composition applied to the mucous membrane It is set as appropriate according to the use of the product, the formulation form, the method of use and the like. For example, based on the total amount of the composition applied to mucosa of the present invention, the content of the component (C) is 0.0001 to 5 w / v%, preferably 0.001 to 3 w / v%, more preferably 0.005 to 2 w / v in the total amount. %, Particularly preferably 0.01 to 1 w / v%.
上記(C)成分の含有量は、粘膜適用組成物において保存効力の増強作用を一層高めるという観点から好適である。 The content of the component (C) is suitable from the viewpoint of further enhancing the effect of enhancing the storage efficacy in the composition applied to mucosa.
本発明の粘膜適用組成物における、(A)成分に対する(C)成分の含有比率は、特に制限はなく、(B)成分及び(C)成分の種類、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物に含まれる(A)成分の総含有量１質量部に対して、(C)成分の含有比率が、総含有量で0.001〜1000質量部、好ましくは0.005〜500質量部、より好ましくは0.01〜100質量部、更に好ましくは0.05〜50質量部、特に好ましくは0.1〜20質量部である。 The content ratio of the component (C) to the component (A) in the composition applied to the mucosa of the present invention is not particularly limited, the types of the components (B) and (C), the use of the composition applied to the mucous membrane, and the formulation form It is set as appropriate according to the method of use. For example, the content ratio of the component (C) is 0.001 to 1000 parts by mass, preferably 0.005 to 1 part by mass with respect to 1 part by mass of the total content of the component (A) contained in the composition for mucosa of the present invention. 500 parts by mass, more preferably 0.01 to 100 parts by mass, still more preferably 0.05 to 50 parts by mass, and particularly preferably 0.1 to 20 parts by mass.
上記 (A)成分に対する(C)成分の含有比率により、本発明の効果をより一層高めることができる。 The effect of the present invention can be further enhanced by the content ratio of the component (C) to the component (A).
本発明の粘膜適用組成物における、(B)成分に対する(C)成分の含有比率は、特に制限はなく、(B)成分及び(C)成分の種類、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物に含まれる(B)成分の総含有量１質量部に対して、(C)成分の含有比率が、総含有量で0.0005〜1000質量部、好ましくは0.001〜500質量部、より好ましくは0.02〜150質量部、更に好ましくは0.005〜50質量部、特に好ましくは0.01〜15質量部、最も好ましくは0.1〜5質量部である。 The content ratio of the component (C) to the component (B) in the composition applied to the mucosa of the present invention is not particularly limited, and the types of the components (B) and (C), the use of the composition applied to the mucosa, and the formulation form It is set as appropriate according to the method of use. For example, the content ratio of the component (C) is 0.0005 to 1000 parts by mass, preferably 0.001 to 1 part by mass with respect to 1 part by mass of the total content of the component (B) contained in the mucosa-applied composition of the present invention. 500 parts by mass, more preferably 0.02 to 150 parts by mass, still more preferably 0.005 to 50 parts by mass, particularly preferably 0.01 to 15 parts by mass, and most preferably 0.1 to 5 parts by mass.
上記 (B)成分に対する(C)成分の含有比率により、本発明の効果をより一層高めることができる。 The effect of the present invention can be further enhanced by the content ratio of the component (C) to the component (B).
（４）緩衝剤
本発明の粘膜適用組成物は、(A)〜(C)成分の他に、更に緩衝剤（(D)成分）を含有することが好ましい。これにより、本発明の効果をより一層向上させることができる。
(4) Buffer Agent The composition for applying to mucosa of the present invention preferably further contains a buffer agent (component (D)) in addition to the components (A) to (C). Thereby, the effect of the present invention can be further improved.
本発明の粘膜適用組成物に含有させることが好ましい緩衝剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような緩衝剤の一例として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、トリス緩衝剤、アスパラギン酸及び／又はその塩、イプシロン-アミノカプロン酸等が挙げられる。これらの緩衝剤は１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 The buffering agent preferably contained in the composition for applying to mucosa of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, aspartic acid and / or salts thereof, epsilon-aminocaproic acid, and the like. Can be mentioned. These buffering agents may be used alone or in any combination of two or more.
ホウ酸緩衝剤としては、ホウ酸及び／又はその塩を用いることができ、ホウ酸塩としては、ホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩等が例示される。リン酸緩衝剤としては、リン酸及び／又はその塩を用いることができ、リン酸塩としては、リン酸アルカリ金属塩、リン酸アルカリ土類金属塩等が例示される。炭酸緩衝剤としては、炭酸及び／又はその塩を用いることができ、炭酸塩としては、炭酸アルカリ金属塩、炭酸アルカリ土類金属塩等が例示される。クエン酸緩衝剤としては、クエン酸及び／又はその塩を用いることができ、クエン酸塩としては、クエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩等が例示される。また、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤及びクエン酸緩衝剤として、それぞれ水和物を用いてもよい。 As the boric acid buffer, boric acid and / or a salt thereof can be used. Examples of the boric acid salt include an alkali metal borate and an alkaline earth metal borate. As the phosphate buffer, phosphoric acid and / or a salt thereof can be used. Examples of the phosphate include an alkali metal phosphate, an alkaline earth metal phosphate, and the like. Carbonic acid and / or a salt thereof can be used as the carbonate buffer, and examples of the carbonate include alkali metal carbonates, alkaline earth metal carbonates, and the like. Citric acid and / or a salt thereof can be used as the citrate buffer, and examples of the citrate include alkali metal citrate and alkaline earth metal citrate. Moreover, you may use a hydrate as a borate buffer, a phosphate buffer, a carbonate buffer, and a citrate buffer, respectively.
より具体的な例として、ホウ酸緩衝剤として、ホウ酸(オルトホウ酸、メタホウ酸、テトラホウ酸等)又はその塩(ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウム、ホウ酸アンモニウム、ホウ砂等)；リン酸緩衝剤として、リン酸又はその塩(リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸三ナトリウム、リン酸二カリウム、リン酸一水素カルシウム、リン酸二水素カルシウム等)；炭酸緩衝剤として、炭酸又はその塩（炭酸水素ナトリウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸カルシウム、炭酸水素カリウム、炭酸マグネシウム等）；クエン酸緩衝剤として、クエン酸又はその塩（クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等）；酢酸緩衝剤として、酢酸又はその塩（酢酸アンモニウム、酢酸カリウム、酢酸カルシウム、酢酸ナトリウム等）；アスパラギン酸又はその塩（アスパラギン酸ナトリウム、アスパラギン酸マグネシウム、アスパラギン酸カリウム等）等が例示できる。これらの緩衝剤の中でも、ホウ酸又はその塩（特に、ホウ酸とホウ砂との組み合わせ）及びリン酸又はその塩（特に、リン酸水素二ナトリウムとリン酸二水素ナトリウムとの組合せ）、クエン酸又はその塩（特に、クエン酸とクエン酸ナトリウムとの組合せ）が好ましい。 As a more specific example, boric acid buffer, boric acid (orthoboric acid, metaboric acid, tetraboric acid, etc.) or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) ; Phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, diphosphate phosphate; Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); Citric acid or a salt thereof as a citrate buffer Salt (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate Acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.) ) Etc. can be illustrated. Among these buffers, boric acid or a salt thereof (particularly a combination of boric acid and borax) and phosphoric acid or a salt thereof (particularly a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), citric acid, Acid or a salt thereof (particularly a combination of citric acid and sodium citrate) is preferred.
本発明の粘膜適用組成物に上記(D)成分の緩衝剤を含有させる場合、その含有量は、該界面活性剤の種類、他の配合成分の種類及び含有量、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物の総量を基準として、(D)成分の緩衝剤の含有量は、総量で0.01〜10w/v％、好ましくは0.05〜8w/v％、更に好ましくは0.1〜5w/v％、さらにより好ましくは0.2〜3w/v％、特に好ましくは0.5〜2.5w/v％である。上記範囲であれば、本願発明の効果をより顕著に奏することができる。 When the composition for application to the mucosa of the present invention contains the buffer of the component (D), the content is the type of the surfactant, the type and content of the other compounding ingredients, and the use of the composition for application to the mucosa. It is appropriately set according to the formulation form, usage method and the like. For example, based on the total amount of the composition applied to mucosa of the present invention, the content of the buffer of component (D) is 0.01 to 10 w / v%, preferably 0.05 to 8 w / v%, more preferably 0.1 to 10% in total. 5 w / v%, even more preferably 0.2 to 3 w / v%, particularly preferably 0.5 to 2.5 w / v%. If it is the said range, the effect of this invention can be show | played more notably.
（５）(B)成分及び(C)成分以外の界面活性剤
本発明の粘膜適用組成物は、更に、(B)成分及び(C)成分以外の界面活性剤（(E)成分）を含有することが好ましい。これにより、本発明の効果をより一層向上させることができる。
(5) Surfactant other than component (B) and component (C) The composition for mucosa of the present invention further contains a surfactant (component (E)) other than component (B) and component (C). It is preferable to do. Thereby, the effect of the present invention can be further improved.
(E)成分の界面活性剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば特に制限されず、非イオン性界面活性剤、両性界面活性剤、陰イオン性界面活性剤及び陽イオン性界面活性剤のいずれであってもよい。 The surfactant of component (E) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant, an amphoteric surfactant, Either an anionic surfactant or a cationic surfactant may be used.
非イオン性界面活性剤としては、具体的には、；POE(40)硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油40）、POE(60)硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油60）等のPOE硬化ヒマシ油；POE(10)ヒマシ油（ポリオキシエチレンヒマシ油10）、POE(35)ヒマシ油（ポリオキシエチレンヒマシ油35）等のPOEヒマシ油；POE(9)ラウリルエーテル等のPOEアルキルエーテル；POE(20)POP(4)セチルエーテル等のPOE-POPアルキルエーテル；POE（196）POP（67）グリコール（ポロクサマー407、プルロニックF127）、POE（200）POP（70）グリコール等のポリオキシエチレン・ポリオキシプロピレンブロックコポリマー等が挙げられる。なお、上記で例示する化合物において、括弧内の数字は付加モル数を示す。 Specific examples of nonionic surfactants include: POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), etc. POE hydrogenated castor oil; POE (10) castor oil (polyoxyethylene castor oil 10), POE castor oil such as POE (35) castor oil (polyoxyethylene castor oil 35); POE alkyl such as POE (9) lauryl ether Ethers; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; polyoxyls such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol Examples include ethylene / polyoxypropylene block copolymers. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.
両性界面活性剤としては、具体的には、アルキルジアミノエチルグリシン又はその塩（例えば、塩酸塩等）等が例示される。 Specific examples of the amphoteric surfactant include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride).
陽イオン性界面活性剤としては、具体的には、塩化ベンザルコニウム、塩化ベンゼトニウム等が例示される。 Specific examples of the cationic surfactant include benzalkonium chloride and benzethonium chloride.
陰イオン性界面活性剤としては、具体的には、アルキルベンゼンスルホン酸塩、アルキル硫酸塩、ポリオキシエチレンアルキル硫酸塩、脂肪族α−スルホメチルエステル、α−オレフィンスルホン酸等が例示される。 Specific examples of the anionic surfactant include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, α-olefin sulfonic acid and the like.
(E)成分の界面活性剤は、好ましくは、非イオン性界面活性剤であり、更に好ましくは、POE硬化ヒマシ油、POEヒマシ油、POE・POPブロックコポリマーであり、特に好ましくは、ポリオキシエチレン硬化ヒマシ油60、ポリオキシエチレンヒマシ油10、ポリオキシエチレンヒマシ油35、ポロクサマー407である。 The surfactant of component (E) is preferably a nonionic surfactant, more preferably POE hydrogenated castor oil, POE castor oil, POE / POP block copolymer, and particularly preferably polyoxyethylene. Hardened castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, and poloxamer 407.
本発明の粘膜適用組成物において、上記(E)成分の界面活性剤は、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。 In the composition for applying to mucosa of the present invention, the surfactant of the above component (E) may be used alone or in combination of two or more.
本発明の粘膜適用組成物に上記(E)成分の界面活性剤を含有させる場合、その含有量は、該界面活性剤の種類、他の配合成分の種類及び含有量、該粘膜適用組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の粘膜適用組成物の総量を基準として、(E)成分の界面活性剤の含有量は、総量で0.001〜3w/v％、好ましくは0.005〜2w/v％、更に好ましくは0.01〜1w/v％、特に好ましくは0.05〜1w/v％である。 When the surfactant of the above component (E) is contained in the mucosa-applied composition of the present invention, the content thereof includes the type of the surfactant, the type and content of other compounding components, the mucosa-applied composition It is appropriately set according to the use, formulation form, method of use and the like. For example, based on the total amount of the composition applied to mucosa of the present invention, the content of the surfactant of the component (E) is 0.001 to 3 w / v%, preferably 0.005 to 2 w / v%, more preferably 0.01 by total amount. ˜1 w / v%, particularly preferably 0.05 to 1 w / v%.
（６）その他の成分
本発明の粘膜適用組成物は、本発明の効果が奏される限り、上記成分の他に、種々の薬理活性成分及び／又は生理活性成分を単独又は適宜組み合わせて適当量含有してもよい。このような成分は特に制限されず、具体的には、眼科用薬及び／又は点鼻薬において用いられる成分としては、次のような成分が挙げられる。
(6) Other components As long as the effect of the present invention is exerted, the composition applied to the mucosa of the present invention is appropriately combined with various pharmacologically active ingredients and / or physiologically active ingredients alone or in combination as appropriate. You may contain. Such components are not particularly limited, and specific examples of components used in ophthalmic drugs and / or nasal drops include the following components.
抗ヒスタミン剤又は抗アレルギー剤：例えば、塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン等。 Antihistamine or antiallergic agent: for example, diphenhydramine hydrochloride, chlorpheniramine maleate and the like.
充血除去剤：例えば、塩酸テトラヒドロゾリン、塩酸ナファゾリン、硫酸ナファゾリン、塩酸エピネフリン、塩酸エフェドリン、塩酸メチルエフェドリン等。 Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
ビタミン：例えば、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、酢酸レチノール、パルミチン酸レチノール、塩酸ピリドキシン、パンテノール、パントテン酸カルシウム、酢酸トコフェロール等。 Vitamins: for example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.
アミノ酸：例えば、アスパラギン酸カリウム、アスパラギン酸マグネシウム、イプシロン-アミノカプロン酸、コンドロイチン硫酸ナトリウム等。 Amino acids: for example, potassium aspartate, magnesium aspartate, epsilon-aminocaproic acid, sodium chondroitin sulfate and the like.
消炎剤：例えば、硫酸亜鉛、乳酸亜鉛、ブロムフェナクナトリウム、グリチルリチン酸二カリウム、プラノプロフェン、アラントイン、アズレンスルホン酸ナトリウム、塩化ベルベリン、硫酸ベルベリン、塩化リゾチーム等。 Anti-inflammatory agents: for example, zinc sulfate, zinc lactate, bromfenac sodium, dipotassium glycyrrhizinate, pranoprofen, allantoin, sodium azulene sulfonate, berberine chloride, berberine sulfate, lysozyme chloride and the like.
その他：例えば、ヒアルロン酸ナトリウム、スルファメトキサゾール、スルファメトキサゾールナトリウム等。 Other: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium and the like.
また、本発明の粘膜適用組成物には、発明の効果が奏される範囲であれば、その用途、製剤形態等に応じて、常法に従い、様々な添加物を適宜選択し、１種又はそれ以上を併用して適当量含有させてもよい。代表的な成分として次の添加物が挙げられる。 In addition, in the composition applied to mucosa of the present invention, various additives are appropriately selected according to conventional methods according to the use, formulation form, etc., as long as the effects of the invention are exerted. An appropriate amount may be added in combination. Typical additives include the following additives.
担体：例えば、水、含水エタノール等の水性担体。 Carrier: An aqueous carrier such as water or hydrous ethanol.
糖：例えば、シクロデキストリン等。 Sugar: For example, cyclodextrin and the like.
糖アルコール：例えば、キシリトール、ソルビトール、マンニトール等。これらはｄ体、ｌ体又はｄｌ体のいずれでもよい。 Sugar alcohol: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
防腐剤、殺菌剤又は抗菌剤：例えば、塩化ベンザルコニウム、塩化ベンゼトニウム、塩酸ポリヘキサニド、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、グルコン酸クロルヘキシジン、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等。 Preservatives, bactericides or antibacterials: for example, benzalkonium chloride, benzethonium chloride, polyhexanide hydrochloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine gluconate, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, Ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like.
粘稠化剤又は増粘剤：アルギン酸ナトリウム、メチルセルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルピロリドン、マクロゴール４０００等。 Thickener or thickener: sodium alginate, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, macrogol 4000 and the like.
油類：ゴマ油、ヒマシ油等。 Oils: sesame oil, castor oil, etc.
等張化剤：例えば、塩化ナトリウム、塩化カリウム等。 Isotonizing agents: for example, sodium chloride, potassium chloride and the like.
安定化剤：例えば、ジブチルヒドロキシトルエン、トロメタモール、亜硫酸水素ナトリウム、亜硫酸ナトリウム等。 Stabilizer: For example, dibutylhydroxytoluene, trometamol, sodium bisulfite, sodium sulfite and the like.
キレート剤：例えば、エチレンジアミン四酢酸二ナトリウム（エデト酸ナトリウム）等。 Chelating agent: For example, ethylenediaminetetraacetic acid disodium (sodium edetate) and the like.
本発明において粘膜適用組成物とは、微生物汚染に対してより高い安全性が求められる点で、粘膜適用水性組成物であることが好ましい。粘膜適用水性組成物における好ましい水の含有量は、該粘膜適用組成物の総量に対して、80w/v％以上の粘膜適用組成物を意味する。該粘膜適用水性組成物における水の含有量は、好ましくは、85w/v％以上、より好ましくは90w/v％以上、更に好ましくは92w/v％以上、特に好ましくは95w/v％以上である。本発明の粘膜適用組成物に用いられる水としては、医薬上、薬理学的に（製薬上）又は生理学的に許容される水を使用すればよく、このような水として、具体的には、蒸留水、常水、精製水、滅菌精製水、注射用水、注射用蒸留水等が例示される。また本発明における粘膜適用組成物の剤型については、例えば、眼科分野や耳鼻科分野で使用可能である限り特に制限されないが、液状が好ましい。これらの定義は第十六改正日本薬局方に基づく。 In the present invention, the mucosa-applied composition is preferably an aqueous mucosa-applied composition in that higher safety against microbial contamination is required. The preferable water content in the aqueous composition for mucosa application means a composition for application to mucosa of 80 w / v% or more based on the total amount of the composition for mucosa application. The water content in the aqueous composition for mucous membrane application is preferably 85 w / v% or more, more preferably 90 w / v% or more, still more preferably 92 w / v% or more, particularly preferably 95 w / v% or more. . As water used for the mucosa-applied composition of the present invention, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used. As such water, specifically, Examples include distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. In addition, the dosage form of the mucosa-applied composition in the present invention is not particularly limited as long as it can be used in, for example, the ophthalmic field or the otolaryngological field, but is preferably a liquid. These definitions are based on the 16th revised Japanese Pharmacopoeia.
（７）粘膜適用組成物の物性
本発明の粘膜適用組成物のｐＨについては、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば特に限定されるものではない。本発明の粘膜適用組成物のｐＨの一例として、4.0〜9.5、好ましくは4.5〜9.0、更に好ましくは5.0〜8.5となる範囲が挙げられる。
(7) Physical properties of mucosa-applied composition The pH of the mucosa-applied composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. Absent. An example of the pH of the composition for mucosa of the present invention is 4.0 to 9.5, preferably 4.5 to 9.0, and more preferably 5.0 to 8.5.
また、本発明の粘膜適用組成物の浸透圧については、生体に許容される範囲内であれば、特に制限されない。本発明の粘膜適用組成物の浸透圧比の一例として、0.5〜5.0、好ましくは0.6〜3.0、更に好ましくは0.7〜2.0、特に好ましくは0.9〜1.55である。浸透圧の調整は、無機塩、多価アルコール、糖アルコール、糖等を用いて、当該技術分野で既知の方法で行うことができる。浸透圧比は、第十六改正日本薬局方に基づき、286mOsm（0.9w/v％塩化ナトリウム水溶液の浸透圧）に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（氷点降下法）を参考にして測定する。なお、浸透圧比測定用標準液（0.9w/v％塩化ナトリウム水溶液）については、塩化ナトリウム（日本薬局方標準試薬）を500〜650℃で40〜50分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その0.900ｇを正確に量り、精製水に溶かし正確に100mLとして調製するか、市販の浸透圧比測定用標準液（0.9w/v％塩化ナトリウム水溶液）を用いればよい。 In addition, the osmotic pressure of the composition for applying to mucosa of the present invention is not particularly limited as long as it is within a range acceptable for a living body. As an example of the osmotic pressure ratio of the composition applied to mucosa of the present invention, it is 0.5 to 5.0, preferably 0.6 to 3.0, more preferably 0.7 to 2.0, particularly preferably 0.9 to 1.55. The adjustment of the osmotic pressure can be performed by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286mOsm (the osmotic pressure of 0.9w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure by referring to the freezing point method. In addition, about the standard solution for osmotic pressure ratio measurement (0.9w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, in a desiccator (silica gel). The solution is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) may be used.
本発明の粘膜適用組成物の粘度については、生体に許容される範囲内であれば、特に制限されない。例えば、回転粘度計（ＲＥ５５０型粘度計、東機産業社製、ローター：1°34‘ｘ24）で測定した25℃における粘度が、0.01〜1000mPa・s、好ましくは0.05〜100mPa・s、更に好ましくは0.1〜10mPa・sである。 The viscosity of the composition for applying to mucosa of the present invention is not particularly limited as long as it is within a range acceptable for a living body. For example, the viscosity at 25 ° C. measured with a rotational viscometer (RE550 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × 24) is 0.01 to 1000 mPa · s, preferably 0.05 to 100 mPa · s, more preferably Is 0.1 to 10 mPa · s.
（８）粘膜適用組成物の用途及び調製方法
本発明の粘膜適用組成物の具体例として、眼科用組成物、耳鼻科用組成物、口腔用組成物等が挙げられ、特に眼科用組成物、耳鼻科用組成物が好ましい。眼科用組成物としては、点眼剤（点眼液又は点眼薬ともいう）［但し、点眼剤には人工涙液を含む。また、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む］、洗眼剤（洗眼液又は洗眼薬ともいう）［但し、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む］、コンタクトレンズ装着液、コンタクトレンズケア用品（コンタクトレンズ消毒剤、コンタクトレンズ用保存剤、コンタクトレンズ用洗浄剤、コンタクトレンズ用洗浄保存剤、コンタクトレンズ用消毒・保存・洗浄剤（コンタクトレンズ用マルチパーパスソリューション））等が挙げられ、耳鼻科用組成物としては、点鼻剤（点鼻液又は点鼻薬ともいう）、鼻洗浄液等が挙げられる。中でも、医薬品として特に高い保存効力が求められる組成物として、点眼剤、洗眼剤、点鼻剤が好ましい。
(8) Use and preparation method of mucosa-applied composition Specific examples of the mucosa-applied composition of the present invention include ophthalmic compositions, otolaryngological compositions, oral compositions, and the like. Otolaryngological compositions are preferred. As an ophthalmic composition, eye drops (also referred to as eye drops or eye drops) [however, eye drops include artificial tears. Eye drops include eye drops that can be applied while wearing contact lenses], eye wash (also referred to as eye wash or eye wash) [However, eye drops include eye drops that can be washed while wearing contact lenses. ], Contact lens mounting fluid, contact lens care products (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative, contact lens disinfectant / storage / cleaning agent (multiple for contact lenses) And the like, and otolaryngological compositions include nasal drops (also referred to as nasal drops or nasal drops), nasal rinses, and the like. Of these, eye drops, eye washes, and nasal drops are preferred as compositions that require particularly high storage efficacy as pharmaceuticals.
本発明の粘膜適用組成物は、保存効力が増強されているために、優れた防腐作用を有している。このため、マルチドーズ型の粘膜適用組成物、即ち製品を一旦開封した後、数回以上に亘り使用される粘膜適用組成物に対して好適に用いられ、該粘膜適用組成物を数日、あるいは数週間以上、安定して保存することができる。 The composition for applying to mucosa of the present invention has an excellent antiseptic action because of its enhanced storage efficacy. For this reason, it is preferably used for a multi-dose type mucosa-applied composition, that is, a mucosa-applied composition that is used several times or more after the product is once opened. It can be stored stably for several weeks or more.
本発明の粘膜適用組成物を収容する容器としては、粘膜適用組成物を収容する容器として通常用いられる容器を用いることができ、ガラス製であってもよく、またプラスチック製であってもよい。本発明の粘膜適用組成物を収容する容器として、プラスチック製を使用する場合、該プラスチック容器の構成材質については、特に制限されないが、例えば、ポリエチレンナフタレート、ポリアリレート、ポリエチレンテレフタレート、ポリプロピレン、ポリエチレン、ポリイミドのいずれか１種、または２種以上の混合体が挙げられる。また、エチレン−２，６−ナフタレート単位、アリレート単位、エチレンテレフタレート単位、プロピレン単位、エチレン単位、イミド単位のいずれか１種を主体として、他のポリエステル単位、イミド単位を含む共重合体が挙げられる。なお、本発明において例えばポリエチレンテレフタレート製容器と記載する場合は、容器の構成材質全体の重量に対し、ポリエチレンテレフタレートが50w/w％以上であるものを意味する。 As the container for storing the composition for applying mucosa of the present invention, a container usually used as a container for storing the composition for applying mucosa can be used, and it may be made of glass or plastic. When the plastic container is used as the container for containing the composition for applying mucosa of the present invention, the constituent material of the plastic container is not particularly limited. For example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one type of polyimide or a mixture of two or more types may be mentioned. In addition, a copolymer containing other polyester units and imide units mainly including any one of ethylene-2,6-naphthalate units, arylate units, ethylene terephthalate units, propylene units, ethylene units, and imide units can be mentioned. . In the present invention, for example, a container made of polyethylene terephthalate means that the polyethylene terephthalate is 50 w / w% or more with respect to the weight of the entire constituent material of the container.
また、本発明の粘膜適用組成物を収容する容器に備えられているノズル等の容器注口周辺部についても、その構造、構成素材等については特に制限されるものではない。ノズル等の容器注口周辺部の構造については、眼科組成物用容器(例えば点眼剤容器)の注出口(例えばノズル)として一般的に採用されている構造であればよく、容器本体と一体に成形されていてもよく、容器本体とは別に成形されていてもよい。注口周辺部また注出口(例えばノズル)の構成素材については、例えば、上記プラスチック容器の構成素材と同様のものが例示される。 Also, the structure, constituent materials, etc. of the peripheral portion of the container inlet such as a nozzle provided in the container for accommodating the composition for applying mucosa of the present invention are not particularly limited. The structure around the container inlet such as a nozzle may be a structure generally employed as an outlet (for example, a nozzle) of a container for an ophthalmic composition (for example, an eye drop container), and is integrated with the container body. It may be molded and may be molded separately from the container body. As the constituent material of the spout peripheral portion or the spout (for example, nozzle), for example, the same material as that of the plastic container is exemplified.
特に、柔軟性、コスト面、及び／又は滴下量のバラツキ抑制効果を良好にさせるという観点からは、ポリエチレン又はポリプロピレンを構成素材として含む注出口が好適である。ポリエチレンの種類としては、高密度ポリエチレン、低密度ポリエチレン等が挙げられるが、中でも低密度ポリエチレンを構成素材として含む注出口が好適である。また、注出口としては、点眼剤容器や点鼻容器に用いられるノズルが好適である。 In particular, from the viewpoint of improving the flexibility, cost, and / or the effect of suppressing variation in the amount of dripping, a spout containing polyethylene or polypropylene as a constituent material is suitable. Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene. Among these, spouts containing low-density polyethylene as a constituent material are suitable. Moreover, as a spout, the nozzle used for an eye drop container or a nasal drop container is suitable.
本発明の粘膜適用組成物を収容する容器及び容器注口周辺部の好ましい組み合わせとしては、ポリエチレンテレフタレート製容器とポリエチレン製容器注口周辺部との組み合わせ、より好ましくはポリエチレンテレフタレート製点眼容器とポリエチレン製ノズルとの組み合わせ、特に好ましくはポリエチレンテレフタレート製点眼容器と低密度ポリエチレン製ノズルとの組み合わせである。 A preferable combination of the container for containing the composition for applying mucosa of the present invention and the peripheral part of the container mouth is a combination of a polyethylene terephthalate container and a peripheral part of the polyethylene container mouth, more preferably a polyethylene terephthalate eye drop container and a polyethylene A combination with a nozzle, particularly preferably a combination of a polyethylene terephthalate eye drop container and a low density polyethylene nozzle.
本発明の粘膜適用組成物は、高い保存効力を有するため、医薬品として好適に使用することができるので、特に薬理活性成分及び／又は生理活性成分を含有する点眼剤として適するものである。このような点眼剤の用途として、ドライアイ用点眼剤、充血除去用点眼剤、抗菌用点眼剤、抗炎症用点眼剤、痒み抑制用点眼剤、疲れ目抑制用点眼剤、目の乾き抑制用点眼剤等の眼科用医薬品や、充血除去用点鼻剤、アレルギー用点鼻剤、抗炎症用点鼻剤等の点鼻用医薬品が挙げられる。 Since the composition for applying to mucosa of the present invention has high storage efficacy and can be suitably used as a pharmaceutical product, it is particularly suitable as an eye drop containing a pharmacologically active ingredient and / or a physiologically active ingredient. Uses of such eye drops include eye drops for dry eye, eye drops for removing hyperemia, eye drops for antibacterial use, eye drops for anti-inflammation, eye drops for suppressing itching, eye drops for suppressing fatigue, eye dryness Examples include ophthalmic drugs such as eye drops, nasal drugs such as nasal drops for removing hyperemia, nasal drops for allergies, and nasal drops for anti-inflammation.
また、本発明は、別の観点から、粘膜適用組成物の製造のための、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルの使用も提供する。 In another aspect, the present invention also provides the use of (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester for the production of a composition for application to mucosa. To do.
更に、本発明は、別の観点から、粘膜適用組成物としての、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含む組成物の使用も提供する。 Furthermore, from another viewpoint, the present invention also provides use of a composition comprising (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester as a composition for applying to mucosa. provide.
更に、本発明は、別の観点から、粘膜適用組成物としての使用のための、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含む組成物を提供する。 Furthermore, the present invention, from another viewpoint, is a composition comprising (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester for use as a composition for applying to mucosa. Offer things.
［２．保存効力の増強方法］
前述したように、本発明の粘膜適用組成物では、(A)成分、(B)成分及び(C)成分を含有させることによって、粘膜適用組成物において保存効力を増強させることができる。
[2. Method for enhancing preservation efficacy]
As described above, in the composition for applying to mucosa of the present invention, the preservative efficacy in the composition for applying to mucosa can be enhanced by containing the component (A), the component (B) and the component (C).
従って、本発明は、更に別の観点から、(A)クロロブタノール、(B)モノステアリン酸ポリエチレングリコール、及び (C)ポリオキシエチレンソルビタン脂肪酸エステルを、粘膜適用組成物に含有させることにより、該粘膜適用組成物における保存効力を増強する方法を提供する。 Therefore, the present invention, from yet another point of view, by containing (A) chlorobutanol, (B) polyethylene glycol monostearate, and (C) polyoxyethylene sorbitan fatty acid ester in the mucosa-applied composition, A method for enhancing the storage efficacy in a mucosal composition is provided.
また、本発明は、(A)クロロブタノールを含有する粘膜適用組成物に、(B)モノステアリン酸ポリエチレングリコール及び(C)ポリオキシエチレンソルビタン脂肪酸エステルを含有させることにより、該粘膜適用組成物における保存効力を増強する方法をも提供する。 Further, the present invention provides a composition for applying to mucosa by containing (B) polyethylene glycol monostearate and (C) polyoxyethylene sorbitan fatty acid ester in the composition for applying to mucosa containing (A) chlorobutanol. Also provided is a method of enhancing storage efficacy.
この方法において、(A)成分、(B)成分及び(C)成分が共存するのであれば、それらの添加は同時であっても、別々であってもよく、その順序も特に限定されない。使用する(A)成分、(B)成分及び(C)成分の種類、それらの含有量（または配合量）、それらの比率、その他に配合する成分の種類、含有量（または配合量）、粘膜適用組成物の製剤形態、容器の種類、組み合わせ、実施方法等については、前記「１．粘膜適用組成物」と同様である。 In this method, as long as the component (A), the component (B), and the component (C) coexist, their addition may be simultaneous or separate, and the order thereof is not particularly limited. Component (A), Component (B) and Component (C) to be used, their content (or blending amount), their ratio, other components to be blended, content (or blending amount), mucous membrane The formulation form of the applied composition, the type of container, the combination, the implementation method, and the like are the same as those in “1. Mucosal applied composition”.
中でも、これらの方法は、粘膜適用組成物が、マルチドーズ型の粘膜適用組成物、即ち製品を一旦開封した後、数回以上に亘り使用される粘膜適用組成物に対して好適に用いられる。このような粘膜適用組成物としてはマルチドーズ型の点眼剤、マルチドーズ型の洗眼剤、マルチドーズ型のコンタクトレンズ装着液、マルチドーズ型のコンタクトレンズケア用品、マルチドーズ型の点鼻剤、マルチドーズ型の鼻洗浄剤等が挙げられる。 なお、本明細書において、粘膜適用組成物における保存効力が増強されているか否かは、後述の実施例に記載の方法によって判定することが可能である。 Among these methods, the mucosa-applied composition is preferably used for a multi-dose mucosa-applied composition, that is, a mucosa-applied composition that is used several times or more after the product is once opened. Such mucosa-applied compositions include multi-dose type eye drops, multi-dose type eye washes, multi-dose type contact lens mounting solutions, multi-dose type contact lens care products, multi-dose type nasal drops, multi-dose Examples include a dose type nasal cleanser. In the present specification, whether or not the preservative efficacy in the composition for applying to mucosa is enhanced can be determined by the method described in Examples described later.
以下に、実施例及び試験例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例等によって限定されるものではない。なお、以下の実施例及び試験例において、ステアリン酸ポリオキシル40としては、医薬品添加物規格２００３のステアリン酸ポリオキシルの規格に適合する酸化エチレンの平均付加モル数が40のものを用い、ステアリン酸ポリオキシル55としては、医薬品添加物規格２００３のステアリン酸ポリオキシルの規格に適合する酸化エチレンの平均付加モル数が55のものを用い、ポリソルベート80としては、日本薬局方に適合するものを用いた。 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like. In the following examples and test examples, polyoxyl stearate 40 having an average added mole number of ethylene oxide conforming to the standard of polyoxystearate of the pharmaceutical additive standard 2003 is 40, and polyoxyl stearate 55 As the polysorbate 80, those having an average added mole number of ethylene oxide that conforms to the standard of polyoxyl stearate of the pharmaceutical additive standard 2003 were used, and those that conform to the Japanese Pharmacopoeia were used as the polysorbate 80.
試験例１（保存効力試験）
下記表１〜表３に示す粘膜適用組成物を、常法に従い調製した。そして、以下の方法で、実施例１〜４及び比較例１〜１３の粘膜適用組成物の保存効力試験を実施した。
Test Example 1 (Preservation efficacy test)
The composition for applying to mucosa shown in Tables 1 to 3 below was prepared according to a conventional method. And the preservation | save efficacy test of the mucosa application composition of Examples 1-4 and Comparative Examples 1-13 was implemented with the following method.
まず、Staphylococcus aureus（ATCC６５３８）を、ソイビーン・カゼイン・ダイジェスト斜面培地の表面に接種して、33℃で、24時間培養した。培養菌体を白金耳で無菌的に採取し、適量の滅菌生理食塩水に浮遊させて、約1×107CFU／mLの生菌を含む細菌浮遊液を調製した。なお、浮遊液の生菌数は、別途培養して計測した。次に、15mLのCORNINGコニカルチューブ（PET）に、ろ過滅菌した実施例１〜４及び比較例１〜１３の粘膜適用組成物を5mLずつ充填した。この粘膜適用組成物に、生菌数（最終濃度）が約105CFU/mLとなるよう、Staphylococcus aureus菌液（生理食塩水で懸濁）を接種し、よく攪拌して試料とした。試料を48時間、遮光下23℃で保存した。48時間後に菌を含む試料を計数に適切な濃度となるよう調製し、レシチン・ポリソルベート８０加・ソイビーン・カゼイン・ダイジェスト・寒天培地（SCDLP寒天培地）上に播種し、33℃にて一晩培養後、観察されたコロニー数をカウントすることにより、生菌数を求めた。結果を表１〜３に併せて示す。 First, Staphylococcus aureus (ATCC 6538) was inoculated on the surface of a soy bean casein digest slope medium and cultured at 33 ° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 × 10 7 CFU / mL viable bacteria. The number of viable bacteria in the suspension was measured by separately culturing. Next, 5 mL of the mucosa-applied compositions of Examples 1 to 4 and Comparative Examples 1 to 13 that were sterilized by filtration were filled into a 15 mL CORNING conical tube (PET). This mucosa-applied composition was inoculated with a Staphylococcus aureus bacterial solution (suspended in physiological saline) so that the viable cell count (final concentration) was about 10 5 CFU / mL, and stirred well to prepare a sample. Samples were stored for 48 hours at 23 ° C., protected from light. 48 hours later, a sample containing bacteria is prepared to an appropriate concentration for counting, seeded on lecithin, polysorbate 80, soybean, casein, digest, agar medium (SCDLP agar medium) and cultured at 33 ° C overnight. Thereafter, the number of viable bacteria was determined by counting the number of colonies observed. A result is combined with Tables 1-3 and shown.
(A)〜(C)成分のいずれも含有しない基剤処方である比較例１、９及び１０と比較して、(A)〜(C)成分のいずれかを含有しない比較例（比較例２〜８、１１〜１３）では、保存効力の向上は殆ど見られないばかりか、却って保存効力が低下する傾向も見られた。 Compared with Comparative Examples 1, 9 and 10 which are base formulations containing none of the components (A) to (C), Comparative Example (Comparative Example 2) which does not contain any of the components (A) to (C) -8, 11-13), not only little improvement in storage efficacy was seen, but also a tendency for storage efficacy to decline was seen.
一方、(A)成分、(B)成分及び(C)成分を含有する実施例１〜４は、他の比較例と比較して、顕著に保存効力が向上していた。 On the other hand, Examples 1 to 4 containing the component (A), the component (B), and the component (C) were significantly improved in storage efficiency as compared with other comparative examples.
製剤例
表４−１〜表４−６に記載の処方で、常法により点眼剤（製剤例１〜９）、点鼻剤（１０及び１１）を調製する。
Formulation Examples Eye drops (Formulation Examples 1 to 9) and nasal drops (10 and 11) are prepared by a conventional method with the formulations described in Tables 4-1 to 4-6.
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| JP5686454B1 (en) * | 2013-12-12 | 2015-03-18 | 株式会社メニコン | Contact lens mounting liquid and method for improving refractive index of contact lens using the same |
| JP2018168200A (en) * | 2017-03-09 | 2018-11-01 | ロート製薬株式会社 | Method for producing ophthalmic composition, method for giving ophthalmic composition the action of reducing friction of contact lens, and method for giving ophthalmic composition the action of reducing sticking of contact lens to eye surface |
| JP2019059718A (en) * | 2017-09-22 | 2019-04-18 | ロート製薬株式会社 | Ophthalmic composition for contact lenses |
| JP7553496B2 (en) | 2016-08-09 | 2024-09-18 | ロート製薬株式会社 | Ophthalmic preparations |
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| JP2004256519A (en) * | 2003-02-07 | 2004-09-16 | Senju Pharmaceut Co Ltd | Chlorobutanol-containing artificial tear liquid |
| WO2005025539A1 (en) * | 2003-09-10 | 2005-03-24 | Senju Pharmaceutical Co., Ltd. | Ophthalmic composition for contact lens |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5686454B1 (en) * | 2013-12-12 | 2015-03-18 | 株式会社メニコン | Contact lens mounting liquid and method for improving refractive index of contact lens using the same |
| JP2015132804A (en) * | 2013-12-12 | 2015-07-23 | 株式会社メニコン | Contact lens wearing solution and refractive index improvement method of contact lens using the same |
| JP7553496B2 (en) | 2016-08-09 | 2024-09-18 | ロート製薬株式会社 | Ophthalmic preparations |
| JP2018168200A (en) * | 2017-03-09 | 2018-11-01 | ロート製薬株式会社 | Method for producing ophthalmic composition, method for giving ophthalmic composition the action of reducing friction of contact lens, and method for giving ophthalmic composition the action of reducing sticking of contact lens to eye surface |
| JP2019059718A (en) * | 2017-09-22 | 2019-04-18 | ロート製薬株式会社 | Ophthalmic composition for contact lenses |
| JP7195838B2 (en) | 2017-09-22 | 2022-12-26 | ロート製薬株式会社 | Ophthalmic composition for contact lenses |
| JP7499829B2 (en) | 2017-09-22 | 2024-06-14 | ロート製薬株式会社 | Ophthalmic composition for contact lenses |
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