TW202332446A - Ophthalmic pharmaceutical composition with improved preservative effectiveness or light stability - Google Patents
Ophthalmic pharmaceutical composition with improved preservative effectiveness or light stability Download PDFInfo
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- TW202332446A TW202332446A TW112113506A TW112113506A TW202332446A TW 202332446 A TW202332446 A TW 202332446A TW 112113506 A TW112113506 A TW 112113506A TW 112113506 A TW112113506 A TW 112113506A TW 202332446 A TW202332446 A TW 202332446A
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- pharmaceutically acceptable
- acceptable salt
- carteolol
- pharmaceutical composition
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- 239000003755 preservative agent Substances 0.000 title claims abstract description 56
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 49
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 65
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- 238000000034 method Methods 0.000 claims description 30
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QQDRLKRHJOAQDC-FBHGDYMESA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 QQDRLKRHJOAQDC-FBHGDYMESA-N 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 230000001332 colony forming effect Effects 0.000 description 1
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- 210000004087 cornea Anatomy 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
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- 229940090570 dipivefrin hydrochloride Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
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- 238000011156 evaluation Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
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- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 239000002997 ophthalmic solution Substances 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
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- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
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- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 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
- 235000013311 vegetables Nutrition 0.000 description 1
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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Abstract
Description
本發明關於包含為β阻斷劑之卡替洛爾(carteolol)之眼科藥用組成物、製備該眼科藥用組成物的方法及其醫藥用途。本發明亦關於用於卡替洛爾之增強防腐有效性、改善光穩定性、及/或降低分解性。 The present invention relates to an ophthalmic pharmaceutical composition containing carteolol as a β-blocker, a method for preparing the ophthalmic pharmaceutical composition and its medical use. The present invention also relates to enhanced preservative effectiveness, improved photostability, and/or reduced decomposition of carteolol.
卡替洛爾已知為具有化學名稱為5-[3-[(1,1-二甲基乙基)胺基]-2-羥基丙氧基]-3,4-二氫喹啉-2(1H)-酮之β阻斷劑，且已知治療有效於青光眼及高眼壓的眼科用途。滴眼劑通常需要含有防腐藥劑或防腐劑以避免使用時併入微生物之污染。該等防腐藥劑或防腐劑通常包括苯札氯銨(苯札氯銨)、苄索氯銨(benzethonium chloride)、氯己定葡萄糖酸鹽(chlorhexidine gluconate)、對羥基苯甲酸酯類(parabens)、氯丁醇(chlorobutanol)、及山梨酸鹽(sorbate)。然而，該等防腐藥劑及防腐劑可負面影響人類組織如角膜。 Carteolol is known with the chemical name 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydroquinoline-2 A beta-blocker of ( 1H )-ketone and known to be effective in the treatment of glaucoma and ophthalmic use in ocular hypertension. Eye drops usually need to contain preservatives or preservatives to avoid the introduction of microbial contamination during use. Such preservatives or preservatives usually include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, parabens, Chlorobutanol, and sorbate. However, these preservatives and preservatives can negatively affect human tissues such as the cornea.
替代使用防腐藥劑或防腐劑，已知藉由添 加硼酸或其鹽，對滴眼劑賦予防腐有效性的方法等，然而，可能引起如眼緣炎之超敏症狀為副作用(參照PTL 1)。 An alternative to the use of preservatives or preservatives, known by adding Methods such as adding boric acid or its salts to impart preservative effectiveness to eye drops may cause side effects such as hypersensitivity symptoms such as ocular inflammation (see PTL 1).
無防腐藥劑或防腐劑的滴眼劑包括單一劑量包裝及單次用拋棄式滴眼劑，即單位劑量滴眼劑，其中單一劑量係經個別包裝。例如，PTL 2揭示其中單一劑量經個別包裝之包括鹽酸鹽卡替洛爾的無抑菌劑的滴眼劑。然而，該單一劑量滴眼劑，對於每次投藥需要拋棄式個別容器，且就保存設備的成本及穩當性等而言，可能不適合於長期連續投藥。 Preservative-free or preservative-free eye drops include single-dose packaging and single-use disposable eye drops, that is, unit-dose eye drops, in which single doses are individually packaged. For example, PTL 2 discloses bacteriostatic-free eye drops including carteolol hydrochloride in which single doses are individually packaged. However, this single-dose eye drop requires a disposable individual container for each administration, and may not be suitable for long-term continuous administration in terms of cost and stability of storage equipment.
需要長期連續投藥的眼疾的治療，如青光眼及高眼壓，需要具有高防腐有效性的安定滴眼劑。 The treatment of eye diseases that require long-term continuous administration, such as glaucoma and intraocular hypertension, requires diazepam eye drops with high antiseptic effectiveness.
某些β阻斷劑在光照射下分解，而卡替洛爾為該等β阻斷劑之一者。因此，通常在保存及使用中需要保護包含卡替洛爾的滴眼劑免於光照。 Carteolol is one of some beta-blockers that decomposes under light exposure. Therefore, it is generally necessary to protect carteolol-containing eye drops from light during storage and use.
[文獻列單] [Literature list]
[專利文獻] [Patent Document]
[PTL 1]WO2011/013794小冊 [PTL 1]WO2011/013794 Brochure
[PTL 2]CN101461780A [PTL 2]CN101461780A
藉由本發明所解決的問題之一為提供具有卡替洛爾之增強的防腐有效性及/或改善的穩定性的眼科用藥用組成物。另一問題為提供用於卡替洛爾之增強防腐 有效性、改善光穩定性、及/或降低分解性的方法。 One of the problems solved by the present invention is to provide an ophthalmic pharmaceutical composition having enhanced preservative effectiveness and/or improved stability of carteolol. Another problem is to provide enhanced antisepsis for carteolol effectiveness, improving photostability, and/or reducing decomposition.
本發明者們經由強力的研究已發現該等問題可藉由組合卡替洛爾或其醫藥可接受鹽與依地酸(edetic acid)或其醫藥可接受鹽而解決，且達成本發明。 The inventors of the present invention have discovered through intensive research that these problems can be solved by combining carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, and achieved the present invention.
本發明之一態樣係提供一種眼科藥用組成物，其包含卡替洛爾或其醫藥可接受鹽以及依地酸或其醫藥可接受鹽。 One aspect of the present invention provides an ophthalmic pharmaceutical composition, which includes carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof.
本發明之另一具體例亦提供用於卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽之增強防腐有效性的方法，包含組合卡替洛爾或其醫藥可接受鹽以及依地酸或其醫藥可接受鹽。 Another embodiment of the present invention also provides a method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof, including combining carteolol or a pharmaceutically acceptable salt thereof. salt and edetate or its pharmaceutically acceptable salt.
本發明之又一具體例亦提供卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽及/或維持劑(sustaining agent)之改善光穩定性或降低分解性的方法，包含組合卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽及/或維持劑。 Another specific example of the present invention also provides a method for improving the photostability or reducing the decomposability of carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof and/or a sustaining agent. Comprised of a combination of carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof and/or a maintenance agent.
本發明之又一具體例亦提供用於製備包含卡替洛爾或其醫藥可接受鹽以及依地酸或其醫藥可接受鹽之眼科藥用組成物的方法，包含混合卡替洛爾或其醫藥可接受鹽以及依地酸或其醫藥可接受鹽。 Another specific example of the present invention also provides a method for preparing an ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof, comprising mixed carteolol or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salts and edetate or its pharmaceutically acceptable salts.
本發明之藥用組成物可具有防腐有效性或防治微生物生長而無防腐藥劑或防腐劑。本發明之藥用組 成物亦可改善光穩定性。本發明之藥用組成物可具有增強的防腐有效性及/或改善的光穩定性，且其亦有用於治療如青光眼或高眼壓之需要長時期連續投藥的疾病。 The pharmaceutical compositions of the present invention may have antiseptic effectiveness or control microbial growth without preservative agents or preservatives. Medicinal composition of the present invention The finished product can also improve light stability. The pharmaceutical composition of the present invention may have enhanced preservative effectiveness and/or improved photostability, and may also be used to treat diseases such as glaucoma or ocular hypertension that require continuous administration over a long period of time.
本發明中，對卡替洛爾或其醫藥可接受鹽添加依地酸或其醫藥可接受鹽，其可本質地而微弱地防治微生物生長，可增強卡替洛爾或其醫藥可接受鹽的防腐有效性或抗菌功效以及允許提供無防腐藥劑或防腐劑的滴眼劑，結果為具有低的光穩定性的卡替洛爾之光穩定性經改善。此外，添加張力劑，例如丙二醇，及/或維持劑，例如海藻酸，可增強卡替洛爾或其醫藥可接受鹽之防腐有效性或抗菌功效或改善的光穩定性。 In the present invention, edetate or its pharmaceutically acceptable salt is added to carteolol or its pharmaceutically acceptable salt, which can intrinsically and weakly prevent the growth of microorganisms and can enhance the efficacy of carteolol or its pharmaceutically acceptable salt. Preservative effectiveness or antimicrobial efficacy and allows the provision of preservative-free or preservative-free eye drops, with the result that the photostability of carteolol, which has low photostability, is improved. Furthermore, the addition of a tonicity agent, such as propylene glycol, and/or a maintaining agent, such as alginic acid, may enhance the preservative effectiveness or antibacterial efficacy or improve the photostability of carteolol or a pharmaceutically acceptable salt thereof.
本發明可包括下文所述具體例。 The present invention may include specific examples described below.
項1.一種眼科藥用組成物，包含卡替洛爾或其醫藥可接受鹽及依地酸或其醫藥可接受鹽。 Item 1. An ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof.
項2.一種用於改善卡替洛爾或其醫藥可接受鹽的防腐有效性及/或光穩定性的眼科藥用組成物，其包含依地酸或其醫藥可接受鹽。 Item 2. An ophthalmic pharmaceutical composition for improving the preservative effectiveness and/or photostability of carteolol or its pharmaceutically acceptable salt, which contains edetate or its pharmaceutically acceptable salt.
項3.如項1或2的組成物，進一步包含張力劑。張力劑的實例包括丙二醇、甘油、聚乙二醇、海藻糖、麥芽糖、蔗糖、葡萄糖、山梨醇、甘露醇、氯化鈉、氯化鉀、氯化鈣、氯化鎂、及其組合。 Item 3. The composition of Item 1 or 2, further comprising a tonicity agent. Examples of tonicity agents include propylene glycol, glycerol, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof.
項4.如項1至3中任一項的組成物，進一步包含維持劑。維持劑的實例包括羥基乙基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、聚乙烯醇、羧乙烯聚合物、聚乙烯吡咯啶酮、羧甲基纖維素、聚丙烯酸、聚丙烯酸鈉、海藻酸、海藻酸鈉、及其組合。 Item 4. The composition according to any one of Items 1 to 3, further comprising a maintaining agent. Examples of maintaining agents include hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethylcellulose, polyacrylic acid, polyvinylpyrrolidone Sodium acrylate, alginic acid, sodium alginate, and combinations thereof.
項5.如項1至4中任一項的組成物，進一步包含緩衝劑及pH調節劑。 Item 5. The composition according to any one of Items 1 to 4, further comprising a buffer and a pH adjuster.
項6.如項1至5中任一項的組成物，進一步包含前列腺素F2α衍生物。前列腺素F2α衍生物的實例包括拉坦前列腺素(latanoprost)、比馬前列腺素(bimatoprost)、曲伏前列腺素(travoprost)、及他氟前列腺素(tafluprost)。 Item 6. The composition according to any one of Items 1 to 5, further comprising a prostaglandin F2α derivative. Examples of prostaglandin F2α derivatives include latanoprost, bimatoprost, travoprost, and tafluprost.
項7.如項1至6中任一項的組成物，進一步包含碳酸酐酶抑制劑。碳酸酐酶抑制劑的實例包括多佐胺(dorzolamide)、布林佐胺(brinzolamide)、乙醯佐胺(acetazolamide)、及其醫藥可接受鹽。 Item 7. The composition according to any one of Items 1 to 6, further comprising a carbonic anhydrase inhibitor. Examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide, acetazolamide, and pharmaceutically acceptable salts thereof.
項8.如項1至7中任一項的組成物，進一步包含具有眼壓降低功效的另一藥劑如腎上腺素α2促效劑及ROCK(Rho激酶)抑制劑。腎上腺素α2促效劑的實例包括酒石酸溴莫尼定(brimonidine tartrate)、鹽酸地匹福林(dipivefrin hydrochloride)、及克氯尼定(clonidine)。ROCK抑制劑的實例包括鹽酸利帕蘇迪水合物(ripasudil hydrochloride hydrate)及甲磺酸奈他蘇迪(netarsudil mesylate)。 Item 8. The composition according to any one of Items 1 to 7, further comprising another agent having an intraocular pressure reducing effect such as an epinephrine α2 agonist and a ROCK (Rho kinase) inhibitor. Examples of epinephrine alpha 2 agonists include brimonidine tartrate, dipivefrin hydrochloride, and clonidine. Examples of ROCK inhibitors include ripasudil hydrochloride hydrate and netarsudil mesylate.
項9.如項1至8中任一項的組成物，其中卡替洛爾或其醫藥可接受鹽對於該組成物的總量之含量範圍為0.1至5 w/v%。 Item 9. The composition according to any one of items 1 to 8, wherein the content of carteolol or its pharmaceutically acceptable salt based on the total amount of the composition ranges from 0.1 to 5 w/v%.
項10.如項1至9中任一項的組成物，其中依地酸或其醫藥可接受鹽對於該組成物的總量之含量範圍為0.01至0.2w/v%。 Item 10. The composition according to any one of items 1 to 9, wherein the content of edetate acid or its pharmaceutically acceptable salt based on the total amount of the composition ranges from 0.01 to 0.2 w/v%.
項11.如項1至10中任一項的組成物，其中依地酸或其醫藥可接受鹽對於包含在組成物的卡替洛爾或其醫藥可接受鹽的含量之比例範圍為0.002至2.0w/w。 Item 11. The composition according to any one of Items 1 to 10, wherein the ratio of edetic acid or a pharmaceutically acceptable salt thereof to the content of carteolol or a pharmaceutically acceptable salt thereof contained in the composition ranges from 0.002 to 2.0w/w.
項12.如項1至11中任一項的組成物，其中pH範圍為5.0至8.0。 Item 12. The composition according to any one of items 1 to 11, wherein the pH range is from 5.0 to 8.0.
項13.如項1至12中任一項的組成物，其係滴眼劑型態。 Item 13. The composition according to any one of Items 1 to 12, which is in the form of eye drops.
項14.如項1至13中任一項的組成物，其係水性滴眼劑型態或懸浮滴眼劑型態。 Item 14. The composition according to any one of Items 1 to 13, which is in the form of aqueous eye drops or suspension eye drops.
項15.如項1至14中任一項的組成物，其係使用作為多劑量型滴眼劑。 Item 15. The composition according to any one of Items 1 to 14, which is used as a multi-dose eye drop.
項16.如項1至15中任一項的組成物，其係用於治療青光眼或高眼壓。 Item 16. The composition according to any one of Items 1 to 15, which is used to treat glaucoma or ocular hypertension.
項17.如項1至16中任一項的組成物，其係與前列腺素調配物組合使用。該前列腺素調配物意指包含前列腺素F2α衍生物的調配物。 Item 17. The composition according to any one of Items 1 to 16, used in combination with a prostaglandin formulation. By prostaglandin formulation is meant a formulation comprising a prostaglandin F2α derivative.
項18.一種增強卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽的防腐有效性的方法，包含組合卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽。 Item 18. A method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, comprising combining carteolol or a pharmaceutically acceptable salt thereof and edetic acid or its pharmaceutically acceptable salt. Pharmaceutically acceptable salts.
項19.一種依地酸或其醫藥可接受鹽的用途，其係用於 增強卡替洛爾或其醫藥可接受鹽的防腐有效性。 Item 19. Use of edetate or its pharmaceutically acceptable salt, which is used for Enhance the preservative effectiveness of carteolol or its pharmaceutically acceptable salt.
項20.一種增強卡替洛爾或其醫藥可接受鹽與丙二醇的防腐有效性的方法，包含組合卡替洛爾或其醫藥可接受鹽與丙二醇。 Item 20. A method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof and propylene glycol, comprising combining carteolol or a pharmaceutically acceptable salt thereof and propylene glycol.
項21.一種丙二醇的用途，其係用於增強卡替洛爾或其醫藥可接受鹽的防腐有效性。 Item 21. Use of propylene glycol for enhancing the preservative effectiveness of carteolol or its pharmaceutically acceptable salt.
項22.一種依地酸或其醫藥可接受鹽及丙二醇的組合的用途，其係用於增強卡替洛爾或其醫藥可接受鹽的防腐有效性。 Item 22. Use of a combination of edetate acid or a pharmaceutically acceptable salt thereof and propylene glycol to enhance the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof.
項23.一種改善卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽的光穩定性的方法，包含組合卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽。 Item 23. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, comprising combining carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts.
項24.一種依地酸或其醫藥可接受鹽的用途，其係用於改善卡替洛爾或其醫藥可接受鹽的光穩定性。 Item 24. Use of edetate or a pharmaceutically acceptable salt thereof for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof.
項25.一種用於改善卡替洛爾或其醫藥可接受鹽與海藻酸的光穩定性的方法，包含組合卡替洛爾或其醫藥可接受鹽與海藻酸。 Item 25. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof and alginic acid, comprising combining carteolol or a pharmaceutically acceptable salt thereof and alginic acid.
項26.一種海藻酸的用途，其係用於改善卡替洛爾或其醫藥可接受鹽的光穩定性。 Item 26. Use of alginic acid for improving the photostability of carteolol or its pharmaceutically acceptable salt.
項27.一種依地酸或其醫藥可接受鹽及海藻酸的組合的用途，其係用於改善卡替洛爾或其醫藥可接受鹽的光穩定性。 Item 27. Use of a combination of edetate acid or a pharmaceutically acceptable salt thereof and alginic acid to improve the photostability of carteolol or a pharmaceutically acceptable salt thereof.
項28.一種用於製備眼科藥用組成物的方法，包含混合卡替洛爾或其醫藥可接受鹽與依地酸或其醫 藥可接受鹽，可視需要同時具有pH調節劑、或丙二醇、海藻酸或其組合的步驟，其中該pH調節劑係經混合以使所得組成物的pH範圍為5.0至8.0，以及丙二醇、海藻酸、或其組合係經混合以使所得組成物的滲透壓比範圍為0.8至1.2。 Item 28. A method for preparing an ophthalmic pharmaceutical composition, comprising mixing carteolol or a pharmaceutically acceptable salt thereof and edetate or a medically acceptable salt thereof. Pharmaceutically acceptable salts, optionally having a pH adjuster, or propylene glycol, alginic acid or a combination thereof, wherein the pH adjuster is mixed so that the pH range of the resulting composition is 5.0 to 8.0, and propylene glycol, alginic acid , or a combination thereof is mixed so that the resulting composition has an osmotic pressure ratio ranging from 0.8 to 1.2.
本發明包括下述說明的具體例以及其任何組合。本文所使用成分的起始物質可為如水合物之溶劑合物形式或無水物，只要為醫藥可接受的即可。 The present invention includes the specific examples described below and any combination thereof. The starting materials for the ingredients used herein may be in solvate form such as hydrates or anhydrous forms as long as they are pharmaceutically acceptable.
本發明之藥用組成物包含卡替洛爾或其醫藥可接受鹽及依地酸或其醫藥可接受鹽。 The pharmaceutical composition of the present invention includes carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof.
本發明之藥用組成物可無須防腐藥劑或防腐劑而展現防腐有效性。該防腐藥劑或防腐劑包括，但不限於，苯札氯銨(苯札氯銨)、氯化苯索寧(benzethonium chloride)、氯己定葡萄糖酸鹽(chlorhexidine gluconate)、對羥基苯甲酸酯類(parabens)、氯丁醇(chlorobutanol)、及山梨酸酯(sorbate)。本發明藥用組成物的一具體例可不包含防腐藥劑或防腐劑。本發明藥用組成物的另一具體例可不包含硼酸或其鹽。本發明藥用組成物的再一具體例可包含硼酸或其鹽。 The pharmaceutical compositions of the present invention can exhibit preservative effectiveness without the need for preservative agents or preservatives. The antiseptic agent or preservative includes, but is not limited to, benzalkonium chloride (benzethonium chloride), chlorhexidine gluconate (chlorhexidine gluconate), parabens (parabens), chlorobutanol (chlorobutanol), and sorbate (sorbate). A specific example of the pharmaceutical composition of the present invention may not contain preservatives or preservatives. Another specific example of the pharmaceutical composition of the present invention may not contain boric acid or its salt. Another specific example of the pharmaceutical composition of the present invention may include boric acid or a salt thereof.
一具體例中，本發明之藥用組成物可包含卡替洛爾或其醫藥可接受鹽對於該組成物的總量為含量範圍0.1至5w/v%。卡替洛爾或其醫藥可接受鹽對於該組成物總量的較佳含量(濃度)包括範圍0.5及2.5w/v%。更佳的範圍為1至2w/v%。 In a specific example, the pharmaceutical composition of the present invention may include carteolol or a pharmaceutically acceptable salt thereof in a content ranging from 0.1 to 5 w/v% of the total amount of the composition. The preferred content (concentration) of carteolol or its pharmaceutically acceptable salt relative to the total amount of the composition includes a range of 0.5 and 2.5 w/v%. A better range is 1 to 2 w/v%.
卡替洛爾的醫藥可接受鹽包括卡替洛爾與無機酸的鹽。 較佳者為鹽酸鹽卡替洛爾。 Pharmaceutically acceptable salts of carteolol include salts of carteolol with inorganic acids. The preferred one is carteolol hydrochloride.
本發明的藥用組成物可進一步包含依地酸或其醫藥可接受鹽對於該組成物的總量為含量範圍0.01至0.2w/v%。依地酸或其醫藥可接受鹽對於該組成物總量的較佳含量(濃度)包括範圍0.01及0.15w/v%。更佳的範圍為0.02至0.1w/v%，再佳的範圍為0.03至0.07w/v%。 The pharmaceutical composition of the present invention may further comprise edetate or a pharmaceutically acceptable salt thereof in a content range of 0.01 to 0.2 w/v% based on the total amount of the composition. The preferred content (concentration) of edetate or its pharmaceutically acceptable salt relative to the total amount of the composition includes a range of 0.01 and 0.15 w/v%. A more preferred range is 0.02 to 0.1 w/v%, and an even more preferred range is 0.03 to 0.07 w/v%.
包含於該組成物的依地酸或其醫藥可接受鹽的含量對於包含於該組成物的卡替洛爾或其醫藥可接受鹽的含量可為比例範圍0.002至2.0w/w。較佳比例範圍為0.004至0.3w/w，更佳為0.008至0.2w/w，再佳為0.015至0.07w/w，特佳為0.025至0.06w/w。 The content of edetate or a pharmaceutically acceptable salt thereof contained in the composition to the content of carteolol or a pharmaceutically acceptable salt thereof contained in the composition may be in a ratio range of 0.002 to 2.0 w/w. The preferred ratio range is 0.004 to 0.3w/w, more preferably 0.008 to 0.2w/w, still more preferably 0.015 to 0.07w/w, particularly preferably 0.025 to 0.06w/w.
依地酸的醫藥可接受鹽包括依地酸(乙二胺四乙酸：EDTA)與無機酸的鹽。較佳者為依地酸二鈉鹽水合物。 Pharmaceutically acceptable salts of edetate include salts of edetate (ethylenediaminetetraacetic acid: EDTA) and inorganic acids. Preferred is edetate disodium salt hydrate.
依地酸或其醫藥可接受鹽可增強卡替洛爾或其醫藥可接受鹽本身具有的防腐有效性，改善光穩定性，及/或降低卡替洛爾的分解性。 Edetate acid or its pharmaceutically acceptable salt can enhance the preservative effectiveness of carteolol or its pharmaceutically acceptable salt itself, improve photostability, and/or reduce the decomposition of carteolol.
本發明之藥用組成物可視需要進一步包含添加劑成分如張力劑、維持劑、緩衝劑、pH調節劑、助溶劑及溶劑。 The pharmaceutical composition of the present invention may further contain additive ingredients such as tonicity agents, maintainers, buffers, pH adjusters, co-solvents and solvents if necessary.
該張力劑包括，但不限於，丙二醇、甘油、聚乙二醇、海藻糖、麥芽糖、蔗糖、葡萄糖、山梨醇、甘露醇、氯化鈉、氯化鉀、氯化鈣、氯化鎂、及其組合。較佳者為丙二醇或氯化鈉。 The tonicity agent includes, but is not limited to, propylene glycol, glycerin, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof . Preferred ones are propylene glycol or sodium chloride.
包含於組成物的張力劑的含量(濃度)包括，但不限於，例如組成物之滲透壓比範圍為0.8及1.2的含量，較佳範圍為0.9及1.0。該含量具體範圍為0.5至2.0w/v%，較佳為1.0至1.6w/v%。 The content (concentration) of the tonicity agent included in the composition includes, but is not limited to, for example, a content in which the osmotic pressure ratio of the composition ranges between 0.8 and 1.2, with a preferred range being 0.9 and 1.0. The specific range of the content is 0.5 to 2.0 w/v%, preferably 1.0 to 1.6 w/v%.
包含於該組成物的張力劑含量對於包含於該組成物的卡替洛爾或其醫藥可接受鹽的含量可為範圍0.08至20w/w，較佳為0.16至4w/w，更佳為0.2至2w/w。 The content of the tonicity agent included in the composition may range from 0.08 to 20 w/w, preferably from 0.16 to 4 w/w, and more preferably from 0.2 to the content of carteolol or its pharmaceutically acceptable salt included in the composition. to 2w/w.
包含於該組成物的張力劑含量對於依地酸或其醫藥可接受鹽的含量可為範圍3至200w/w，較佳為4至100w/w，更佳為6至70w/w。 The content of the tonicity agent included in the composition may range from 3 to 200 w/w, preferably from 4 to 100 w/w, and more preferably from 6 to 70 w/w for the content of edetate or its pharmaceutically acceptable salt.
該維持劑包括，但不限於，羥基乙基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、聚乙烯醇、羧乙烯聚合物、聚乙烯吡咯啶酮、羧基甲基纖維素、聚丙烯酸、聚丙烯酸鈉、海藻酸、海藻酸鈉、及其組合。較佳者為海藻酸。 The maintaining agent includes, but is not limited to, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethylcellulose, Polyacrylic acid, sodium polyacrylate, alginic acid, sodium alginate, and combinations thereof. The preferred one is alginic acid.
包含於該組成物的維持劑含量(濃度)包括，但不限於，含量範圍0.1至5w/v%。較佳者為含量範圍0.5至2w/v%，更佳為0.8至1.2w/v%。 The maintainer content (concentration) included in the composition includes, but is not limited to, a content ranging from 0.1 to 5 w/v%. Preferably, the content range is 0.5 to 2w/v%, and more preferably, it is 0.8 to 1.2w/v%.
包含於組成物的維持劑含量對於包含於該組成物的卡替洛爾或其醫藥可接受鹽的含量可為比例範圍0.25至2w/w，較佳為0.4至1.2w/w。 The content of the maintainer included in the composition may be in a ratio range of 0.25 to 2 w/w, preferably 0.4 to 1.2 w/w, relative to the content of carteolol or a pharmaceutically acceptable salt thereof included in the composition.
包含於該組成物的維持劑含量對於包含於該組成物的依地酸或其醫藥可接受鹽的含量可為比例範圍5至100w/w，較佳為10至40w/w。 The content of the maintainer included in the composition may be in a ratio range of 5 to 100 w/w, preferably 10 to 40 w/w, relative to the content of edetate or a pharmaceutically acceptable salt thereof included in the composition.
該緩衝劑包括，但不限於，磷酸鹽如磷酸鈉、磷酸二氫鈉、磷酸氫二鈉、磷酸鉀、磷酸二氫鉀、及磷酸氫二鉀，硼酸及硼酸鹽如硼酸鈉及硼酸鉀，檸檬酸及檸檬酸鹽如檸檬酸鈉及檸檬酸二鈉，乙酸及乙酸鹽如乙酸鈉、乙酸鉀，碳酸鹽如碳酸鈉及碳酸氫鈉，及其組合。較佳者為磷酸鹽。更佳者為磷酸二氫鈉及磷酸氫二鈉。 The buffering agents include, but are not limited to, phosphates such as sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, boric acid and borate salts such as sodium borate and potassium borate, Citric acid and citrate salts such as sodium citrate and disodium citrate, acetic acid and acetate salts such as sodium acetate and potassium acetate, carbonates such as sodium carbonate and sodium bicarbonate, and combinations thereof. Preferred is phosphate. More preferred ones are sodium dihydrogen phosphate and disodium hydrogen phosphate.
包含於組成物的緩衝劑的含量(濃度)包括，但不限於，含量範圍0.01至1w/v%，較佳為0.04至0.4w/v%。 The content (concentration) of the buffer included in the composition includes, but is not limited to, a content ranging from 0.01 to 1 w/v%, preferably 0.04 to 0.4 w/v%.
該pH調節劑包括，但不限於，酸如鹽酸、乳酸、檸檬酸、磷酸及乙酸，及鹼金屬鹼如氫氧化鈉、氫氧化鉀、碳酸鈉及碳酸氫鈉。較佳者為鹽酸或氫氧化鈉。 The pH adjuster includes, but is not limited to, acids such as hydrochloric acid, lactic acid, citric acid, phosphoric acid and acetic acid, and alkali metal bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate. The preferred ones are hydrochloric acid or sodium hydroxide.
包含於組成物的pH調節劑的含量(濃度)包括，但不限於，使該組成物的pH值調節成為範圍5.0及8.5的含量。較佳地，組成物的pH值調節成為範圍5.0及8.0。更佳地，pH值調節成為範圍6.0至8.0，再佳地為範圍6.2及7.2。 The content (concentration) of the pH adjuster included in the composition includes, but is not limited to, a content that adjusts the pH value of the composition to a range of 5.0 and 8.5. Preferably, the pH value of the composition is adjusted to a range of 5.0 and 8.0. More preferably, the pH value is adjusted to a range of 6.0 to 8.0, more preferably a range of 6.2 and 7.2.
該助溶劑包括，但不限於，蔬菜脂質及油如聚山梨醇酯80、聚氧伸乙基氫化蓖麻油60、聚乙二醇(macrogol)4000、聚乙烯醇、泰洛沙泊(tyloxapol)、聚氧伸乙基聚氧伸丙基二醇、聚乙二醇硬脂酸酯(polyoxyl stearate)、及大豆油。較佳為聚山梨醇酯80。 The co-solvent includes, but is not limited to, vegetable lipids and oils such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, polyvinyl alcohol, tyloxapol , polyoxyethylene polyoxypropyl glycol, polyoxyl stearate, and soybean oil. Polysorbate 80 is preferred.
包含於組成物的助溶劑的含量(濃度)包括，但不限於，含量範圍0.05至5w/v%，較佳為0.1至3w/v%，更佳為0.1至2w/v%。 The content (concentration) of the co-solvent included in the composition includes, but is not limited to, a content range of 0.05 to 5 w/v%, preferably 0.1 to 3 w/v%, and more preferably 0.1 to 2 w/v%.
該溶劑包括，但不限於，純化水、無菌純化 水、及注射用水。較佳者為無菌純化水或注射用水。 The solvent includes, but is not limited to, purified water, sterile purified water, and water for injection. The preferred one is sterile purified water or water for injection.
本發明之藥用組成物可進一步包含前列腺素F2α衍生物。包含於組成物的前列腺素F2α衍生物對於組成物總量的含量可為範圍0.0005至0.1w/v%。包含於組成物的前列腺素F2α衍生物對於組成物總量的較佳含量(濃度)可為範圍0.001至0.05w/v%，更佳為0.0015至0.03w/v%。 The pharmaceutical composition of the present invention may further comprise a prostaglandin F2α derivative. The content of the prostaglandin F2α derivative included in the composition may range from 0.0005 to 0.1 w/v% based on the total amount of the composition. The preferred content (concentration) of the prostaglandin F2α derivative contained in the composition may be in the range of 0.001 to 0.05 w/v%, more preferably 0.0015 to 0.03 w/v%, based on the total amount of the composition.
前列腺素F2α衍生物包括，但不限於，拉坦前列腺素、比馬前列腺素、曲伏前列腺素、及他氟前列腺。 Prostaglandin F2α derivatives include, but are not limited to, latanoprost, bimatoprost, travoprost, and tafluprost.
另一具體例中，本發明可為與包含前列腺素F2α衍生物調配物(後文中亦稱為「前列腺素調配物」)組合使用的藥用組成物。本發明之藥用組成物可同時或於前列腺素F2α衍生物投藥之前或之後一定時間對個體投藥。 In another specific example, the present invention can be a pharmaceutical composition used in combination with a formulation containing a prostaglandin F2α derivative (hereinafter also referred to as a "prostaglandin formulation"). The pharmaceutical composition of the present invention can be administered to an individual at the same time or at a certain time before or after the administration of the prostaglandin F2α derivative.
本發明之藥用組成物可進一步包含碳酸酐酶抑制劑。包含於組成物之碳酸酐酶抑制劑對於組成物總量的含量可為範圍0.1至5w/v%。包含於組成物之碳酸酐酶抑制劑對於組成物總量的較佳含量(濃度)可為範圍0.5至2.5w/v%，更佳為1至2w/v%。 The pharmaceutical composition of the present invention may further comprise a carbonic anhydrase inhibitor. The content of the carbonic anhydrase inhibitor included in the composition may range from 0.1 to 5 w/v% based on the total amount of the composition. The preferred content (concentration) of the carbonic anhydrase inhibitor included in the composition may be in the range of 0.5 to 2.5 w/v%, more preferably 1 to 2 w/v%, based on the total amount of the composition.
碳酸酐酶抑制劑包括，但不限於，多佐胺、布林佐胺、乙醯佐胺、及其醫藥可接受鹽。 Carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, and pharmaceutically acceptable salts thereof.
本發明之藥用組成物可進一步包含具有眼壓降低功效之另一藥劑。包含於組成物的具有眼壓降低功效之藥劑對於該組成物總量的含量可為範圍0.1至5w/v%。包含於組成物的具有眼壓降低功效之藥劑對於該組成物總 量的較佳含量(濃度)可為範圍0.5至2.5w/v%，更佳為1至2w/v%。 The pharmaceutical composition of the present invention may further comprise another agent having an intraocular pressure lowering effect. The content of the agent with intraocular pressure lowering effect included in the composition may range from 0.1 to 5 w/v% based on the total amount of the composition. The agent with intraocular pressure lowering effect contained in the composition has a total effect on the composition. The preferred content (concentration) of the amount may be in the range of 0.5 to 2.5 w/v%, more preferably 1 to 2 w/v%.
具有眼壓降低功效之藥劑包括，但不限於，腎上腺素α2促效劑及ROCK(Rho激酶)抑制劑。腎上腺素α2促效劑的實例包括酒石酸溴莫尼定、鹽酸地匹福林、及克氯尼定。ROCK抑制劑的實例包括鹽酸利帕蘇迪水合物及甲磺酸奈他蘇迪。 Agents with intraocular pressure lowering effects include, but are not limited to, epinephrine alpha2 agonists and ROCK (Rho kinase) inhibitors. Examples of epinephrine alpha 2 agonists include brimonidine tartrate, dipifrine hydrochloride, and clonidine. Examples of ROCK inhibitors include lipasudid hydrochloride hydrate and netasudid mesylate.
本發明之藥用組成物較佳可為眼科溶液形式。更佳者為包含水性溶劑如純化水、無菌純化水或注射用水之水性滴眼劑或懸浮滴眼劑。本發明之藥用組成物亦可為單位劑量形式滴眼劑，其中單一劑量係經個別包裝，或可為可重複使用之多劑量形式滴眼劑。較佳者為多劑量形式滴眼劑。 The pharmaceutical composition of the present invention may preferably be in the form of an ophthalmic solution. More preferably, they are aqueous eye drops or suspension eye drops containing an aqueous solvent such as purified water, sterile purified water or water for injection. The pharmaceutical composition of the present invention may also be in the form of unit dose eye drops, wherein a single dose is individually packaged, or may be in the form of reusable multi-dose eye drops. Preferred are eye drops in multi-dose form.
本發明之藥用組成物可有用於治療青光眼如原發性隅角開放性青光眼(primary open-angle glaucoma)、原發性隅角閉鎖性青光眼(primary closed-angle glaucoma)、發育性青光眼(developmental glaucoma)、繼發性青光眼(secondary glaucoma)、正常眼壓性青光眼(normal tension glaucoma)、及眼疾病如高眼壓。卡替洛爾可降低眼內壓，以及本發明之藥用組成物亦可有用於治療青光眼如原發性隅角開放性青光眼、原發性隅角閉鎖性青光眼、發育性青光眼、繼發性青光眼、正常眼壓性青光眼、及眼疾病如高眼壓。 The pharmaceutical composition of the present invention can be used to treat glaucoma such as primary open-angle glaucoma, primary closed-angle glaucoma, and developmental glaucoma. glaucoma), secondary glaucoma (secondary glaucoma), normal tension glaucoma (normal tension glaucoma), and eye diseases such as high intraocular pressure. Carteolol can reduce intraocular pressure, and the pharmaceutical composition of the present invention can also be used to treat glaucoma such as primary open angle glaucoma, primary angle atresia glaucoma, developmental glaucoma, and secondary glaucoma. Glaucoma, normal tension glaucoma, and eye diseases such as intraocular hypertension.
本發明之一具體例提供包含卡替洛爾或其 醫藥可接受鹽及依地酸或其醫藥可接受鹽的藥用組成物，其中卡替洛爾或其醫藥可接受鹽除了其主要功效以外所具有的微弱防腐有效性係經增強。 One specific example of the present invention provides a method containing carteolol or its Pharmaceutical compositions of pharmaceutically acceptable salts and edetate or its pharmaceutically acceptable salts, wherein the weak preservative effectiveness of carteolol or its pharmaceutically acceptable salts in addition to its main efficacy is enhanced.
另一具體例中，依地酸或其醫藥可接受鹽可於與卡替洛爾或其醫藥可接受鹽的混合溶液中增強卡替洛爾或其醫藥可接受鹽的防腐有效性。卡替洛爾或其醫藥可接受鹽的防腐有效性可進一步藉由對該混合溶液添加張力劑而增強。 In another specific example, edetate acid or its pharmaceutically acceptable salt can enhance the preservative effectiveness of carteolol or its pharmaceutically acceptable salt in a mixed solution with carteolol or its pharmaceutically acceptable salt. The preservative effectiveness of carteolol or its pharmaceutically acceptable salt can be further enhanced by adding a tonicity agent to the mixed solution.
本發明之另一具體例係提供包含卡替洛爾或其醫藥可接受鹽及依地酸或其醫藥可接受鹽的藥用組成物，其中卡替洛爾或其醫藥可接受鹽的低的光穩定性係經改善或其分解性係降低。 Another specific example of the present invention provides a pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetate acid or a pharmaceutically acceptable salt thereof, wherein the concentration of carteolol or a pharmaceutically acceptable salt thereof is low. The photostability is improved or the decomposability is reduced.
另一具體例中，依地酸或其醫藥可接受鹽可於與卡替洛爾或其醫藥可接受鹽的混合溶液中改善卡替洛爾或其醫藥可接受鹽的光穩定性或降低分解性。對該混合溶液添加維持劑可進一步改善卡替洛爾或其醫藥可接受鹽的光穩定性或進一步降低卡替洛爾或其醫藥可接受鹽的分解性。 In another specific example, edetate acid or its pharmaceutically acceptable salt can be used in a mixed solution with carteolol or its pharmaceutically acceptable salt to improve the photostability or reduce the decomposition of carteolol or its pharmaceutically acceptable salt. sex. Adding a maintaining agent to the mixed solution can further improve the photostability of carteolol or its pharmaceutically acceptable salt or further reduce the decomposability of carteolol or its pharmaceutically acceptable salt.
本發明之另一具體例係提供用於製備眼科藥用組成物的方法。本發明之用於製備的方法包含混合卡替洛爾或其醫藥可接受鹽與依地酸或其醫藥可接受鹽的步驟。卡替洛爾或其醫藥可接受鹽及依地酸或其醫藥可接受鹽可視需要與上述之pH調節劑混合而使所得藥用組成物的pH調節成為範圍5.0及8.5，較佳為5.0及8.0，更佳為6.0及8.0，再佳為6.0及7.2。卡替洛爾或其醫藥可接受鹽及依地酸或其醫藥可接受鹽亦可視需要與上述之張力劑、 維持劑或其組合混合。可添加該張力劑而使所得藥用組成物的滲透壓比調節成為範圍0.8及1.2，較佳為0.9及1.1。 Another embodiment of the present invention provides a method for preparing an ophthalmic pharmaceutical composition. The method for preparation of the present invention includes the step of mixing carteolol or a pharmaceutically acceptable salt thereof and edetate or a pharmaceutically acceptable salt thereof. Carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof may be mixed with the above-mentioned pH adjuster as necessary to adjust the pH of the resulting pharmaceutical composition to a range of 5.0 and 8.5, preferably 5.0 and 5.0. 8.0, better 6.0 and 8.0, even better 6.0 and 7.2. Carteolol or its pharmaceutically acceptable salts and edetate or its pharmaceutically acceptable salts may also be combined with the above-mentioned tonicity agents, if necessary. Maintenance agent or combination thereof. The tonicity agent can be added to adjust the osmotic pressure ratio of the resulting pharmaceutical composition to a range of 0.8 and 1.2, preferably 0.9 and 1.1.
[實施例] [Example]
本發明，以下述試驗及實施例更詳細說明本發明，但不侷限於該等。除非另行指明，本文中濃度意指單位體積重量百分比，亦即「w/v%」，其同義於「g/100mL」。 The present invention will be described in more detail with the following tests and examples, but is not limited thereto. Unless otherwise specified, concentration herein means weight percent per unit volume, also known as "w/v%", which is synonymous with "g/100mL".
<防腐有效性測試> <Anti-corrosion effectiveness test>
下述試驗中對於測試溶液之防腐有效性係根據日本藥典第17版所記載之防腐有效性的測試方法予以評估，參考文獻資訊。 The preservative effectiveness of the test solutions in the following tests was evaluated based on the test method for preservative effectiveness recorded in the 17th edition of the Japanese Pharmacopoeia, with reference to literature information.
具體地，係使用如大腸桿菌(Escherichia coli)ATCC 8739、綠膿桿菌(Pseudomonas aeruginosa)ATCC 9027、金黃色葡萄球菌(Staphylococcus aureus)ATCC 6538之細菌，及/或如白色念珠菌(Candida albicans)ATCC 10231及黑黴菌(Aspergillus brasiliensis)ATCC 16404之真菌，製備對應的菌液。各菌液接種至測試溶液使成為包含105至106CFU(菌落形成單位)/mL，以及所得物儲存於20至25℃。存活細菌計數係於接種後第7、14及28日測定。防腐有效性以對於所接種細菌之計數之細菌計數的變化為基準而測定。對於如大腸桿菌、綠膿桿菌及金黃色葡萄球菌，測定為「充分」的情況是其中細菌計數於接種後第7日降低1.0對數值(log)或更多，以及於接種後第14日降低3.0對數值或更多，以及其中於接種後第28日的細菌計數的降低係 等於或低於接種後第14日。對於如白色念珠菌及黑黴菌之真菌，測定為「充分」的情況是接種後第7日的細菌計數，等於或低於接種的細菌計數，以及接種後第14及28日的細菌計數係等於或低於接種的細菌計數。 Specifically, bacteria such as Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538, and/or bacteria such as Candida albicans ATCC are used. 10231 and Aspergillus brasiliensis ATCC 16404 fungi, prepare the corresponding bacterial liquid. Each bacterial solution was inoculated into the test solution to contain 10 5 to 10 6 CFU (colony forming units)/mL, and the resultant was stored at 20 to 25°C. Survival bacterial counts were determined on days 7, 14, and 28 after inoculation. Preservative effectiveness is measured based on the change in bacterial count relative to the count of inoculated bacteria. For E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus, "adequate" is determined to be a situation in which the bacterial count decreases by 1.0 logarithm (log) or more on day 7 post-inoculation and decreases by day 14 post-inoculation 3.0 log or more, and wherein the reduction in bacterial count on day 28 post-inoculation is equal to or lower than day 14 post-inoculation. For fungi such as Candida albicans and black mold, "sufficiency" is determined when the bacterial count on day 7 after inoculation is equal to or lower than the inoculated bacterial count, and when the bacterial counts on days 14 and 28 after inoculation are equal to or below the inoculated bacterial count.
<試驗1>：對於卡替洛爾的防腐有效性測試 <Test 1>: Test of antiseptic effectiveness of carteolol
對於卡替洛爾的防腐有效性係根據下述方法評估。 The preservative effectiveness of carteolol was evaluated according to the method described below.
<製備實施例1至10的測試溶液> <Test solutions of Preparation Examples 1 to 10>
實施例1至10的測試溶液的成分示於表1。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1，且對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加5N氫氧化鈉或1%鹽酸調節為5.0、6.0、7.0、8.0或8.5，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The components of the test solutions of Examples 1 to 10 are shown in Table 1. Measure carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate and NaCl, and adjust the osmotic pressure ratio of the solution to 0.9 to 1.1 when adding the same amount, and add sterile ingredients to the mixture to be dissolved. Purified water. The pH value of the solution was adjusted to 5.0, 6.0, 7.0, 8.0 or 8.5 by adding 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例1至4：不含有鹽酸鹽卡替洛爾的測試溶液> <Preparation of Comparative Examples 1 to 4: Test solutions not containing carteolol hydrochloride>
比較例1至4的測試溶液的成分示於表1。測量無水磷酸氫二鈉、磷酸二氫鈉二水合物及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1，且對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加5N氫氧化鈉或1%鹽酸調節為5.0、6.0、7.0或8.0，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The components of the test solutions of Comparative Examples 1 to 4 are shown in Table 1. Measure anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate and NaCl to adjust the osmotic pressure ratio of the solution to 0.9 to 1.1 when added in equal amounts, and add sterile purified water to the mixture to be dissolved. The pH value of the solution was adjusted to 5.0, 6.0, 7.0 or 8.0 by adding 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表1]
測定實施例1至10及比較例1至4的測試溶液的防腐有效性。對於各實施例及比較例的防腐有效性的測試結果示於表2。 The preservative effectiveness of the test solutions of Examples 1 to 10 and Comparative Examples 1 to 4 was determined. The test results of the anti-corrosion effectiveness of each embodiment and comparative example are shown in Table 2.
由對於各細菌的防腐有效性的測試結果而言，展現實施例1至10對於真菌之防腐有效性測試為充分以及基本上顯示對抗細菌之防腐有效性同樣充分。不含有鹽酸鹽卡替洛爾的比較例1至4於防腐有效性測試中均為不充分。結果顯示鹽酸鹽卡替洛爾具有防腐有效性。 From the test results of the antiseptic effectiveness against each bacteria, it is shown that Examples 1 to 10 are sufficient for the antiseptic effectiveness test against fungi and basically show that the preservative effectiveness against bacteria is equally sufficient. Comparative Examples 1 to 4, which did not contain carteolol hydrochloride, were all insufficient in the preservative effectiveness test. The results show that carteolol hydrochloride has antiseptic effectiveness.
[表2]
<試驗2>：添加依地酸二鈉水合物對於防腐有效性的功效 <Test 2>: Effect of adding disodium edetate hydrate on antiseptic effectiveness
藉由依地酸二鈉水合物之鹽酸鹽卡替洛爾的防腐有效性的增強係根據下述方法證實。 The enhancement of the antiseptic effectiveness of carteolol hydrochloride by disodium edetate hydrate was demonstrated according to the following method.
<製備實施例11至15的測試溶液> <Test solutions of Preparation Examples 11 to 15>
實施例11至15的測試溶液的成分示於表3。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1，且對欲溶解的混合物添加無菌純化水。溶液的pH值藉由 添加5N氫氧化鈉或1%鹽酸調節為5.0、6.0或7.0，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The components of the test solutions of Examples 11 to 15 are shown in Table 3. Measure carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate and NaCl, and adjust the osmotic pressure ratio of the solution to 0.9 to 1.1 when adding the same amount, and add sterile ingredients to the mixture to be dissolved. Purified water. The pH value of a solution is given by Add 5N sodium hydroxide or 1% hydrochloric acid to adjust to 5.0, 6.0 or 7.0, and add sterile purified water to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例5至8：不含有鹽酸鹽卡替洛爾的測試溶液> <Preparation of Comparative Examples 5 to 8: Test solutions not containing carteolol hydrochloride>
比較例5至8的測試溶液的成分示於表4。測量依地酸二鈉水合物、無水磷酸氫二鈉、磷酸二氫鈉二水合物、及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1，且對混合物添加規定容積的無菌純化水。溶液的pH值藉由添加5N氫氧化鈉或1%鹽酸調節為5.0、6.0、7.0或8.0，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The components of the test solutions of Comparative Examples 5 to 8 are shown in Table 4. Measure disodium edetate hydrate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and NaCl to adjust the osmotic pressure ratio of the solution to 0.9 to 1.1 in equal amounts, and add a prescribed volume of Sterile purified water. The pH value of the solution was adjusted to 5.0, 6.0, 7.0 or 8.0 by adding 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表3]
測定實施例11至15及比較例5至8的測試溶液對抗如大腸桿菌、綠膿桿菌及金黃色葡萄球菌之細菌的防腐有效性。對於各實施例及比較例的防腐有效性的測試結果示於表5。 The test solutions of Examples 11 to 15 and Comparative Examples 5 to 8 were determined for their antiseptic effectiveness against bacteria such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The test results of the anti-corrosion effectiveness of each embodiment and comparative example are shown in Table 5.
實施例11至15基本上顯現對抗細菌的防腐有效性，但比較例5至8於防腐有效性測試中為不充分。結果顯示鹽酸鹽卡替洛爾及依地酸二鈉水合物的組合增強防腐有效性。 Examples 11 to 15 substantially showed preservative effectiveness against bacteria, but Comparative Examples 5 to 8 were insufficient in the preservative effectiveness test. The results show that the combination of carteolol hydrochloride and edetate disodium hydrate enhances the antiseptic effectiveness.
[表5]
<試驗3>：添加丙二醇對於防腐有效性的功效 <Test 3>: Effect of adding propylene glycol on preservative effectiveness
添加丙二醇對於鹽酸鹽卡替洛爾的防腐有效性的功效係根據下述方法於pH 5.0及6.0證實。 The efficacy of the addition of propylene glycol on the preservative effectiveness of carteolol hydrochloride was demonstrated at pH 5.0 and 6.0 according to the method described below.
<實施例16至19的測試溶液> <Test solutions of Examples 16 to 19>
實施例16至19的測試溶液的成份示於表6。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物依地酸二鈉水合物、及丙二醇而製備表6所示組成物。對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加1%鹽酸調節為5.0或6.0，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The ingredients of the test solutions of Examples 16 to 19 are shown in Table 6. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, and propylene glycol were measured to prepare the composition shown in Table 6. Add sterile purified water to the mixture to be dissolved. The pH value of the solution was adjusted to 5.0 or 6.0 by adding 1% hydrochloric acid, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例9至16的測試溶液> <Preparation of test solutions for Comparative Examples 9 to 16>
比較例9至16的測試溶液的組成示於表7。混合鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物、及丙二醇(對於比較例9至12)，無水磷酸氫二鈉、磷酸二氫鈉二水合物丙二醇、及NaCl，使其等添加量成為溶液的滲透壓比經調節為0.9至1.1(對於比較例13及14)，或依地酸二鈉水合物、無水磷酸氫二鈉、磷酸二氫鈉二水合物丙二醇、及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1(對於比較例15及16)至溶解。溶液的pH值藉由添加1%鹽酸調節為5.0或6.0，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Comparative Examples 9 to 16 are shown in Table 7. Mix carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and propylene glycol (for Comparative Examples 9 to 12), anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, propylene glycol, and NaCl, the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1 (for Comparative Examples 13 and 14) when added in equal amounts, or disodium edetate hydrate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate Propylene glycol and NaCl were added in equal amounts to adjust the osmotic pressure ratio of the solution to 0.9 to 1.1 (for Comparative Examples 15 and 16) until dissolved. The pH value of the solution was adjusted to 5.0 or 6.0 by adding 1% hydrochloric acid, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表6]
[表7]
測定實施例16至19及比較例9至16的測試溶液對抗細菌如大腸桿菌、綠膿桿菌及金黃色葡萄球菌的防腐有效性。對於各實施例及比較例的防腐有效性的測試結果示於表8。 The test solutions of Examples 16 to 19 and Comparative Examples 9 to 16 were determined for their antiseptic effectiveness against bacteria such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The test results of the anti-corrosion effectiveness of each Example and Comparative Example are shown in Table 8.
其中對包含鹽酸鹽卡替洛爾及依地酸二鈉水合物的組成物添加丙二醇的實施例16至19符合對抗大腸桿菌、綠膿桿菌及金黃色葡萄球菌所有三者的要件而於防腐有效性測試中為充分。其含有鹽酸鹽卡替洛爾但不含有依地酸二鈉水合物的比較例9至12不符合對抗大腸桿菌或綠膿桿菌的要件而為不充分。不含有鹽酸鹽卡替洛爾或依地酸二鈉水合物但含有丙二醇的比較例13及14於防腐有效性測試中為不充分。不含有鹽酸鹽卡替洛爾但含有丙二醇及依地酸二鈉水合物的比較例15及16不符合防腐有效性測試中的要件而為不充分。結果解明於鹽酸鹽卡替洛爾、依地酸二鈉水合物、及丙二醇的組合顯示防腐有效性。 Examples 16 to 19 in which propylene glycol is added to a composition containing carteolol hydrochloride and edetate disodium hydrate meet the requirements for combating all three of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus and are useful in antisepsis. Validity tested as adequate. Comparative Examples 9 to 12, which contained carteolol hydrochloride but did not contain edetate disodium hydrate, did not meet the requirements for combating Escherichia coli or Pseudomonas aeruginosa and were therefore insufficient. Comparative Examples 13 and 14, which did not contain carteolol hydrochloride or edetate disodium hydrate but contained propylene glycol, were insufficient in the preservative effectiveness test. Comparative Examples 15 and 16, which did not contain carteolol hydrochloride but contained propylene glycol and edetate disodium hydrate, did not meet the requirements in the antiseptic effectiveness test and were considered insufficient. The results demonstrated that the combination of carteolol hydrochloride, edetate disodium hydrate, and propylene glycol showed antiseptic effectiveness.
[表8]
<試驗4>：添加海藻酸對於防腐有效性的功效 <Test 4>: Effect of adding alginic acid on preservative effectiveness
藉由海藻酸之鹽酸鹽卡替洛爾防腐有效性的增強係根據下述方法證實。 The enhancement of the antiseptic effectiveness of carteolol by alginic acid hydrochloride was demonstrated according to the following method.
<製備實施例20及21的測試溶液> <Test solutions of Preparation Examples 20 and 21>
實施例20及21的測試溶液的組成示於表9。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物依地酸二鈉水合物、丙二醇、及海藻酸而製備示於表9的組 成物，對欲溶解的混合物添加無菌純化水及5N氫氧化鈉。溶液的pH值藉由添加5N氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Examples 20 and 21 are shown in Table 9. The composition shown in Table 9 was prepared by measuring carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium phosphate dihydrate dihydrate, disodium edetate hydrate, propylene glycol, and alginic acid. To form a substance, add sterile purified water and 5N sodium hydroxide to the mixture to be dissolved. The pH value of the solution was adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例17及18的測試溶液：不含有海藻酸的測試溶液> <Preparation of test solutions for Comparative Examples 17 and 18: Test solutions not containing alginic acid>
比較例17及18的測試溶液的組成示於表9。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物依地酸二鈉水合物、及丙二醇而製備示於表9的組成物。對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加5N氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Comparative Examples 17 and 18 are shown in Table 9. The compositions shown in Table 9 were prepared by measuring carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, and propylene glycol. Add sterile purified water to the mixture to be dissolved. The pH value of the solution was adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表9]
測定實施例20及21與比較例17及18的測試溶液對抗如大腸桿菌、綠膿桿菌及金黃色葡萄球菌之細菌的防腐有效性。對於各實施例及比較例之防腐有效性的測試結果示於表10。 The test solutions of Examples 20 and 21 and Comparative Examples 17 and 18 were determined for their antiseptic effectiveness against bacteria such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The test results of the anti-corrosion effectiveness of each embodiment and comparative example are shown in Table 10.
[表10]
<試驗5>：添加依地酸二鈉水合物對於光穩定性的功效 <Test 5>: Effect of adding disodium edetate hydrate on photostability
藉由依地酸二鈉水合物之鹽酸鹽卡替洛爾的光穩定性的改善係根據下述方法證實。 Improvement in the photostability of carteolol by disodium edetate hydrate hydrochloride was confirmed according to the following method.
<實施例22至25的測試溶液> <Test solutions of Examples 22 to 25>
實施例22至25的測試溶液的組成示於表11。混合鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物及依地酸二鈉水合物而製備示於表11的組成物。對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加5N氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Examples 22 to 25 are shown in Table 11. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and edetate disodium hydrate were mixed to prepare the composition shown in Table 11. Add sterile purified water to the mixture to be dissolved. The pH value of the solution was adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例19及20的測試溶液：不含有依地酸二鈉水合物的測試溶液> <Preparation of test solutions of Comparative Examples 19 and 20: Test solutions not containing disodium edetate hydrate>
比較例19及20的測試溶液的組成示於表12。混合鹽酸鹽卡替洛爾、無水磷酸氫二鈉、及磷酸二氫鈉二水合物而製備示於表12的組成物。對欲溶解的混合物添加無菌純化水。溶液的pH值藉由添加5N氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Comparative Examples 19 and 20 are shown in Table 12. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, and sodium dihydrogen phosphate dihydrate were mixed to prepare the composition shown in Table 12. Add sterile purified water to the mixture to be dissolved. The pH value of the solution was adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表11]
[表12]
測定實施例22至25與比較例19及20的測試溶液的光穩定性。以來自白燈之具有3000 Lx亮度的白光以及來自化學燈之具有50μW/cm2光強度的紫外光照射400小時。光照後之各樣品溶液與儲存於4℃無光照黑暗處的樣品溶液比較，且於各樣品溶液中測定分解產物中鹽酸鹽卡替洛爾光解下所產生的3,4-脫氫卡替洛爾的量及分解產物的總量。結果示於表13。鹽酸鹽卡替洛爾的分解產物於高效液相層析(HPLC)分析。 The photostability of the test solutions of Examples 22 to 25 and Comparative Examples 19 and 20 was determined. Irradiate for 400 hours with white light with a brightness of 3000 Lx from a white lamp and ultraviolet light with a light intensity of 50 μW/ cm from a chemical lamp. Each sample solution after illumination was compared with the sample solution stored in a dark place without light at 4°C, and the 3,4-dehydrocarboxylic acid produced by the photolysis of carteolol hydrochloride in the decomposition product was measured in each sample solution. The amount of tenolol and the total amount of decomposition products. The results are shown in Table 13. The decomposition products of carteolol hydrochloride were analyzed by high performance liquid chromatography (HPLC).
(3,4-脫氫卡替洛爾的量測定用HPLC條件) (HPLC conditions for quantitative determination of 3,4-dehydrocarteolol)
管柱：液相層析用5μm之十八矽基化矽膠係負載於內直徑4.6mm及長度15cm的不鏽鋼管。 Column: 5 μm 18-silica-based silica gel for liquid chromatography is loaded on a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm.
移動相：對1-己烷磺酸鈉(1.51g)添加乙酸(100；3mL)及水(1000mL)，且溶解混合物。對該溶液(830mL)添加乙 腈(170mL)。 Mobile phase: Add acetic acid (100; 3 mL) and water (1000 mL) to sodium 1-hexane sulfonate (1.51 g), and dissolve the mixture. To this solution (830 mL) was added B Nitrile (170mL).
偵測器：紫外吸收儀 Detector: UV absorber
[表13]
為鹽酸鹽卡替洛爾光解產物之3,4-脫氫卡替洛爾的量及分解產物的總量係藉由對卡替洛爾溶液添加依地酸二鈉水合物而為濃度依賴性降低。結果顯示依地酸二鈉水合物改善鹽酸鹽卡替洛爾的光穩定性。 The amount of 3,4-dehydrocarteolol which is a photolysis product of carteolol hydrochloride and the total amount of decomposition products are determined by adding disodium edetate hydrate to the carteolol solution. Reduced dependence. The results show that disodium edetate hydrate improves the photostability of carteolol hydrochloride.
<試驗6>：添加海藻酸對於光穩定性的功效 <Test 6>: Effect of adding alginic acid on photostability
藉由海藻酸之鹽酸鹽卡替洛爾的光穩定性的改善係根據下述方法證實。 The improvement of the photostability of carteolol by alginic acid hydrochloride was confirmed according to the following method.
<實施例26至29、60、及61的測試溶液> <Test solutions of Examples 26 to 29, 60, and 61>
實施例26至29、60、及61的測試溶液的組成示於表14。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物依地酸二鈉水合物、丙二醇、及海藻酸而製備示於表14的組成物。對混合物添加無菌純化水。對混合物添加5N氫氧化鈉且攪拌至溶解。溶液的pH值藉由添加5N 氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The compositions of the test solutions of Examples 26 to 29, 60, and 61 are shown in Table 14. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, propylene glycol, and alginic acid were measured to prepare the composition shown in Table 14. Sterile purified water was added to the mixture. 5N sodium hydroxide was added to the mixture and stirred until dissolved. The pH of the solution is adjusted by adding 5N Sodium hydroxide was adjusted to 6.7, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
<製備比較例21至28的測試溶液：不含有依地酸二鈉水合物及/或海藻酸的測試溶液> <Preparation of test solutions for Comparative Examples 21 to 28: test solutions not containing disodium edetate hydrate and/or alginic acid>
比較例21至28的測試溶液示於表15。測量鹽酸鹽卡替洛爾、無水磷酸氫二鈉、磷酸二氫鈉二水合物依地酸二鈉水合物、丙二醇、及NaCl，使其等添加量成為溶液的滲透壓比調節為0.9至1.1，而製備示於15的組成物，且對對欲溶解的混合物添加無菌純化水。然後，對於比較例21及25，對溶液添加海藻酸且攪拌，以及對混合物添加5N氫氧化鈉以溶解海藻酸。溶液的pH值藉由添加5N氫氧化鈉調節為6.7，且對溶液添加無菌純化水以獲得規定容積。溶液經由0.22-μm-膜過濾器過濾，以及5mL之各溶液裝載至測試溶液用之無菌玻璃容器。 The test solutions of Comparative Examples 21 to 28 are shown in Table 15. Measure carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, propylene glycol, and NaCl, and adjust the osmotic pressure ratio of the solution to 0.9 to 0.9 to 1.1, prepare the composition shown in 15, and add sterile purified water to the mixture to be dissolved. Then, for Comparative Examples 21 and 25, alginic acid was added to the solution and stirred, and 5N sodium hydroxide was added to the mixture to dissolve the alginic acid. The pH value of the solution was adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to the solution to obtain the specified volume. The solutions were filtered through a 0.22-μm-membrane filter, and 5 mL of each solution was loaded into sterile glass containers for test solutions.
[表14]
[表15]
測定實施例26至29、60、及61與比較例21至28的光穩定性。以來自白燈之具有3000 Lx亮度的白光以及來自化學燈之具有50μW/cm2光強度的紫外光照射400小時。測定光照後之各樣品溶液中，分解產物中鹽酸鹽卡替洛爾光解下所產生的3,4-脫氫卡替洛爾的量及分解產物的總量。結果示於表16。光解下的鹽酸鹽卡替洛爾分解產物係於高效液相層析(HPLC)分析。 The photostability of Examples 26 to 29, 60, and 61 and Comparative Examples 21 to 28 were measured. Irradiate for 400 hours with white light with a brightness of 3000 Lx from a white lamp and ultraviolet light with a light intensity of 50 μW/ cm from a chemical lamp. In each sample solution after illumination, the amount of 3,4-dehydrocarteolol produced by the photolysis of carteolol hydrochloride among the decomposition products and the total amount of decomposition products were measured. The results are shown in Table 16. The decomposition products of carteolol hydrochloride under photolysis were analyzed by high performance liquid chromatography (HPLC).
(3,4-脫氫卡替洛爾的量測定用HPLC條件) (HPLC conditions for quantitative determination of 3,4-dehydrocarteolol)
管柱：液相層析用5μm之十八矽基化矽膠係負載於內直徑4.6mm及長度15cm的不鏽鋼管。 Column: 5 μm 18-silica-based silica gel for liquid chromatography is loaded on a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm.
移動相：對1-己烷磺酸鈉(1.51g)添加乙酸(100；3mL) 及水(1000mL)，且溶解混合物。對溶液(830mL)添加乙腈(170mL)。 Mobile phase: Add acetic acid (100; 3mL) to sodium 1-hexanesulfonate (1.51g) and water (1000 mL) and dissolve the mixture. Acetonitrile (170 mL) was added to the solution (830 mL).
偵測器：紫外吸收儀 Detector: UV absorber
[表16]
對包含鹽酸鹽卡替洛爾及依地酸二鈉水合物的溶液添加海藻酸，顯著地降低鹽酸鹽卡替洛爾的光解，且當海藻酸或依地酸二鈉水合物之一者或二者皆不添加時，為鹽酸鹽卡替洛爾光解下的分解產物的3,4-脫氫卡替洛爾增加。相較於僅添加海藻酸(比較例21及25)或依地酸二 鈉水合物(比較例23、24、27、及28)的樣品，3,4-脫氫卡替洛爾的量及分解產物的總量在不含有海藻酸及依地酸二鈉水合物的比較例22及26中顯著增加。該等結果建議海藻酸及依地酸二鈉水合物降低鹽酸鹽卡替洛爾的光解且改善光穩定性。其亦建議海藻酸及依地酸二鈉水合物的組合改善鹽酸鹽卡替洛爾的光穩定性。 The addition of alginic acid to a solution containing carteolol hydrochloride and edetate disodium hydrate significantly reduces the photolysis of carteolol hydrochloride, and when alginic acid or edetate disodium hydrate is When one or both are not added, 3,4-dehydrocarteolol, which is a decomposition product of carteolol hydrochloride under photolysis, increases. Compared with adding only alginic acid (Comparative Examples 21 and 25) or edetate di For samples of sodium hydrate (Comparative Examples 23, 24, 27, and 28), the amount of 3,4-dehydrocarteolol and the total amount of decomposition products were determined when the samples did not contain alginic acid and disodium edetate hydrate. Significantly increased in Comparative Examples 22 and 26. These results suggest that alginic acid and edetate disodium hydrate reduce the photolysis of carteolol hydrochloride and improve photostability. It is also suggested that the combination of alginic acid and edetate disodium hydrate improves the photostability of carteolol hydrochloride.
<測試結果的評估> <Evaluation of test results>
結果展現本發明之藥用組成物於日本藥典第17版，參考資訊，所記載的防腐有效性測試中為充分，以及降低鹽酸鹽卡替洛爾的光解，導致光照下的穩定性。 The results show that the pharmaceutical composition of the present invention is sufficient in the preservative effectiveness test recorded in the 17th edition of the Japanese Pharmacopoeia, reference information, and reduces the photolysis of carteolol hydrochloride, resulting in stability under light.
本發明中，展現對β阻斷劑添加依地酸二鈉水合物，視需要的張力劑，例如丙二醇，及/或維持劑，例如海藻酸，使得β阻斷劑維持防腐有效性而不需要會引起副作用疑慮之防腐劑如苯札氯銨及硼酸，甚至是在傳統滴眼劑瓶允許使用多劑量的情況。亦展現本發明之藥用組成物具有如此優良的光穩定性而活性成分不於光照下分解，即便儲存組成物而無免於光照的保護。 In the present invention, it is shown that adding disodium edetate hydrate, optional tonicity agent, such as propylene glycol, and/or maintaining agent, such as alginic acid, to the β-blocker allows the β-blocker to maintain the preservative effectiveness without the need for Preservatives such as benzalkonium chloride and boric acid can raise concerns about side effects, even when multiple doses are allowed in traditional eye drop bottles. It also shows that the pharmaceutical composition of the present invention has such excellent light stability that the active ingredients do not decompose under light, even if the composition is stored without protection from light.
<調配例1>：包含前列腺素F2α衍生物的調配物的調配實施例 <Preparation Example 1>: Preparation Example of a Preparation Containing a Prostaglandin F2α Derivative
實施例30至39及比較例29係根據下述方法製備。 Examples 30 to 39 and Comparative Example 29 were prepared according to the following method.
<實施例30> <Example 30>
測量及混合拉坦前列腺素(0.005g)、聚山梨醇酯80(0.1g)、及純化水(80g)，且混合物溫熱至60℃以溶解。然後，混合物冷卻至室溫。對此溶液添加鹽酸鹽卡替洛爾(2.0 g)、海藻酸(1.0g)、硼酸(1.0g)、及依地酸二鈉水合物(0.1g)。混合物藉由添加氫氧化鈉而溶解，且混合物的pH值經調節為6.5。然後，對混合物添加純化水使得總量為100g。溶液經由孔徑0.2-μm-膜過濾器過濾以製備實施例30。 Measure and mix latanoprost (0.005g), polysorbate 80 (0.1g), and purified water (80g), and warm the mixture to 60°C to dissolve. Then, the mixture was cooled to room temperature. To this solution was added carteolol hydrochloride (2.0 g), alginic acid (1.0g), boric acid (1.0g), and edetate disodium hydrate (0.1g). The mixture was dissolved by adding sodium hydroxide, and the pH of the mixture was adjusted to 6.5. Then, purified water was added to the mixture so that the total amount became 100 g. The solution was filtered through a 0.2-μm-pore size membrane filter to prepare Example 30.
<實施例31> <Example 31>
測量及混合拉坦前列腺素(0.005g)、聚山梨醇酯80(0.1g)、及純化水(80g)，且混合物溫熱至60℃以溶解。然後，混合物冷卻至室溫。對此溶液添加鹽酸鹽卡替洛爾(2.0g)、海藻酸(1.0g)、氯化鈉(0.4g)、磷酸二氫鈉二水合物(0.04g)、無水磷酸氫二鈉(0.04g)、及依地酸二鈉水合物(0.1g)。混合物藉由添加氫氧化鈉溶解，且混合物的pH值經調節為6.5。溶液經由孔徑0.2-μm-膜過濾器過濾以製備實施例31。 Measure and mix latanoprost (0.005g), polysorbate 80 (0.1g), and purified water (80g), and warm the mixture to 60°C to dissolve. Then, the mixture was cooled to room temperature. To this solution, carteolol hydrochloride (2.0g), alginic acid (1.0g), sodium chloride (0.4g), sodium dihydrogen phosphate dihydrate (0.04g), and anhydrous disodium hydrogenphosphate (0.04 g), and disodium edetate hydrate (0.1g). The mixture was dissolved by adding sodium hydroxide, and the pH of the mixture was adjusted to 6.5. The solution was filtered through a 0.2-μm-pore size membrane filter to prepare Example 31.
<實施例32> <Example 32>
測量而混合拉坦前列腺素(0.005g)及純化水(80g)，且混合物溫熱至60℃以溶解。然後，混合物冷卻至室溫。對此溶液添加鹽酸鹽卡替洛爾(2.0g)、海藻酸(1.0g)、氯化鈉(0.4g)、磷酸二氫鈉二水合物(0.04g)、無水磷酸氫二鈉(0.04g)、及依地酸二鈉水合物(0.1g)。混合物藉由添加氫氧化鈉溶解，且混合物的pH值經調節為6.5。然後，對混合物添加純化水使得總量為100g。溶液經由孔徑0.2-μm-膜過濾器過濾以製備實施例32。 Measure and mix latanoprost (0.005g) and purified water (80g), and warm the mixture to 60°C to dissolve. Then, the mixture was cooled to room temperature. To this solution, carteolol hydrochloride (2.0g), alginic acid (1.0g), sodium chloride (0.4g), sodium dihydrogen phosphate dihydrate (0.04g), and anhydrous disodium hydrogenphosphate (0.04 g), and disodium edetate hydrate (0.1g). The mixture was dissolved by adding sodium hydroxide, and the pH of the mixture was adjusted to 6.5. Then, purified water was added to the mixture so that the total amount became 100 g. The solution was filtered through a 0.2-μm-pore size membrane filter to prepare Example 32.
<實施例33、36、及39> <Examples 33, 36, and 39>
實施例33、36、及39係根據實施例30所記載的方法 製備。 Examples 33, 36, and 39 are based on the method described in Example 30 Preparation.
<實施例34、35、37、及38> <Examples 34, 35, 37, and 38>
實施例34、35、37、及38係根據實施例31所記載的方法製備。 Examples 34, 35, 37, and 38 were prepared according to the method described in Example 31.
<比較例29> <Comparative Example 29>
測量及混合拉坦前列腺素(0.005g)、聚山梨醇酯80(0.2g)、及純化水(80g)，且混合物溫熱至60℃以溶解。然後，混合物冷卻至室溫。對此溶液添加海藻酸(1.0g)、硼酸(1.5g)、及依地酸二鈉水合物(0.2g)。混合物藉由添加氫氧化鈉溶解，且混合物的pH值經調節為6.5。然後，對混合物添加純化水使得總量為100g。溶液經由孔徑0.2-μm-膜過濾器過濾為比較例29。 Measure and mix latanoprost (0.005g), polysorbate 80 (0.2g), and purified water (80g), and warm the mixture to 60°C to dissolve. Then, the mixture was cooled to room temperature. To this solution were added alginic acid (1.0g), boric acid (1.5g), and edetate disodium hydrate (0.2g). The mixture was dissolved by adding sodium hydroxide, and the pH of the mixture was adjusted to 6.5. Then, purified water was added to the mixture so that the total amount became 100 g. The solution was filtered through a 0.2-μm pore size membrane filter as Comparative Example 29.
[表17]
<調配例2> <Preparation example 2>
不含有苯札氯銨的實施例40至47係根據下述方法製備。 Examples 40 to 47, which did not contain benzalkonium chloride, were prepared according to the following method.
<實施例40> <Example 40>
測量及混合純化水(80g)、鹽酸鹽卡替洛爾(1.0g)、海藻酸(1.0g)、丙二醇(1.3g)、磷酸二氫鈉二水合物(0.04g)、無水磷酸氫二鈉(0.04g)、及依地酸二鈉水合物(0.01g)。藉由添加氫氧化鈉且攪拌溶解混合物以及該混合物的pH 值經調節為6.7。然後，對混合物添加純化水使得總量為100g。攪拌該溶液及經由孔徑0.2-μm-膜過濾器過濾以製備實施例40。 Measure and mix purified water (80g), carteolol hydrochloride (1.0g), alginic acid (1.0g), propylene glycol (1.3g), sodium dihydrogen phosphate dihydrate (0.04g), anhydrous dihydrogen phosphate Sodium (0.04g), and disodium edetate hydrate (0.01g). Dissolve the mixture by adding sodium hydroxide and stirring and the pH of the mixture The value is adjusted to 6.7. Then, purified water was added to the mixture so that the total amount became 100 g. The solution was stirred and filtered through a 0.2-μm-pore size membrane filter to prepare Example 40.
<實施例41至47> <Examples 41 to 47>
實施例41至47係根據實施例40記載的方法而製備。 Examples 41 to 47 were prepared according to the method described in Example 40.
[表18]
<調配例3>：包含碳酸酐酶抑制劑的調配物的調配實施例 <Preparation Example 3>: Preparation Example of a Preparation Containing a Carbonic Anhydrase Inhibitor
實施例48至59係根據下述方法製備。 Examples 48 to 59 were prepared according to the following method.
<實施例48> <Example 48>
測量且於水中溶解鹽酸鹽卡替洛爾(2.0g)、鹽酸多佐胺(1.113g)、依地酸二鈉水合物(0.01g)、D-甘露醇(2.0g)、及檸檬酸鈉水合物(0.3g)。所得溶液以孔徑0.2μm的膜過濾器過濾而無菌化。溶液與藉由溶解羥基乙基纖維素(0.5g)於水中的步驟所獲得的溶液組合且藉由高壓蒸氣無菌化。合併溶液的pH值藉由添加氫氧化鈉經調節為5.7。然後，對該溶液添加純化水以製備具有總量100g的實施例48。 Measure and dissolve carteolol hydrochloride (2.0g), dorzolamide hydrochloride (1.113g), edetate disodium hydrate (0.01g), D-mannitol (2.0g), and citric acid in water Sodium hydrate (0.3g). The obtained solution was filtered through a membrane filter with a pore size of 0.2 μm to sterilize it. The solution was combined with the solution obtained by dissolving hydroxyethylcellulose (0.5 g) in water and sterilized by high pressure steam. The pH of the combined solution was adjusted to 5.7 by adding sodium hydroxide. Then, purified water was added to the solution to prepare Example 48 with a total amount of 100 g.
<實施例49至51> <Examples 49 to 51>
實施例49至51係根據實施例48記載的方法製備。 Examples 49 to 51 were prepared according to the method described in Example 48.
<實施例52> <Example 52>
測量及溶解純化水(80g)、鹽酸鹽卡替洛爾(2.0g)、鹽酸多佐胺(1.113g)、依地酸二鈉水合物(0.01g)、丙二醇(0.7g)、及檸檬酸鈉水合物(0.3g)。溶液的pH值藉由添加氫氧化鈉經調節為5.7。然後，對溶液添加純化水使為總量100g。攪拌該溶液且經由孔徑0.2μm的膜過濾器過濾以製備實施例52。 Measure and dissolve purified water (80g), carteolol hydrochloride (2.0g), dorzolamide hydrochloride (1.113g), edetate disodium hydrate (0.01g), propylene glycol (0.7g), and lemon Sodium acid hydrate (0.3g). The pH of the solution was adjusted to 5.7 by adding sodium hydroxide. Then, purified water was added to the solution so that the total amount was 100 g. The solution was stirred and filtered through a membrane filter with a pore size of 0.2 μm to prepare Example 52.
<實施例53至55> <Examples 53 to 55>
實施例53至55係根據實施例52揭示的方法製備。 Examples 53 to 55 were prepared according to the method disclosed in Example 52.
<實施例56> <Example 56>
測量泰洛沙泊(0.025g)裝載至圓柱型玻璃容器且藉由添加經加熱至60℃的純化水(6g)而溶解。對溶液添加布林佐胺(1.0g)及釔氧化鋯珠粒(12g)，以及密封該容器且於121℃加熱20分鐘。冷卻混合物，且然後於50rpm旋轉20小時而成為布林佐胺懸浮物。分別測量鹽酸鹽卡替洛爾(2.0g)、依地酸二鈉水合物(0.01g)、及丙二醇(1.0g)且溶解於純化水(50g)。於60℃，對溶液添加其中卡波姆(carbopol)(0.4g)係均質地分散於純化水(25g)的溶液。所得溶液於121℃加熱20分鐘，以及之後該溶液的pH值藉由添加使用作為溶劑之氫氧化鈉經調節為7.2。過濾布林佐胺懸浮物以移除釔氧化鋯珠粒且與溶劑合併，以及對混合物添加純化水使成為100g以製備實施例56。 Measurement Tyloxapol (0.025 g) was loaded into a cylindrical glass container and dissolved by adding purified water (6 g) heated to 60°C. Brinzolamide (1.0 g) and yttrium zirconia beads (12 g) were added to the solution, and the container was sealed and heated at 121°C for 20 minutes. The mixture was cooled and then spun at 50 rpm for 20 hours to form a brinzolamide suspension. Carteolol hydrochloride (2.0 g), edetate disodium hydrate (0.01 g), and propylene glycol (1.0 g) were measured separately and dissolved in purified water (50 g). At 60° C., a solution in which carbopol (0.4 g) was homogeneously dispersed in purified water (25 g) was added to the solution. The resulting solution was heated at 121° C. for 20 minutes, and then the pH of the solution was adjusted to 7.2 by adding sodium hydroxide used as solvent. The brinzolamide suspension was filtered to remove the yttrium zirconia beads and combined with the solvent, and purified water was added to the mixture to make 100 g to prepare Example 56.
<實施例57至59> <Examples 57 to 59>
實施例57至59係根據實施例56揭示的方法製備。 Examples 57 to 59 were prepared according to the method disclosed in Example 56.
[表19]
<試驗7>：實施例30至39及比較例29之調配物的防腐有效性測試 <Test 7>: Preservative effectiveness test of the formulations of Examples 30 to 39 and Comparative Example 29
根據防腐有效性測試，評估實施例30至39及比較例29之調配物的防腐有效性。結果示於下表。 The formulations of Examples 30 to 39 and Comparative Example 29 were evaluated for their preservative effectiveness according to the Preservative Effectiveness Test. The results are shown in the table below.
[產業可利用性] [Industrial Availability]
本發明之藥用組成物可具有增強的防腐有效性及/或改善的光穩定性，且其可有用於治療眼疾病如青光眼及高眼壓。 The pharmaceutical composition of the present invention may have enhanced preservative effectiveness and/or improved photostability, and may be useful in treating eye diseases such as glaucoma and ocular hypertension.
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| JP4361294B2 (en) | 2003-02-25 | 2009-11-11 | ロート製薬株式会社 | Ketotifen-containing composition |
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