KR20170122773A - Ophthalmic composition - Google Patents
Ophthalmic composition Download PDFInfo
- Publication number
- KR20170122773A KR20170122773A KR1020177026380A KR20177026380A KR20170122773A KR 20170122773 A KR20170122773 A KR 20170122773A KR 1020177026380 A KR1020177026380 A KR 1020177026380A KR 20177026380 A KR20177026380 A KR 20177026380A KR 20170122773 A KR20170122773 A KR 20170122773A
- Authority
- KR
- South Korea
- Prior art keywords
- ophthalmic composition
- salt
- propylene glycol
- hyaluronic acid
- acid
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 119
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 177
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical compound 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 65
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000774 hypoallergenic effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000020046 sherry Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-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
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- 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
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Y10S514/912—
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
본 발명은, 히알루론산 또는 그의 염을 함유하는 점안액 등의 안과용 조성물의 동점도의 유지율을 높게 유지하는 것을 목적으로 한다.
본 발명은, 0.001∼0.5%(w/v)의 히알루론산 또는 그의 염, 0.0005∼0.02%(w/v)의 클로르헥시딘류, 0.03∼1.5%(w/v)의 프로필렌 글리콜 및 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유하는 안과용 조성물을 제공한다.The object of the present invention is to maintain the retention ratio of the kinetic viscosity of an ophthalmic composition such as an eye drop containing hyaluronic acid or its salt at a high level.
The present invention relates to a composition comprising 0.001 to 0.5% (w / v) of hyaluronic acid or its salt, 0.0005 to 0.02% (w / v) of chlorhexidines, 0.03 to 1.5% (w / v) of propylene glycol and 0.015% / v) or less of ethylenediamine acetic acid salts.
Description
본 발명은, 안과용 조성물, 안과 조성물의 동점도(動粘度)의 경시 변화를 억제하고/하거나 방부력 또는 보존 효력을 높게 유지하는 방법에 관한 것이다.The present invention relates to an ophthalmic composition, a method for suppressing a change in the kinetic viscosity (kinematic viscosity) of the ophthalmic composition over time, and / or maintaining a repelling force or preservation effect.
히알루론산 또는 그의 염은 드라이아이의 치료제로서 널리 알려져 있고, 예컨대 일본에서는 점안제로서 범용되고 있다. 점안제는, 복수 회에 걸쳐 사용하는 것을 목적으로 하고, 캡에 의한 개봉 및 재밀봉을 자유롭게 행할 수 있는 멀티도우즈형이 많이 이용된다. 한편 멀티도우즈형의 점안제는, 장기간 사용하는 것을 전제로 하기 때문에 방부제를 첨가해 둘 필요가 있다.Hyaluronic acid or a salt thereof is widely known as a therapeutic agent for dry eye, and is generally used as an eye drop in Japan, for example. The eyedropper is used for a plurality of times, and a multi-tooth type which can be freely opened and re-sealed by a cap is often used. On the other hand, a multi-dose type eye drop is required to be used for a long period of time, so it is necessary to add a preservative.
안과용 방부제로는, 종래, 염화벤잘코늄이 널리 알려져 있다. 최근, 그 대체로서, 클로르헥시딘류를 사용하는 것이 제안되어 있다(예컨대, 특허문헌 1). 또한, 점안액의 안정화제로서, 에틸렌디아민사아세트산염류가 널리 배합되어 있다(예컨대, 특허문헌 2).As an ophthalmic preservative, benzalkonium chloride has been widely known. Recently, it has been proposed to use chlorhexidine derivatives as an alternative (for example, Patent Document 1). As stabilizers for eye drops, ethylenediamine acetic acid salts are widely used (for example, Patent Document 2).
그러나, 본 발명자들의 검토에 따르면, 히알루론산 또는 그의 염과 클로르헥시딘류를 함유하는 점안액에 대해서는, 경시적으로 점안액의 동점도가 저하된다고 하는 문제점이 발견되었다.However, according to the studies of the present inventors, it has been found that the eye drops containing hyaluronic acid or salts thereof and chlorhexidine derivatives have a problem that the kinematic viscosity of the eye drops is lowered over time.
본 발명은, 히알루론산 또는 그의 염을 함유하는 점안액 등의 안과용 조성물의 동점도의 유지율을 높게 유지하는 것을 목적으로 한다.The object of the present invention is to maintain the retention ratio of the kinetic viscosity of an ophthalmic composition such as an eye drop containing hyaluronic acid or its salt at a high level.
본 발명자들은, 히알루론산 또는 그의 염과 클로르헥시딘류를 함유하는 점안제 등의 안과용 조성물에, 프로필렌 글리콜을 배합함과 더불어, 에틸렌디아민사아세트산염류의 배합 농도를 0.015%(w/v) 이하로 함으로써, 안과용 조성물의 동점도를 장기간에 걸쳐 안정하게 유지할 수 있는 것을 발견하여, 본 발명을 완성하기에 이르렀다. 구체적으로는, 본 발명은 이하의 것을 제공한다.The present inventors have found that by mixing propylene glycol and an ethylenediamine acetic acid salt in an ophthalmic composition such as eye drops containing hyaluronic acid or a salt thereof and chlorhexidines in an amount of not more than 0.015% (w / v) , And that the kinetic viscosity of the ophthalmic composition can be stably maintained over a long period of time, thus completing the present invention. Specifically, the present invention provides the following.
[1] 0.001∼0.5%(w/v)의 히알루론산 또는 그의 염, 0.0005∼0.02%(w/v)의 클로르헥시딘류, 0.03∼1.5%(w/v)의 프로필렌 글리콜 및 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유하는 안과용 조성물.(W / v) of propyleneglycol and 0.015% (w / v) of hyaluronic acid or its salt, 0.0005 to 0.02% (w / v) of chlorhexidines, 0.03 to 1.5% v) or less of ethylenediamine acetic acid salts.
[2] 상기 히알루론산 또는 그의 염이 0.01∼0.3%(w/v)인 [1]에 기재된 안과용 조성물.[2] The ophthalmic composition according to [1], wherein the hyaluronic acid or its salt is 0.01 to 0.3% (w / v).
[3] 상기 클로르헥시딘류가 0.0007∼0.008%(w/v)인 [1]에 기재된 안과용 조성물.[3] The ophthalmic composition according to [1], wherein the chlorhexidine is 0.0007 to 0.008% (w / v).
[4] 상기 프로필렌 글리콜이 0.05∼1.0%(w/v)인 [1]에 기재된 안과용 조성물.[4] The ophthalmic composition according to [1], wherein the propylene glycol is 0.05 to 1.0% (w / v).
[5] 상기 에틸렌디아민사아세트산염류가 0.01%(w/v) 이하인 [1]에 기재된 안과용 조성물.[5] The ophthalmic composition according to [1], wherein the ethylenediamine acetic acid salt is 0.01% (w / v) or less.
[6] pH가 5.5∼8인 [1]∼[5] 중 어느 하나에 기재된 안과용 조성물.[6] The ophthalmic composition according to any one of [1] to [5], wherein the pH is 5.5 to 8.
[7] 삼투압이 0.4∼1.1인 [1]∼[6] 중 어느 하나에 기재된 안과용 조성물.[7] The ophthalmic composition according to any one of [1] to [6], wherein the osmotic pressure is 0.4 to 1.1.
[8] 의약용 점안제, 소프트 콘택트 렌즈용 점안제 또는 소프트 콘택트 렌즈용 장착제(裝着劑)인 [1]∼[7] 중 어느 하나에 기재된 안과용 조성물.[8] The ophthalmic composition according to any one of [1] to [7], which is a medicament eyedrop, an eyedrop for a soft contact lens or a fixator for a soft contact lens.
또한, 상기 [1] 내지 [8]의 각 구성은, 임의로 2 이상을 선택하여 조합할 수 있다.Further, the respective constitutions of [1] to [8] may be arbitrarily selected from two or more.
[9] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 동점도의 경시 변화를 억제하는 방법.[9] A method for inhibiting changes in the kinetic viscosity of an ophthalmic composition with time by incorporating propylene glycol and ethylenediamine acetic acid salts into an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidine.
[10] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 0.03∼1.5%(w/v)의 프로필렌 글리콜과 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 동점도의 경시 변화를 억제하는 방법.[10] An ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines, which contains 0.03 to 1.5% (w / v) propylene glycol and 0.015% (w / v) or less of ethylenediamine acetic acid, A method for inhibiting changes in the kinetic viscosity of an ophthalmic composition over time.
[11] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 방부력 또는 보존 효력을 높게 유지하는 방법.[11] A method for preserving the ophthalmic composition with high repelling force or preservation effect by containing propylene glycol and ethylenediamine acetic acid salts in an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidine.
[12] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 0.03∼1.5%(w/v)의 프로필렌 글리콜과 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 방부력 또는 보존 효력을 높게 유지하는 방법.[12] An ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines, which comprises 0.03 to 1.5% (w / v) of propylene glycol and 0.015% (w / v) or less of ethylenediamine acetic acid, A method of maintaining high ocular or ophthalmic composition retention or preservation efficacy.
[13] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지하는 방법.[13] A method for inhibiting changes in the dynamic viscosity of an ophthalmic composition over time by incorporating propylene glycol and ethylenediamine acetic acid salts into an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines, How to keep.
[14] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물에 0.03∼1.5%(w/v)의 프로필렌 글리콜과 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유시키는 것에 의한, 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지하는 방법.[14] An ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines, which comprises 0.03 to 1.5% (w / v) of propylene glycol and 0.015% (w / v) or less of ethylenediamine acetic acid salt, A method for inhibiting a change in the kinetic viscosity of an ophthalmic composition over time and also maintaining a buoyancy or preservation effect.
[15] 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는, 안과 조성물의 동점도의 경시 변화의 억제제로서, 상기 안과 조성물이 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 것인 억제제.[15] An inhibitor for inhibiting changes in the dynamic viscosity of an ophthalmic composition over time, comprising propylene glycol and ethylenediamine acetic acid, wherein the ophthalmic composition contains hyaluronic acid or its salt and chlorhexidine.
[16] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물의 동점도의 경시 변화를 억제하기 위해서 이용되는, 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 조성물.[16] A composition containing propylene glycol and ethylenediamine acetic acid salts, which is used for inhibiting a change in the kinetic viscosity of an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidine derivatives with time.
[17] 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하고, 안과 조성물의 방부력 또는 보존 효력을 높게 유지하는 방부제 또는 보존제로서, 상기 안과 조성물이 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 것인 방부제 또는 보존제.[17] A preservative or preservative containing propylene glycol and ethylenediamine acetic acid salts, wherein the ophthalmic composition contains hyaluronic acid or its salt and chlorhexidine, Or preservative.
[18] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물의 방부력 또는 보존 효력을 높게 유지하기 위해서 이용되는, 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 조성물.[18] A composition containing propylene glycol and ethylenediamine acetic acid salts, which is used to maintain a high flushing or preserving effect of an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines.
[19] 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지하기 위해서 이용되는, 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 함유하는 조성물.[19] A pharmaceutical composition containing propylene glycol and ethylenediamine acetic acid, which is used for inhibiting a change in the kinetic viscosity of an ophthalmic composition containing hyaluronic acid or a salt thereof and chlorhexidines with a lapse of time, Composition.
또한, 상기 [9] 내지 [19]의 각 구성의 성분 농도는, 본 발명의 실시형태에 준하여 적절하게 바람직한 범위 및 조합으로 한정할 수 있다.In addition, the component concentrations of the respective constituents of [9] to [19] can be appropriately determined according to the embodiments of the present invention in a preferable range and combination.
본 발명에 따르면, 히알루론산 또는 그의 염과 클로르헥시딘류를 함유하는 점안액 등의 안과용 조성물은, 그 동점도의 경시 변화를 억제할 수 있고, 또한, 방부력 내지 보존 효력을 높게 유지하는 것이 가능해진다.According to the present invention, an ophthalmic composition such as an eye drop containing hyaluronic acid or a salt thereof and a chlorhexidine can inhibit changes in the kinetic viscosity over time and can maintain a high repelling force and a high preservation effect.
이하, 본 발명의 실시형태에 대해서 상세히 설명한다.Hereinafter, embodiments of the present invention will be described in detail.
본 실시형태의 안과용 조성물은, 히알루론산 또는 그의 염, 클로르헥시딘류 및 프로필렌 글리콜을 함유하고, 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유하는 것이다. 본 실시형태는, 종래 에틸렌디아민사아세트산염류가 안과용 조성물의 안정화제로서 널리 배합되어 왔음에도 불구하고, 그 배합량을 극히 미량(0.015% 이하)으로 한 경우에 점안액의 동점도를 안정하게 유지할 수 있는 것을 발견한 것이다. 즉, 본 실시형태의 안과용 조성물은, 0.001∼0.5%(w/v)의 히알루론산 또는 그의 염, 0.0005∼0.02%(w/v)의 클로르헥시딘류, 0.03∼1.5%(w/v)의 프로필렌 글리콜 및 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유하여도 좋다.The ophthalmic composition of this embodiment contains hyaluronic acid or a salt thereof, chlorhexidines and propylene glycol, and contains 0.015% (w / v) or less of ethylenediamine acetic acid salts. Although this embodiment has heretofore been widely used as a stabilizer for ophthalmic compositions, it has been found that when the amount of the ethylenediamine acetic acid salt is extremely small (0.015% or less), the kinematic viscosity of the eye drop can be stably maintained . That is, the ophthalmic composition of the present embodiment is characterized by containing 0.001 to 0.5% (w / v) of hyaluronic acid or its salt, 0.0005 to 0.02% (w / v) of chlorhexidines, 0.03 to 1.5% (w / v) Propylene glycol and 0.015% (w / v) or less ethylenediamine acetic acid salts.
이하, 각 성분마다 설명한다.Hereinafter, each component will be described.
히알루론산 또는 그의 염Hyaluronic acid or its salt
본 실시형태에 있어서의 히알루론산은, 하기 일반식 (1)로 표시되는 화합물이다.The hyaluronic acid in the present embodiment is a compound represented by the following general formula (1).
[식 중, n은 자연수를 나타낸다][Wherein n represents a natural number]
본 실시형태에 있어서의 「히알루론산」으로서 바람직한 것은, 평균 분자량이 50만∼390만인 히알루론산이며, 더욱 바람직한 것은, 평균 분자량이 50만∼120만인 히알루론산이다.Preferred as the "hyaluronic acid" in the present embodiment is hyaluronic acid having an average molecular weight of 500,000 to 390,000, and more preferably hyaluronic acid having an average molecular weight of 500,000 to 120,000.
히알루론산의 염으로는, 의약으로서 허용되는 염이라면 특별히 제한은 없고, 염산, 브롬화수소산, 요오드화수소산, 질산, 황산, 인산 등의 무기산과의 염, 아세트산, 푸마르산, 말레산, 호박산, 시트르산, 타르타르산, 아디프산, 글루콘산, 글루코헵토산, 글루쿠론산, 테레프탈산, 메탄술폰산, 젖산, 마뇨산, 1,2-에탄디술폰산, 이세티온산, 락토비온산, 올레인산, 파모산, 폴리갈락투론산, 스테아르산, 타닌산, 트리플루오로메탄술폰산, 벤젠술폰산, p-톨루엔술폰산, 황산라우릴에스테르, 황산메틸, 나프탈렌술폰산, 술포살리실산 등의 유기산과의 염; 브롬화메틸, 요오드화메틸 등으로의 4급 암모늄염; 브롬 이온, 염소 이온, 요오드 이온 등의 할로겐 이온과의 염; 리튬, 나트륨, 칼륨 등의 알칼리 금속과의 염; 칼슘, 마그네슘 등의 알칼리 토류 금속과의 염; 철, 아연 등으로의 금속염; 암모니아와의 염; 트리에틸렌디아민, 2-아미노에탄올, 2,2-이미노비스(에탄올), 1-데옥시-1-(메틸아미노)-2-D-소르비톨, 2-아미노-2-(히드록시메틸)-1,3-프로판디올, 프로카인, N,N-비스(페닐메틸)-1,2-에탄디아민 등의 유기 아민과의 염 등을 들 수 있다.The salt of hyaluronic acid is not particularly limited as long as it is a salt acceptable as a pharmaceutical and includes salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, , Adipic acid, gluconic acid, glucoheptanoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, mannose acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, Salts with organic acids such as hydrochloric acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid ester, methyl sulfate, naphthalenesulfonic acid and sulfosalicylic acid; Quaternary ammonium salts with methyl bromide, methyl iodide and the like; A salt with a halogen ion such as a bromide ion, a chlorine ion or an iodine ion; Salts with alkali metals such as lithium, sodium and potassium; Salts with alkaline earth metals such as calcium and magnesium; Metal salts such as iron and zinc; Salts with ammonia; (Methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1 , 3-propanediol, procaine, and salts with organic amines such as N, N-bis (phenylmethyl) -1,2-ethanediamine.
본 실시형태에 있어서의 「히알루론산의 염」으로는, 하기 일반식 (2)로 표시되는 나트륨염(이하, 「히알루론산나트륨」이라고 함)이 바람직하다.As the "salt of hyaluronic acid" in the present embodiment, a sodium salt represented by the following general formula (2) (hereinafter referred to as "sodium hyaluronate") is preferable.
[식 중, m은 자연수를 나타낸다][Wherein m represents a natural number]
본 실시형태에 있어서의 「히알루론산 또는 그의 염」은, 수화물 또는 용매화물의 형태를 취하고 있어도 좋다.The " hyaluronic acid or its salt " in the present embodiment may take the form of a hydrate or a solvate.
히알루론산에 기하 이성체 또는 광학 이성체가 존재하는 경우에는, 상기 이성체 또는 이들의 염도 본 발명의 범위에 포함된다. 또한, 히알루론산에 프로톤 호변 이성이 존재하는 경우에는, 상기 호변 이성체 또는 이들의 염도 본 발명의 범위에 포함된다.When a geometric isomer or an optical isomer is present in hyaluronic acid, the above isomer or a salt thereof is also included in the scope of the present invention. In addition, in the case where hyaluronic acid has proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.
히알루론산 또는 그의 염, 수화물 혹은 용매화물에, 결정 다형 및 결정 다형군(결정 다형 시스템)이 존재하는 경우에는, 이들의 결정 다형체 및 결정 다형군(결정 다형 시스템)도 본 발명의 범위에 포함된다. 여기서, 결정 다형군(결정 다형 시스템)이란, 이들 결정의 제조, 정출, 보존 등의 조건 및 상태(또한, 본 상태에는 제제화한 상태도 포함함)에 따라, 결정형이 변화되는 경우의 각 단계에 있어서의 개개의 결정형 및 그 과정 전체를 의미한다.When crystalline polymorphs and crystalline polymorphic groups (crystalline polymorphism systems) exist in hyaluronic acid or its salts, hydrates or solvates, these crystalline polymorphs and crystalline polymorphic groups (crystal polymorphism systems) are also included in the scope of the present invention. do. Herein, the crystalline polymorphism group (crystalline polymorphism system) refers to a crystalline polymorphism in each step in the case where the crystal form is changed in accordance with conditions and conditions such as production, crystallization, storage and the like of these crystals Means the individual crystal form and the whole process thereof.
「히알루론산 또는 그의 염」은, 유기합성화학 분야에서의 통상적인 방법에 따라 제조할 수도 있고, 일본 특허 공개 평성 제1-115902호 공보에 기재된 방법에 따라 제조할 수도 있다. 또한, 「히알루론산 또는 그의 염」은, 시그마사 등에 의해 시판되고 있는 것을 이용할 수도 있고, 예컨대, 「히알루론산나트륨」은 시그마사에서 시판되고 있다(카탈로그 번호: H5388).The " hyaluronic acid or its salt " may be produced according to a conventional method in the field of organic synthetic chemistry, or may be prepared according to the method described in JP-A-1-115902. For example, "sodium hyaluronate" is commercially available from Sigma Co. (catalog number: H5388). "Hyaluronic acid or its salt" may be commercially available from Sigma.
본 실시형태의 안과용 조성물은, 「히알루론산 또는 그의 염」을 유일한 유효 성분으로서 함유하여도 좋고, 또한, 「히알루론산 또는 그의 염」 이외의 유효 성분을 함유할 수도 있다. 본 실시양태의 안과용 조성물은, 「히알루론산 또는 그의 염」 이외의 유효 성분으로서, 예컨대, 크로모글릭산 또는 그의 염, 프라노프로펜을 함유하지 않을 수도 있다. 본 발명에 있어서, 「유효 성분」이란, 약리학적 효과가 있는 성분을 의미한다.The ophthalmic composition of the present embodiment may contain "hyaluronic acid or its salt" as a sole effective ingredient and may also contain an active ingredient other than "hyaluronic acid or its salt". The ophthalmic composition of this embodiment may not contain, for example, cromoglicic acid or its salt or pranopropene as an active ingredient other than " hyaluronic acid or its salt ". In the present invention, " active ingredient " means a component having a pharmacological effect.
본 실시형태의 안과용 조성물에 있어서의 「히알루론산 또는 그의 염」의 농도는, 하한치로는 0.001%(w/v)가 바람직하고, 0.01%(w/v)가 보다 바람직하며, 0.05%(w/v)가 더욱 바람직하고, 상한치로는 0.5%(w/v)가 바람직하며, 0.3%(w/v)가 보다 바람직하다.The lower limit of the concentration of "hyaluronic acid or its salt" in the ophthalmic composition of the present embodiment is preferably 0.001% (w / v), more preferably 0.01% (w / v) w / v), and the upper limit is preferably 0.5% (w / v), more preferably 0.3% (w / v).
클로르헥시딘류Chlorhexidines
클로르헥시딘류로는, 예컨대 글루콘산클로르헥시딘, 아세트산클로르헥시딘, 염산클로르헥시딘 등을 들 수 있고, 바람직하게는 글루콘산클로르헥시딘이다. 클로르헥시딘류의 농도는, 하한치로는 0.0005%(w/v)가 바람직하고, 0.0007%(w/v)가 보다 바람직하며, 0.0008%(w/v)가 더욱 바람직하고, 상한치로는 0.02%(w/v)가 바람직하며, 0.01%(w/v)가 보다 바람직하고, 0.008%(w/v)가 더욱 바람직하다.Examples of the chlorhexidines include chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride and the like, preferably chlorhexidine gluconate. The lower limit of the concentration of chlorhexidine is preferably 0.0005% (w / v), more preferably 0.0007% (w / v), still more preferably 0.0008% (w / v) w / v), more preferably 0.01% (w / v), still more preferably 0.008% (w / v).
본 실시형태의 안과용 조성물은, 클로르헥시딘류 이외의 방부제를 함유할 수도 있고, 예컨대, 염화벤잘코늄을 함유하는 것이어도 좋으며, 그 농도로는, 0.002%(w/v) 이하가 바람직하고, 0.0015%(w/v) 이하가 보다 바람직하다. 그러나, 본 실시형태의 안과용 조성물은, 염화벤잘코늄을 함유하지 않는 것이 바람직하고, 클로르헥시딘류를 유일한 방부제로서 함유하는 것이 보다 바람직하다.The ophthalmic composition of the present embodiment may contain a preservative other than chlorhexidine, and may contain, for example, benzalkonium chloride. The concentration thereof is preferably 0.002% (w / v) or less, more preferably 0.0015 % (w / v) or less is more preferable. However, the ophthalmic composition of the present embodiment is preferably free of benzalkonium chloride, and more preferably contains chlorhexidine as a unique preservative.
프로필렌 글리콜Propylene glycol
본 실시형태의 안과용 조성물에 있어서의 프로필렌 글리콜의 농도는, 하한치로는 0.03%(w/v)가 바람직하고, 0.05%(w/v)가 보다 바람직하며, 상한치로는 1.5%(w/v)가 바람직하고, 1.0%(w/v)가 보다 바람직하다.The lower limit of the concentration of propylene glycol in the ophthalmic composition of the present embodiment is preferably 0.03% (w / v), more preferably 0.05% (w / v) v) is preferable, and 1.0% (w / v) is more preferable.
에틸렌디아민사아세트산염류Ethylenediamine acetic acid salts
본 실시형태의 안과용 조성물에 있어서의 에틸렌디아민사아세트산염류란, 에데트산 또는 그의 염으로서, 수화물의 형태라도 좋고, 또한, 산과 염을 혼합하여 사용할 수도 있다. 에데트산의 염으로는, 예컨대 에데트산나트륨, 에데트산이나트륨, 에데트산사나트륨 등의 알칼리 금속류를 들 수 있고, 수화물로는 예컨대 에데트산이나트륨의 2수화물 등의 에데트산나트륨 수화물을 들 수 있다.The ethylenediamine acetic acid salts in the ophthalmic composition of the present embodiment may be in the form of a hydrate, as an edetic acid or a salt thereof, or a mixture of an acid and a salt. Examples of the salt of edetic acid include alkali metals such as sodium edetate, disodium edetate and sodium edetate. Examples of the hydrate include sodium edetate sodium hydrate such as disodium edetate dihydrate. have.
본 실시형태의 안과용 조성물에 있어서의 에틸렌디아민사아세트산염류의 농도는, 0.015%(w/v) 이하이고, 바람직하게는 0.01%(w/v) 이하이며, 0.003%(w/v) 이하여도 좋고, 0.001%(w/v) 이하여도 좋다. 또한, 본 실시형태의 안과용 조성물은 에틸렌디아민사아세트산염류를 전혀 함유하지 않아도 좋다.The concentration of ethylenediamine acetic acid salts in the ophthalmic composition of the present embodiment is 0.015% (w / v) or less, preferably 0.01% (w / v) or less and 0.003% Or may be 0.001% (w / v) or less. In addition, the ophthalmic composition of the present embodiment may not contain ethylenediamine acetic acid salts at all.
본 실시형태의 안과용 조성물의 pH는, 하한치로는 5.5가 바람직하고, 6이 보다 바람직하며, 6 초과가 더욱 바람직하고, 상한치로는 8이 바람직하며, 7.5가 보다 바람직하고, 7이 더욱 바람직하다. 이러한 pH의 범위이면, 안과용 조성물에 있어서의 히알루론산 또는 그의 염을 안정화함과 더불어, 안과용의 조성물로서 저자극성인 등 적합하게 이용할 수 있다.The lower limit of the pH of the ophthalmic composition of the present embodiment is preferably 5.5, more preferably 6, more preferably 6, and the upper limit is preferably 8, more preferably 7.5, further preferably 7 Do. When the pH is within this range, hyaluronic acid or a salt thereof in the ophthalmic composition can be stabilized and used as an ophthalmic composition, such as hypoallergenic.
완충제Buffer
본 실시형태의 안과용 조성물은, 상기한 바람직한 범위의 pH로 조정하기 위해서, 완충제를 더 함유하는 것이 바람직하다. 완충제로는, ε-아미노카프론산, 인산나트륨, 인산수소나트륨, 인산이수소나트륨, 아세트산나트륨 등을 들 수 있다. 본 실시형태의 안과용 조성물의 pH를 상기한 바람직한 범위로 조정할 수 있는 것이면, 완충제의 첨가량(농도)은 특별히 한정되지 않는다.The ophthalmic composition of the present embodiment preferably further contains a buffer to adjust the pH to the above-mentioned preferable range. Examples of the buffer include ε-aminocaproic acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate and the like. The addition amount (concentration) of the buffering agent is not particularly limited as long as the pH of the ophthalmic composition of the present embodiment can be adjusted to the above preferable range.
그 밖의 첨가제Other additives
본 실시형태의 안과용 조성물은, 상기한 바람직한 범위의 pH로 조정하기 위해서, pH 조절제를 더 함유하는 것이어도 좋다. pH 조절제로는, 본 실시형태의 안과용 조성물의 pH를 조절할 수 있는 것이면 특별히 한정되지 않지만, 구체예로는, 묽은 염산, 수산화나트륨 등을 들 수 있다. 본 실시형태의 안과용 조성물의 pH를 상기한 바람직한 범위로 조정할 수 있는 것이면, pH 조절제의 첨가량(농도)은 특별히 한정되지 않는다.The ophthalmic composition of the present embodiment may further contain a pH adjusting agent in order to adjust the pH to the above preferable range. The pH adjuster is not particularly limited as long as it can control the pH of the ophthalmic composition of the present embodiment, but specific examples thereof include dilute hydrochloric acid, sodium hydroxide and the like. The addition amount (concentration) of the pH adjusting agent is not particularly limited as far as the pH of the ophthalmic composition of the present embodiment can be adjusted to the preferable range described above.
본 실시형태의 안과용 조성물의 삼투압은, 안과용 조성물로서 허용되는 범위라면 특별히 제한은 없지만, 하한치로서는 0.4가 바람직하고, 0.6이 보다 바람직하며, 0.9 초과가 더욱 바람직하고, 상한치로서는 1.3이 바람직하며, 1.2가 보다 바람직하고, 1.1 이하가 더욱 바람직하다. 본 명세서에 있어서, 삼투압은, 제16 개정 일본 약국방의 삼투압 측정법(오스몰 농도 측정법)에 기재된 방법에 의해 측정되는 값이다.The osmotic pressure of the ophthalmic composition of the present embodiment is not particularly limited as long as it is an acceptable range for the ophthalmic composition. The lower limit of the osmotic pressure is preferably 0.4, more preferably 0.6, still more preferably 0.9 and the upper limit is 1.3 , More preferably 1.2, and even more preferably 1.1 or less. In the present specification, the osmotic pressure is a value measured by the method described in the Osmotic Pressure Measurement Method (Osm concentration measurement method) of the Japanese Pharmacopoeia of the 16th revision.
본 실시형태의 안과용 조성물은, 수성 조성물인 것이 바람직하다. 본 발명에 있어서 「수성 조성물」이란, 물을 기제로 하는 조성물을 의미한다. 본 실시형태의 안과용 조성물은, 수성 조성물로서, 전술한 히알루론산 또는 그의 염, 클로르헥시딘류 및 프로필렌 글리콜을 적어도 함유하는 수용액인 것이 바람직하고, 예컨대 후술하는 점안제로서 점안액으로 할 수 있다.The ophthalmic composition of the present embodiment is preferably an aqueous composition. In the present invention, " aqueous composition " means a composition based on water. The ophthalmic composition of the present embodiment is preferably an aqueous solution containing at least the aforementioned hyaluronic acid or a salt thereof, chlorhexidine and propylene glycol, and may be an eye drop as an eye drop described later, for example.
본 실시형태의 안과용 조성물에는, 필요에 따라 제약학적으로 허용되는 첨가제를 첨가할 수 있다.To the ophthalmic composition of this embodiment, a pharmaceutically acceptable additive may be added as needed.
본 실시형태의 안과용 조성물은, 예컨대 통상적인 방법에 의해 조제할 수 있고, 예컨대, 히알루론산 또는 그의 염, 클로르헥시딘류 및 프로필렌 글리콜, 그리고, 필요에 따라 배합하는 에틸렌디아민사아세트산염류, 완충제, pH 조절제 등을 물에 용해하고, 필요에 따라 pH 조절제를 더 첨가하는 것 등에 의해 pH를 조정하여, 얻을 수 있다.The ophthalmic composition of the present embodiment can be prepared, for example, by a conventional method, and examples thereof include hyaluronic acid or salts thereof, chlorhexidines and propylene glycol, ethylenediamine acetic acid salts, buffers, pH By adjusting the pH by dissolving a pH adjusting agent in water and adding a pH adjusting agent as necessary.
본 실시형태의 안과용 조성물은, 의약용, 콘택트 렌즈용 등의 점안제로서 적합하게 이용할 수 있는 것 외에 콘택트 렌즈용 장착제로서도 이용할 수 있다. 특히 염화벤잘코늄을 함유하지 않는 경우에는, 소프트 콘택트 렌즈용 점안제 또는 장착제로서 적합하게 이용할 수 있다. 의약 용도로는, 예컨대, 드라이아이(안구건조 증후군), 쇼그렌 증후군, 스티븐스·존슨 증후군 등의 내인성 질환에 따른 각결막 상피 장애뿐만 아니라, 수술후, 약제성, 외상, 콘택트 렌즈 착용 등에 의한 외인성 질환에 따른 각결막 상피 장애의 치료에도 이용할 수 있다.The ophthalmic composition of the present embodiment can be suitably used as an eye drop for medicines, contact lenses and the like, and can also be used as a mounting agent for a contact lens. In particular, when it does not contain benzalkonium chloride, it can be suitably used as an eye drop or a mounting agent for a soft contact lens. Examples of medicinal use include not only conjunctival epithelial disorders due to endogenous diseases such as dry eye syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, but also ocular diseases such as post-operative, postoperative, Can be used for the treatment of each conjunctival epithelium disorder.
본 실시형태의 안과용 조성물은, 동점도의 경시 변화를 낮게 억제할 수 있어, 예컨대, 50∼70℃, 대표적으로는 60℃에 있어서, 2주일 동안 정치하는 가혹 시험의 조건 하에 있어서도, 동점도의 경시 변화를 낮게 억제할 수 있다. 구체적으로는, 본 실시형태의 안과용 조성물에 대해서, 예컨대, 60℃로 2주일 동안 정치하기 전과 후에 대해서, 각각 후술하는 동점도 측정 시험에 의해 측정하는 동점도의 유지율의 하한치로는 바람직하게는 70%, 보다 바람직하게는 75%, 더욱 바람직하게는 77%이며, 상한치로는 100%가 바람직하지만, 예컨대, 95%, 90%, 85% 등이어도 상기 용도에 적합하게 이용할 수 있다.The ophthalmic composition of the present embodiment can suppress the change with time in the kinetic viscosity to a low level. Even under the condition of a severe test in which, for example, it is allowed to stand at 50 to 70 캜, typically 60 캜 for two weeks, The change can be suppressed to a low level. Specifically, for the ophthalmic composition of the present embodiment, the lower limit of the retention ratio of the kinetic viscosity measured by the kinetic viscosity measurement test described below is preferably 70% or more, for example, before and after standing at 60 DEG C for two weeks, , More preferably 75%, further preferably 77%, and the upper limit is preferably 100%, but 95%, 90%, 85% or the like can be suitably used for the above applications.
본 실시형태의 안과용 조성물이 이와 같이 동점도가 높은 유지율을 갖는 것은, 그 유효 성분인 히알루론산 또는 그의 염의 안정화, 바람직하게는 장기간에 걸친 안정화를 가능하게 할 수 있었던 것에 의한 것으로 생각된다. 본 실시형태의 안과용 조성물에 있어서의 히알루론산 또는 그의 염의 안정화는, 종래 안과용 조성물의 안정화제로서 널리 배합되어 온 에틸렌디아민사아세트산염류를, 오히려 0.015%(w/v) 이하의 배합 농도로 억제함으로써, 가능하게 할 수 있던 것으로 추찰된다.The reason why the ophthalmic composition of the present embodiment has such a high retention rate as the kinetic viscosity is believed to be that stabilization of hyaluronic acid or a salt thereof, which is an effective ingredient thereof, preferably stabilizes over a long period of time. The stabilization of hyaluronic acid or a salt thereof in the ophthalmic composition of the present embodiment can be achieved by mixing the ethylenediamine acetic acid salt, which has been widely compounded as a stabilizer for conventional ophthalmic compositions, at a concentration of 0.015% (w / v) By suppressing it, it is presumed that it could be made possible.
본 실시형태의 안과용 조성물은, 배합하는 클로르헥시딘류에 의해, 우수한 방부 효과를 유지할 수 있다. 구체적으로는, 본 실시형태의 안과용 조성물에 대해서, 후술하는 보존 효력 시험에 의해 측정하는 보존 효력(본 명세서에 있어서, 「방부력」이라고도 함)은, 이 콜라이(E. coli), 피. 애루기노사(P. aeruginosa), 또는 에스. 아우레우스(S. aureus)에 대해서는, 보존 2주일 또는 4주일에서 3.0 이상이고, 씨. 알비칸스(C. albicans), 또는 에이. 브라실리엔시스(A. brasiliensis)에 대해서는, 보존 2주일 또는 4주일에서 균이 증가하지 않는 것이다.The ophthalmic composition of the present embodiment can maintain an excellent preservative effect by the blending of chlorhexidine. Concretely, the preservative effect (also referred to as " repellency " in the present specification) of the ophthalmic composition of this embodiment measured by the preservation strength test described later can be measured in E. coli , P. aeruginosa , or S. For S. aureus , it is 3.0 or more in two weeks or four weeks of storage; Albicans (C. albicans), or A. For A. brasiliensis , the bacteria do not increase in two or four weeks of storage.
본 발명의 안과용 조성물은, 상기한 바와 같이 동점도의 유지율이 높아, 방부력 내지 보존 효력을 더욱 높게 유지할 수 있기 때문에, 안과용 조성물로서, 예컨대 멀티도우즈형의 안과용 조성물로서도, 전술의 의약용, 콘택트 렌즈용 등의 각 용도에 필요로 되는 약효 등의 효과를 안정되게 발휘할 수 있다.As described above, the ophthalmic composition of the present invention has a high retentivity at the kinematic viscosity and can maintain the ophthalmic composition at a higher level, so that it can be used as an ophthalmic composition, for example, as a multi- It is possible to stably exhibit effects such as the effect of medicines required for each application such as for use in contact lenses and the like.
히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물(이하, 본 명세서에 있어서 「대상 안과 조성물」이라고 하는 경우가 있음)에, 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 함유시킴으로써, 대상 안과 조성물의 동점도의 경시 변화를 억제할 수 있고, 또한, 대상 안과 조성물의 방부력 또는 보존 효력을 높게 유지할 수 있으며, 또한, 대상 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지할 수도 있다.By containing propylene glycol and ethylenediamine acetic acid salts in an ophthalmic composition containing hyaluronic acid or its salt and chlorhexidines (hereinafter referred to as " target ophthalmic composition " in the present specification), the kinetic viscosity It is possible to suppress the change with time of the target ophthalmic composition and to maintain the retention force or preservation effect of the target ophthalmic composition at a high level and also to suppress the change with time of the kinetic viscosity of the target ophthalmic composition and to maintain the retention force or preservation effect have.
이와 같이 대상 안과 조성물의 동점도의 경시 변화를 억제하는 방법, 대상 안과 조성물의 방부력 또는 보존 효력을 높게 유지하는 방법, 또한, 대상 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지하는 방법도 또한, 본 발명의 하나이다.Thus, it is possible to suppress the change of the kinetic viscosity of the target ophthalmic composition over time, to maintain the repelling force or preservation effect of the target ophthalmic composition, and to suppress the change of the kinetic viscosity of the ophthalmic composition with time, Is also one of the present invention.
이들 각 방법은, 대상 안과 조성물에 프로필렌 글리콜과 에틸렌디아민사아세트산염류를 첨가한 경우에 있어서의 대상 안과 조성물과, 프로필렌 글리콜과 에틸렌디아민사아세트산염류와의 합계의 0.03∼1.5%(w/v)가 되는 농도로 프로필렌 글리콜을 함유시키고, 또한, 상기 합계의 0.015%(w/v) 이하가 되는 농도로 에틸렌디아민사아세트산염류를 함유시키는 것이 바람직하다.Each of these methods is characterized in that 0.03 to 1.5% (w / v) of the total amount of the target ophthalmic composition in the case of adding propylene glycol and ethylenediamine acetic acid to the target ophthalmic composition and propylene glycol and ethylenediamine acetic acid, By weight, and further containing ethylenediamine acetic acid salts at a concentration of 0.015% (w / v) or less of the total amount of the propylene glycol.
프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 조성물은, 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물(대상 안과 조성물)의 동점도의 경시 변화를 억제하기 위해서 이용할 수 있고, 또한, 대상 안과 조성물의 방부력 또는 보존 효력을 높게 유지하기 위해서 이용할 수 있으며, 또한, 대상 안과 조성물의 동점도의 경시 변화를 억제하고, 또한 방부력 또는 보존 효력을 높게 유지하기 위해서 이용할 수도 있다. 상기한 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 조성물은, 상기 조성물과, 상기 조성물을 첨가하는 대상 안과 조성물의 합계에 있어서, 0.03∼1.5%(w/v)의 프로필렌 글리콜 및 0.015%(w/v) 이하의 에틸렌디아민사아세트산염류를 함유하게 되는 조성물인 것이 바람직하다.Propylene glycol and ethylenediamine acetic acid salts can be used for suppressing the temporal change in kinetic viscosity of an ophthalmic composition (target ophthalmic composition) containing hyaluronic acid or a salt thereof and chlorhexidine, and further, Or the preservation effect of the ophthalmic composition of the present invention can be used to keep the buoyant force or the preservation effect of the ophthalmic composition at a high level. The above-mentioned composition containing propylene glycol and ethylenediamine acetic acid salts preferably contains 0.03 to 1.5% (w / v) of propylene glycol and 0.015% (w / v) of the total amount of the composition and the ophthalmic composition to which the composition is added / v) or less of ethylene diamine acetic acid salts.
프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 조성물은, 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는 안과 조성물(대상 안과 조성물)의 동점도의 경시 변화의 억제제로서, 또한, 히알루론산 또는 그의 염 및 클로르헥시딘류를 함유하는, 안과 조성물의 방부력 또는 보존 효력을 높게 유지하는 방부제 또는 보존제로서, 기능할 수 있다.Propylene glycol and ethylenediamine acetic acid salts are used as an inhibitor of changes in the kinetic viscosity of the ophthalmic composition (target ophthalmic composition) containing hyaluronic acid or a salt thereof and chlorhexidines, and also hyaluronic acid or a salt thereof and chlorhexidine As an antiseptic or preservative, which maintains high repellency or preservation efficacy of the ophthalmic composition.
이러한, 프로필렌 글리콜 및 에틸렌디아민사아세트산염류를 함유하는 억제제 및 방부제 혹은 보존제도 또한, 본 발명의 하나이다.Such inhibitors containing propylene glycol and ethylenediamine acetic acid salts and preservatives or preservative systems are also one of the present invention.
상기한 억제제 및 방부제 혹은 보존제는, 각각을 대상 안과 조성물에 첨가한 경우에 있어서의 억제제 또는 방부제 혹은 보존제와 대상 안과 조성물과의 합계의 0.03∼1.5%(w/v)가 되는 농도로 프로필렌 글리콜을 함유하고, 또한, 상기 합계의 0.015%(w/v) 이하가 되는 농도로 에틸렌디아민사아세트산염류를 함유하는 것이 바람직하다.The inhibitor, preservative or preservative may be propylene glycol at a concentration which is 0.03 to 1.5% (w / v) of the total amount of the inhibitor or preservative or the preservative and the ophthalmic composition of the target ophthalmic composition, , And further contains ethylenediamine acetic acid salts at a concentration of 0.015% (w / v) or less of the total amount.
실시예Example
본 발명의 안과용 조성물의 일 실시양태로서 점안액에 대해서, 이하에 처방예 및 시료 조제예를 들어 더욱 구체적으로 설명하였으나, 본 발명은 이들의 처방예 및 시료 조제예에만 한정되는 것은 아니다.The eye drops as an embodiment of the ophthalmic composition of the present invention are described in detail below with reference to the prescription examples and sample preparation examples. However, the present invention is not limited to these prescription examples and sample preparation examples.
[처방예][Prescription Example]
처방예 1Prescription Example 1
점안제(0.3%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.3% (w / v))
히알루론산나트륨 0.3 gSodium hyaluronate 0.3 g
클로르헥시딘글루콘산염 0.005 gChlorhexidine gluconate 0.005 g
인산수소이나트륨 0.2 gDisodium hydrogenphosphate 0.2 g
인산이수소나트륨 0.04 gSodium dihydrogenphosphate 0.04 g
염화나트륨 0.6 gSodium chloride 0.6 g
프로필렌 글리콜 0.4 gPropylene glycol 0.4 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.3%(w/v) 히알루론산나트륨 점안액을 조제할 수 있다.0.3% (w / v) sodium hyaluronate eye drops can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them.
처방예 2Prescription Example 2
점안제(0.1%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.1% (w / v))
히알루론산나트륨 0.1 gSodium hyaluronate 0.1 g
클로르헥시딘글루콘산염 0.002 gChlorhexidine gluconate 0.002 g
인산수소이나트륨 0.2 gDisodium hydrogenphosphate 0.2 g
인산이수소나트륨 0.04 gSodium dihydrogenphosphate 0.04 g
염화나트륨 0.5 gSodium chloride 0.5 g
프로필렌 글리콜 0.75 gPropylene glycol 0.75 g
에데트산나트륨 수화물 0.001 gSodium edetate hydrate 0.001 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.1%(w/v) 히알루론산나트륨 점안액을 조제할 수 있다.0.1% (w / v) sodium hyaluronate eye drops can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them.
처방예 3Prescription Example 3
점안제(0.3%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.3% (w / v))
히알루론산나트륨 0.3 gSodium hyaluronate 0.3 g
클로르헥시딘글루콘산염 0.001 gChlorhexidine gluconate 0.001 g
ε-아미노카프론산 0.2 g? -aminocaproic acid 0.2 g
염화나트륨 0.6 gSodium chloride 0.6 g
프로필렌 글리콜 0.5 gPropylene glycol 0.5 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.3%(w/v) 히알루론산나트륨 점안액을 조제할 수 있다.0.3% (w / v) sodium hyaluronate eye drops can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them.
처방예 4Prescription Example 4
점안제(0.2%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.2% (w / v))
히알루론산나트륨 0.2 gSodium hyaluronate 0.2 g
클로르헥시딘글루콘산염 0.0025 gChlorhexidine gluconate 0.0025 g
ε-아미노카프론산 0.2 g? -aminocaproic acid 0.2 g
염화나트륨 0.7 gSodium chloride 0.7 g
프로필렌 글리콜 0.25 gPropylene glycol 0.25 g
에데트산나트륨 수화물 0.002 gSodium edetate hydrate 0.002 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.2%(w/v) 히알루론산나트륨 점안액을 조제할 수 있다.A 0.2% (w / v) sodium hyaluronate ophthalmic solution can be prepared by adding sodium hyaluronate and other components to sterile purified water and sufficiently mixing them.
처방예 5Prescription Example 5
점안제(0.005%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.005% (w / v))
히알루론산나트륨 0.005 gSodium hyaluronate 0.005 g
클로르헥시딘글루콘산염 0.001 gChlorhexidine gluconate 0.001 g
ε-아미노카프론산 0.1 g? -aminocaproic acid 0.1 g
염화나트륨 0.7 gSodium chloride 0.7 g
프로필렌 글리콜 0.3 gPropylene glycol 0.3 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.005%(w/v) 히알루론산나트륨 점안액을 조제할 수 있지만, 다른 유효 성분을 더 함유하여도 좋다.A 0.005% (w / v) sodium hyaluronate ophthalmic solution can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them, but may further contain other active ingredients.
처방예 6Prescription Example 6
점안제(0.05%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.05% (w / v))
히알루론산나트륨 0.05 gSodium hyaluronate 0.05 g
클로르헥시딘글루콘산염 0.001 gChlorhexidine gluconate 0.001 g
ε-아미노카프론산 0.1 g? -aminocaproic acid 0.1 g
염화나트륨 0.7 gSodium chloride 0.7 g
프로필렌 글리콜 0.3 gPropylene glycol 0.3 g
에데트산나트륨 수화물 0.015 gSodium edetate hydrate 0.015 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.05%(w/v) 히알루론산나트륨 점안액을 조제할 수 있지만, 다른 유효 성분을 더 함유하여도 좋다.Sodium hyaluronate and other components may be added to the sterile purified water, and they may be thoroughly mixed to prepare an eye drop of 0.05% (w / v) sodium hyaluronate. However, other active ingredients may be further contained.
처방예 7Prescription Example 7
점안제(0.1%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.1% (w / v))
히알루론산나트륨 0.1 gSodium hyaluronate 0.1 g
클로르헥시딘글루콘산염 0.001 gChlorhexidine gluconate 0.001 g
ε-아미노카프론산 0.1 g? -aminocaproic acid 0.1 g
염화나트륨 0.7 gSodium chloride 0.7 g
프로필렌 글리콜 0.3 gPropylene glycol 0.3 g
에데트산나트륨 수화물 0.01 gSodium edetate hydrate 0.01 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.1%(w/v) 히알루론산나트륨 점안액을 조제할 수 있지만, 다른 유효 성분을 더 함유하여도 좋다.A 0.1% (w / v) sodium hyaluronate ophthalmic solution can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them, but may further contain other active ingredients.
처방예 8Prescription Example 8
점안제(0.3%(w/v)) 100 ㎖ 중In 100 ml of eye drops (0.3% (w / v))
히알루론산나트륨 0.3 gSodium hyaluronate 0.3 g
클로르헥시딘글루콘산염 0.001 gChlorhexidine gluconate 0.001 g
ε-아미노카프론산 0.1 g? -aminocaproic acid 0.1 g
염화나트륨 0.7 gSodium chloride 0.7 g
프로필렌 글리콜 0.3 gPropylene glycol 0.3 g
에데트산나트륨 수화물 0.015 gSodium edetate hydrate 0.015 g
묽은 염산 적량Diluted hydrochloric acid Suitable amount
수산화나트륨 적량Sodium hydroxide Suitable amount
멸균 정제수 적량Sterile purified water Suitable amount
멸균 정제수에 히알루론산나트륨 및 그 이외의 상기 성분을 첨가하고, 이들을 충분히 혼합함으로써, 0.3%(w/v) 히알루론산나트륨 점안액을 조제할 수 있지만, 다른 유효 성분을 더 함유하여도 좋다.0.3% (w / v) sodium hyaluronate eye drops can be prepared by adding sodium hyaluronate and other components described above to sterile purified water and sufficiently mixing them, but they may further contain other active ingredients.
[시료 조제예][Sample Preparation Example]
실시예 1∼3Examples 1-3
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.005 g, 프로필렌 글리콜 0.25 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 6.5으로 한 것을 실시예 1, pH 7.0으로 한 것을 실시예 2, pH 7.5로 한 것을 실시예 3으로 하였다.0.3 g of sodium hyaluronate, 0.005 g of chlorhexidine gluconate, 0.25 g of propylene glycol, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in water to obtain 100 ml of eye drops. Example 2 was prepared by adding dilute hydrochloric acid and / or sodium hydroxide to the resulting ophthalmic solution to adjust the pH to 6.5.
실시예 4∼6Examples 4 to 6
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.005 g, 프로필렌 글리콜 0.25 g, 에데트산나트륨 수화물 0.001 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 6.5로 한 것을 실시예 4, pH 7.0으로 한 것을 실시예 5, pH 7.5로 한 것을 실시예 6으로 하였다.0.3 g of sodium hyaluronate, 0.005 g of chlorhexidine gluconate, 0.25 g of propylene glycol, 0.001 g of sodium edetate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in 100 ml of an eye drop ≪ / RTI > Example 6 was prepared by adding diluted hydrochloric acid and / or sodium hydroxide to the resulting ophthalmic solution to adjust pH to 6.5, and Example 5 to pH 7.0.
실시예 7∼9Examples 7 to 9
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.0008 g, 프로필렌 글리콜 0.25 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 6.5로 한 것을 실시예 7, pH 7.0으로 한 것을 실시예 8, pH 7.5로 한 것을 실시예 9로 하였다.0.3 g of sodium hyaluronate, 0.0008 g of chlorhexidine gluconate, 0.25 g of propylene glycol, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in water to obtain 100 ml of an eye drop. The ophthalmic solution prepared in Example 7 and pH 7.0 was diluted with diluted hydrochloric acid and / or sodium hydroxide to pH 6.5, and adjusted to Example 8 and pH 7.5, respectively.
실시예 10∼12Examples 10 to 12
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.0008 g, 프로필렌 글리콜 0.25 g, 에데트산나트륨 수화물 0.001 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 6.5로 한 것을 실시예 10, pH 7.0으로 한 것을 실시예 11, pH 7.5로 한 것을 실시예 12로 하였다.0.3 g of sodium hyaluronate, 0.0008 g of chlorhexidine gluconate, 0.25 g of propylene glycol, 0.001 g of sodium edetate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in 100 ml of an eye drop ≪ / RTI > Example 12 was prepared by adding diluted hydrochloric acid and / or sodium hydroxide to the resulting ophthalmic solution to give a pH of 6.5.
비교예 1∼3Comparative Examples 1 to 3
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.005 g, 에데트산나트륨 수화물 0.1 g, 염화칼륨 0.15 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 6.5로 한 것을 비교예 1, pH 7.0으로 한 것을 비교예 2, pH 7.5로 한 것을 비교예 3으로 하였다.0.3 g of sodium hyaluronate, 0.005 g of chlorhexidine gluconate, 0.1 g of sodium edetate, 0.1 g of potassium chloride 0.15 g of sodium chloride, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in water to obtain 100 ml of an eye drop. Comparative Example 3 in which diluted hydrochloric acid and / or sodium hydroxide were added to this eye liquid to adjust the pH to 6.5 was compared with Comparative Example 2, and pH 7.5 was set to Comparative Example 3.
비교예 4Comparative Example 4
히알루론산나트륨 0.3 g, 클로르헥시딘글루콘산염 0.005 g, 프로필렌 글리콜 0.25 g, 에데트산나트륨 수화물 0.1 g, 염화나트륨 0.7 g, 인산수소이나트륨 0.2 g 및 인산이수소나트륨 0.04 g을 물에 용해하여 100 ㎖의 점안액을 얻었다. 이 점안액에, 묽은 염산 및/또는 수산화나트륨을 첨가하여 pH 7.5로 한 것을 비교예 4로 하였다.0.3 g of sodium hyaluronate, 0.005 g of chlorhexidine gluconate, 0.25 g of propylene glycol, 0.1 g of sodium edetate hydrate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogenphosphate and 0.04 g of dihydrogenphosphate were dissolved in 100 ml of an eye drop ≪ / RTI > Diluted hydrochloric acid and / or sodium hydroxide was added to this eye drop to adjust the pH to 7.5.
<시험 방법><Test Method>
실시예 1∼12 및 비교예 1∼4에 있어서 조제한 각 히알루론산 함유 점안액에 대해서, 이하와 같이 시험을 행하였다.Each of the hyaluronic acid-containing eye drops prepared in Examples 1 to 12 and Comparative Examples 1 to 4 was subjected to the following test.
[동점도 측정 시험][Test for measuring kinetic viscosity]
「제16 개정 일본 약국방 일반 시험법 점도 측정법 제1법 모세관 점도계법」에 따라, 측정 온도 30℃에 있어서의 동점도를 측정함으로써 동점도 측정 시험을 행하여, 각 점안액의 동점도 안정화 효과를 확인하였다.The kinematic viscosity measurement test was carried out by measuring the kinematic viscosity at a measurement temperature of 30 캜 according to " 16th Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 1 Method Capillary Viscometer Method ", and the effect of stabilizing the viscosity of each of the eye drops was confirmed.
결과를 표 1∼3에 나타낸다. 또한, 표 1∼3 중의 각 배합 성분의 단위는 %(w/v)이고, 각 점안액의 동점도의 단위는 mm2/s이며, 동점도의 유지율의 단위는 %이다.The results are shown in Tables 1 to 3. The unit of each compounding ingredient in Tables 1 to 3 is% (w / v), the unit of kinetic viscosity of each eye liquid is mm 2 / s, and the unit of retention rate of kinetic viscosity is%.
[보존 효력 시험][Conservation Effectiveness Test]
실시예 7∼12에 있어서 조제한 각 히알루론산 함유 점안액에 대해서, 프로필렌 글리콜이 히알루론산 점안액의 보존 효력에 부여하는 영향을 확인하기 위해서, 보존 효력 시험을 행하였다.For each of the hyaluronic acid-containing eye drops prepared in Examples 7 to 12, a preservation effect test was carried out in order to confirm the influence of propylene glycol on the preservative effect of hyaluronic acid eye drops.
보존 효력 시험은, 제16 개정 일본 약국방(이하, 단순히 「일본 약국방」이라고도 함)의 보존 효력 시험법에 준거하여 행하였다. 본 시험에서는, 시험균으로서, 에쉐리키아 콜라이(E. coli; 표 2 중 「EC」), 슈도모나스 애루기노사(P. aeruginosa; 표 2 중 「PA」), 스타필로코커스 아우레우스(S. aureus; 표 2 중 「SA」), 칸디다 알비칸스(C. albicans; 표 2 중 「CA」) 및 아스페르길루스 브라실리엔시스(A. niger; 표 2 중 「AB」)를 이용하였다.The preservation efficacy test was conducted in accordance with the preservation efficacy test method of the 16th Japanese Pharmacopoeia (hereinafter referred to simply as " Japanese Pharmacopoeia "). In this test, as a test bacterium, the Sherry Escherichia coli (E. coli; Table 2 of "EC"), Pseudomonas Ke rugi labor (P. aeruginosa; "PA" in Table 2), Staphylococcus aureus (S . aureus; was used as the "AB" in Table 2); "SA"), Candida albicans (C. albicans in Table 2; "CA" in Table 2) and Aspergillus Bra Sicily N-Sys (A. niger.
결과를 표 2에 나타낸다. 표 2 중, 「ND」는 균이 검출되지 않은 것을 나타낸다.The results are shown in Table 2. In Table 2, " ND " indicates that no bacteria were detected.
(고찰)(Review)
표 1∼2에 나타낸 바와 같이, 클로르헥시딘류 함유 히알루론산 점안액에 있어서, 프로필렌 글리콜을 배합하고, 또한, 0.015%(w/v) 이하, 구체적으로는 0.001%(w/v) 이하의 에데트산나트륨 수화물을 배합하는 경우에는, 60℃, 2주일 보존 후의 동점도 유지율은 모두 77.0% 이상이었다.As shown in Tables 1 and 2, propyleneglycol was blended in the hyaluronic acid drop-wise solution containing chlorhexidines and 0.015% (w / v) or less, specifically 0.001% (w / v) or less of sodium edetate In the case of mixing the hydrate, the kinematic viscosity retention after storage at 60 ° C for two weeks was at least 77.0%.
이것에 대하여, 표 3에 나타낸 바와 같이, 프로필렌 글리콜을 배합하지 않는 경우, 또는 0.1%(w/v)의 에데트산나트륨 수화물을 배합하는 경우에는, 60℃, 2주일 보존 후의 동점도 유지율은 모두 69.7% 이하였다.On the other hand, as shown in Table 3, when propylene glycol was not blended or 0.1% (w / v) sodium edetate hydrate was blended, the kinematic viscosity retention after storage at 60 ° C for two weeks was 69.7 %.
따라서, 클로르헥시딘류 함유 히알루론산 점안액에 있어서, 프로필렌 글리콜을 함유하고, 또한, 에데트산염류의 배합 농도가 0.015%(w/v) 이하인 경우(에데트산염류를 함유하지 않는 경우도 포함함), 프로필렌 글리콜을 함유하지 않는 경우 또는 프로필렌 글리콜을 함유하지만 에데트산나트륨 수화물을 0.1%(w/v) 이상 배합하는 경우에 비하여, 상기 점안액의 동점도 안정성을 개선하는 효과를 갖는다.Therefore, in the case of the propylene glycol-containing hyaluronic acid drop-wise solution containing chlorhexidines, and when the compounding concentration of the edetate salt is 0.015% (w / v) or less (including the case of not containing edetic acid salts) Has an effect of improving the stability of the viscosity of the eye drop as compared with the case of not containing glycol or containing 0.1% (w / v) of propyleneglycol but containing sodium edetate hydrate.
또한, 표 2에 나타낸 바와 같이, 클로르헥시딘류 함유 히알루론산 점안액에 있어서, 프로필렌 글리콜을 배합하고, 또한, 0.015%(w/v) 이하, 구체적으로는 0.001%(w/v) 이하의 에데트산나트륨 수화물을 배합하는 경우에는, 보존 효력은, 이 콜라이, 피. 애루기노사에 대해서는 보존 1주일 이후에서 ND, 에스, 아우레우스에 대해서는 보존 1주일 이후에서 2.6 이상, 2주일 이후에서 ND, 씨. 알비칸스에 대해서는 보존 1주일에서 3.8 이상, 2주일 이후에서 ND, 에이. 브라실리엔시스에 대해서는 모두 0.0 이상에서 분명한 증가는 확인되지 않았다.As shown in Table 2, propylene glycol was blended in the hyaluronic acid drop-wise solution containing chlorhexidines and 0.015% (w / v) or less, specifically 0.001% (w / v) or less of sodium edetate In the case of compounding the hydrate, the preserving effect can be obtained by the following method. For the birds, ND, S, and Aureus after one week of preservation, 2.6 or more after one week of preservation, ND, after two weeks after conservation. For albinans, the preservation was 3.8 days or more in one week, ND, in two weeks or later. For brassicensis, a clear increase of 0.0 or more was not observed.
따라서, 클로르헥시딘류 함유 히알루론산 점안액에 있어서, 프로필렌 글리콜을 함유하고, 또한, 에데트산염류의 배합 농도가 0.015%(w/v) 이하인 경우에는, 상기 점안액의 보존 효력을 높게 유지하는 효과를 갖는다. 이에 따라, 클로르헥시딘류 함유 히알루론산 점안액에 있어서, 프로필렌 글리콜이 히알루론산 점안액의 보존 효력에 부여하는 영향은 실질적으로 없거나 또는 무시할 수 있을 정도인 것이 확인되었다.Therefore, when the compound concentration of propyleneglycol in the hyaluronic acid-containing eye drop containing chlorhexidines is 0.015% (w / v) or less, the preservation effect of the eye drops is kept high. Thus, it was confirmed that the effect of propylene glycol on the preservative effect of the hyaluronic acid eye drop in the hyaluronic acid-containing liquid containing chlorhexidines was substantially absent or negligible.
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