KR101363776B1 - Transparent eye drops composition comprising cyclosporin - Google Patents
Transparent eye drops composition comprising cyclosporin Download PDFInfo
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- KR101363776B1 KR101363776B1 KR1020120151295A KR20120151295A KR101363776B1 KR 101363776 B1 KR101363776 B1 KR 101363776B1 KR 1020120151295 A KR1020120151295 A KR 1020120151295A KR 20120151295 A KR20120151295 A KR 20120151295A KR 101363776 B1 KR101363776 B1 KR 101363776B1
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 68
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 67
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- 229930182912 cyclosporin Natural products 0.000 title claims abstract description 67
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- 229930105110 Cyclosporin A Natural products 0.000 title claims abstract description 33
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- 229940068918 polyethylene glycol 400 Drugs 0.000 claims abstract description 28
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- 206010013774 Dry eye Diseases 0.000 claims abstract description 15
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- 229920002675 Polyoxyl Polymers 0.000 claims description 15
- 239000004359 castor oil Substances 0.000 claims description 15
- 235000019438 castor oil Nutrition 0.000 claims description 15
- 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 claims description 15
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 13
- 229940068968 polysorbate 80 Drugs 0.000 claims description 13
- 229920000053 polysorbate 80 Polymers 0.000 claims description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 3
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- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
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- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
본 발명은 외관상 투명하고 눈에 이물감 및 자극이 없어, 안구건조증의 예방 또는 치료에 유용하게 사용할 수 있는 사이클로스포린, 폴리에틸렌글리콜400 및 계면활성제를 포함하는 사이클로스포린 투명 점안액 조성물을 제공한다.The present invention provides a cyclosporin clear eye drop composition comprising cyclosporin, polyethylene glycol 400 and a surfactant that can be usefully used for the prevention or treatment of dry eye due to its transparent appearance and no foreign body sensation and irritation.
Description
본 발명은 사이클로스포린을 포함하는 투명 점안액 조성물 및 이를 포함하는 안구건조증의 예방 또는 치료용 약학적 조성물에 관한 것으로, 더 자세하게는 사이클로스포린, 폴리에틸렌글리콜400 및 계면활성제로 구성되는 투명 점안액 조성물 및 이를 포함하는 안구건조증의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to a transparent eye drop composition comprising cyclosporin and a pharmaceutical composition for preventing or treating dry eye syndrome including the same, and more particularly, to a transparent eye drop composition comprising cyclosporin, polyethylene glycol 400 and a surfactant, and an eye including the same. It relates to a pharmaceutical composition for preventing or treating dryness.
안구건조증은 임상에서 가장 흔하게 접할 수 있는 질환 중의 하나로서, 눈물삼투압의 증가와 안구 표면의 염증에 동반된 안구의 불편감, 시력장애, 눈물층의 불안정이 나타나는 다요인성 질환으로 알려져 있다. 치료적 접근은 수성층 눈물을 보충하던 단계에서, 누액을 분비시켜 눈물층을 유지하는 쪽으로 관심이 전환되었고, 최근에는 면역반응 및 염증반응에 사이클로스포린 점안액이 사용되고 있다.
Dry eye syndrome is one of the most commonly encountered diseases in clinical practice. It is known to be a multifactorial disease with increased tear osmolarity, ocular discomfort accompanied by ocular surface inflammation, visual disturbance, and tear layer instability. The therapeutic approach has shifted attention to preserving the tear layer by releasing leukocytes at the stage of supplementing the aqueous layer of tears. Recently, cyclosporine eye drops have been used for immune and inflammatory responses.
자가면역증에 의한 안구건조증의 발생은 자가면역반응에 의해 활성화된 T림프구가 안구 표면과 주눈물샘에 침윤하여 전염증성 사이토카인을 다량분비하고, 이러한 염증반응은 만성적인 경과를 거치며 눈물샘이나 안구표면의 상피세포들에 손상을 주어 발생한다.
The development of dry eye syndrome due to autoimmunity is caused by the infiltration of T lymphocytes activated by autoimmune reaction into the ocular surface and the main lacrimal gland, releasing a large amount of proinflammatory cytokines. Such inflammatory reactions are chronic progression, Of the epithelial cells.
사이클로스포린은 11개의 아미노산으로 이루어진 고분자 펩타이드 약물(분자량 1202)로서 T-세포의 성장과 분화를 억제함으로서 강력한 면역억제 활성을 나타내는 약물로서, 안구건조증에 효능이 있는 약물이다.
Cyclosporine is a polymer peptide drug (molecular weight 1202) consisting of 11 amino acids, which inhibits the growth and differentiation of T-cells and thus has strong immunosuppressive activity. It is a drug effective for dry eye syndrome.
그러나, 사이클로스포린은 물에 불용성이므로, 일반적으로 현탁된 형태로 이용하고 있지만, 점안제로 사용하기 위해서는 투명한 수용액상으로 제공하는 것이 바람직하고, 현탁액 형태의 제형은 제조시 전수검사를 하는 무균제제의 점안액에서 전수검사의 어려움이 있고, 또한 눈에 불쾌감을 초래한다. 따라서 투명한 용액 조성물은 눈에 투여하기 위한 가장 바람직한 제형이다.
However, since cyclosporine is insoluble in water, it is generally used in a suspended form. However, it is preferable to provide a clear aqueous liquid form for use as an eye drop. In the case of a suspension type formulation, There is a difficulty in thorough examination, and it also causes discomfort to the eyes. Thus, a clear solution composition is the most desirable formulation for administration to the eye.
이에 본 발명자는 눈에 사용하기에 적합한 사이클로스포린 점안액을 연구하던 중, 폴리에틸렌글리콜400과 계면활성제를 사용할 경우 투명하고 눈에 자극이 적은 사이클로스포린 투명 점안액을 제조할 수 있음을 확인하여, 본 발명을 완성하였다.
[선행기술문헌 정보]
1. 대한민국 공개특허번호 제10-2012-0022574호 (2012.03.12.)
2. 대한민국 등록특허번호 제10-1211902호 (2012.12.06.)
3. 대한민국 공개특허번호 제10-2001-0112315호 (2001.12.20.)
4. 일본 공개특허공보 특개평 05-58906호 (1993.03.09.)
Accordingly, the present inventors completed the present invention by studying cyclosporin eye drops suitable for use in the eye, and when using polyethylene glycol 400 and a surfactant, it was possible to prepare a transparent and eye irritation cyclosporine transparent eye drop. .
[Prior Art Literature Information]
1. Republic of Korea Patent Publication No. 10-2012-0022574 (2012.03.12.)
2. Republic of Korea Patent No. 10-1211902 (2012.12.06.)
3. Republic of Korea Patent Publication No. 10-2001-0112315 (2001.12.20.)
4. Japanese Patent Laid-Open No. 05-58906 (1993.03.09.)
본 발명은 외관상 투명하고 눈에 이물감 및 자극이 없어, 안구건조증의 예방 또는 치료에 유용하게 사용할 수 있는 사이클로스포린을 포함하는 투명 점안액 조성물을 제공하기 위한 것이다.The present invention provides a transparent ophthalmic solution composition containing cyclosporin, which is apparently transparent, free of foreign objects and irritation, and useful for preventing or treating dry eye syndrome.
또한, 본 발명은 상기 투명 점안액 조성물의 제조방법을 제공하기 위한 것이다.
The present invention also provides a method for producing the transparent ophthalmic solution composition.
상기 과제를 해결하고자, 본 발명은 사이클로스포린 1 중량부, 폴리에틸렌글리콜400 50 내지 200 중량부, 폴리옥실40경화피마자유 5 내지 20 중량부, 폴리소르베이트80 2 내지 10 중량부 및 물로 구성된 조성물; 또는 사이클로스포린 1 중량부, 폴리에틸렌글리콜400 20 내지 50 중량부, 폴리옥실40경화피마자유 5 내지 20 중량부, 폴리소르베이트80 2 내지 10 중량부, 프로필렌글리콜 20 내지 40 중량부 및 물로 구성되는 조성물을 포함하는 투명 점안액 조성물을 제공한다.
To solve the above problems, the present invention is a composition consisting of 1 part by weight of cyclosporin, 50 to 200 parts by weight of polyethylene glycol 400, 5 to 20 parts by weight of polyoxyl 40 hardened castor oil, 2 to 10 parts by weight of polysorbate 80 and water; Or 1 part by weight of cyclosporine, 20 to 50 parts by weight of polyethylene glycol 400, 5 to 20 parts by weight of polyoxyl 40 hardened castor oil, 2 to 10 parts by weight of polysorbate 80, 20 to 40 parts by weight of propylene glycol and water It provides a transparent eye drop composition comprising.
본 발명에서 사용되는 용어 '사이클로스포린'은, 11 개의 아미노산으로 이루어진 고분자 펩타이드 약물(분자량 1202)로서 T-세포의 성장과 분화를 억제함으로서 강력한 면역억제 활성을 나타내는 약물을 의미한다. 상기 사이클로스포린은 임상적으로 신장, 간, 심장, 골수, 췌장, 피부, 각막 등의 장기 및 조직의 이식후에 피이식자에게서 일어나는 면역거부반응을 억제하기 위한 목적으로 사용되며, 자가면역반응억제 같은 염증성 질환에 적용되어 왔다. 특히, 본 발명에서는 안구건조증의 예방 또는 치료를 위하여 사용된다.
The term " cyclosporin " used in the present invention refers to a drug that has a strong immunosuppressive activity by inhibiting the growth and differentiation of T-cells as a polymer peptide drug (molecular weight 1202) consisting of 11 amino acids. The cyclosporine is clinically used for the purpose of inhibiting the immune rejection reaction occurring in the graft recipient after transplantation of organs such as the kidney, liver, heart, bone marrow, pancreas, skin, cornea and tissue, Have been applied to diseases. In particular, the present invention is used for prevention or treatment of dry eye syndrome.
사이클로스포린은 물에 불용성이기 때문에, 일반적으로 현탁된 형태로 사용되고 있다. 그러나, 점안제의 용도로 사용하는 경우에는 현탁액이 눈에 이물감을 주어 환자가 사용하기에 불편하고, 현탁액 형태의 제형은 제조시 전수검사를 하는 무균제제의 점안액에서 전수검사의 어려움이 있다. 이에 본 발명은 폴리에틸렌글리콜400과 계면활성제를 첨가하여 사이클로스포린의 투명 점안액 조성물을 제공한다.
Cyclosporine is generally used in suspended form because it is insoluble in water. However, when it is used for eyedrops, it is difficult for the patient to use the suspension because the suspension gives a foreign body to the eyes. In the case of the suspension type formulation, it is difficult to perform complete examination in the eye drop of the aseptic preparation which is subjected to the complete examination at the time of manufacture. Accordingly, the present invention provides a transparent eye drop composition of cyclosporin by adding polyethylene glycol 400 and a surfactant.
본 발명에서 사용되는 용어 '폴리에틸렌글리콜400'은, 산화에틸렌과 물의 부가중합체로 HOCH2 (CH2OCH2)nCH2OH로 나타내며 n은 7 ~ 9이다. 폴리에틸렌글리콜400은 본 발명에서 점도조절제로 사용되는 것으로, 계면활성제와 함께 사이클로스포린의 투명 점안액 조성물을 제공하기 위하여 사용된다.
The term 'polyethylene glycol 400' used in the present invention is HOCH 2 as an addition polymer of ethylene oxide and water. (CH 2 OCH 2 ) nCH 2 OH and n is 7 to 9. Polyethylene glycol 400, which is used as a viscosity modifier in the present invention, is used to provide a clear ophthalmic solution composition of cyclosporin together with a surfactant.
본 발명에서 사용되는 용어 '계면활성제'는, 친수성 부분과 소수성 부분을 동시에 가지고 있는 물질로서 물에 잘 녹지 않는 물질을 물에 녹이기 위하여 일반적으로 사용되는 물질을 의미한다. 본 발명에서는 계면활성제로 폴리옥실40경화피마자유와 폴리소르베이트80을 사용하며, 폴리에틸렌글리콜400과 함께 사이클로스포린의 투명 점안액 조성물을 제공하기 위하여 사용된다. 사이클로스포린의 투명성을 높이기 위하여, 폴리옥실40경화피마자유와 폴리소르베이트80을 사용하는 것이 보다 바람직하다.
The term " surfactant " used in the present invention means a substance commonly used for dissolving a water-insoluble substance in water, which has both a hydrophilic part and a hydrophobic part. In the present invention, polyoxyl 40 hardened castor oil and polysorbate 80 are used as a surfactant and polyethylene glycol 400 is used to provide a clear eye drop composition of cyclosporin. In order to improve the transparency of cyclosporin, it is more preferable to use polyoxyl 40 hardened castor oil and polysorbate 80.
본 발명에서 사용되는 폴리에틸렌글리콜400과 계면활성제는, 사이클로스포린 1 중량부에 대하여, 각각 50-200 중량부 및 5-20 중량부를 사용하는 것이 바람직하다. 각각 상기 범위 이하로 사용하는 경우에는 투명성이 저하되고, 각각 상기 범위를 초과하는 경우에는 점도가 높아져 눈에 이물감을 형성시키는 문제점이 있다. 보다 바람직하게는, 상기 폴리에틸렌글리콜400은 사이클로스포린 1 중량부에 대하여 140-150 중량부인 것이 바람직하다.
The polyethylene glycol 400 and the surfactant used in the present invention are preferably used in an amount of 50-200 parts by weight and 5-20 parts by weight, respectively, based on 1 part by weight of the cyclosporin. When they are used within the above-mentioned range, the transparency is lowered. If they are each in excess of the above range, the viscosity is increased and a foreign matter is formed on the eyes. More preferably, the polyethylene glycol 400 is 140-150 parts by weight based on 1 part by weight of cyclosporin.
본 발명에 따른 투명 점안액 조성물은, 눈에 사용되는 것이기 때문에 눈의 자극을 최소화하기 위하여, pH 7.2 내지 7.5인 것이 바람직하다. 상기 범위를 벗어나게 되면, 산성 또는 염기성의 성질이 강해지기 때문에 눈에 자극을 줄 염려가 있다. 상기 pH를 맞추기 위하여, 본 발명에서는 수산화나트륨, 염화나트륨 또는 이들의 조합을 사용하여 조절하는 것이 바람직하다.
Since the transparent ophthalmic solution composition according to the present invention is used for eyes, it is preferable that the pH is 7.2 to 7.5 in order to minimize irritation to the eyes. If the concentration is out of the above range, the acidic or basic property becomes stronger, which may cause irritation to the eyes. In order to adjust the pH, it is preferred to adjust using the sodium hydroxide, sodium chloride or a combination thereof in the present invention.
또한, 본 발명에 따른 투명 점안액 조성물은, 카르복시메틸셀룰로오스나트륨,히알루론산 나트륨 또는 오메가 3 지방산을 각각 사이클로스포린 1 중량부에 대하여 카르복시메틸셀룰로오스나트륨 1-10 중량부를 추가로 포함할 수 있다. 카르복시메틸셀룰로오스나트륨, 히알루론산 나트륨 또는 오메가 3 지방산은 사이클로스포린의 효능을 돕는 것으로, 안구건조증에 유용하게 사용할 수 있다.
In addition, the transparent ophthalmic solution composition according to the present invention may further comprise 1-10 parts by weight of carboxymethyl cellulose sodium, 1 part by weight of cyclosporin, sodium carboxymethyl cellulose, sodium hyaluronate or omega 3 fatty acid. Sodium carboxymethylcellulose, sodium hyaluronate, or omega-3 fatty acids, which aid in the efficacy of cyclosporine, can be useful for dry eye syndrome.
또한, 본 발명은 상기 투명 점안액 조성물을 포함하는 안구건조증의 예방 또는 치료용 약학적 조성물을 제공한다.
The present invention also provides a pharmaceutical composition for preventing or treating dry eye syndrome comprising the above-mentioned transparent eye drop composition.
본 발명에서 사용되는 용어 '안구건조증'은, 자가면역반응에 의해 활성화된 T림프구가 안구표면과 주눈물샘에 침윤하여 전염증성 사이토카인을 다량분비하고, 이러한 염증 반응은 만성적인 경과를 거치며 눈물샘이나 안구표면의 상피세포들에 손상을 주어 발생하는 질환을 의미한다.
The term " dry eye syndrome " used in the present invention means that T lymphocytes activated by an autoimmune reaction infiltrate into the ocular surface and the main lacrimal gland and secrete a pro-inflammatory cytokine in a large amount. The inflammatory reaction is chronic, Which is caused by damage to the epithelial cells of the ocular surface.
본 발명에 따른 투명 점안액의 사이클로스포린은 면역반응에 의해 활성화된 T림프구를 억제하고 결막의 전염증성 사이토카인을 하향조절한다. 또한, 사이클로스포린의 점안으로 결막내의 술잔세포가 증가하고 상피세포의 증식이 억제된다. 안구건조증 환자에서 본 발명에 따른 사이클로스포린 투명 점안액을 사용하는 경우, 기본눈물분비가 증가하고 각결막상피증이 호전되며, 결막술잔세포의 밀도 및 transforming growth factor(TGF)-β2의 생산이 증가되고 시력개선, 자극감감소, 인공누액 사용횟수 감소등의 주관적인 증상에 효과가 있어, 안구건조증의 예방 또는 치료에 유용하게 사용할 수 있다.
The transparent eye drop cyclosporine according to the present invention inhibits T lymphocytes activated by the immune response and down-regulates the proinflammatory cytokine of the conjunctiva. In addition, the goblet cells in the conjunctiva are increased in the point of the cyclosporin and the proliferation of epithelial cells is suppressed. The use of cyclosporin transparent eye drops according to the present invention in patients with dry eye syndrome increases the basal tear secretion, improves angular conjunctival epithelium, increases the density of conjunctival goblet cells and the production of transforming growth factor (TGF) -β2, It is effective for the subjective symptoms such as improvement, irritation, decrease in the number of artificial tears, and so on, and thus it can be effectively used for preventing or treating dry eye syndrome.
본 발명에서 사용되는 용어 "예방"은, 상기 조성물의 투여로 질환을 억제 또는 지연시키는 모든 행위를 의미한다. 또한, 본 발명에서 사용되는 용어 "치료"는, 상기 조성물의 투여로 질환의 증세가 호전되거나 완치되는 모든 행위를 의미한다. 상기 약학적 조성물은, 투명 점안액 형태로 제조되며, 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.
The term "prophylactic " as used in the present invention means any action that inhibits or delays disease by the administration of the composition. The term "treatment" as used in the present invention means all the actions of improving or ameliorating symptoms of the disease upon administration of the composition. The pharmaceutical composition is prepared in the form of a transparent eye drop, and may further comprise suitable carriers, excipients and diluents commonly used.
또한, 본 발명은 상기 조성물의 제조를 위하여, 사이클로스포린에 계면활성제를 첨가하여 용해시키는 단계(단계 1); 물에 폴리에틸렌글리콜400을 첨가하여 용해시키는 단계(단계 2); 단계 2에서 제조된 용액에 단계 1에서 제조된 용액을 첨가하는 단계(단계 3); 및 단계 3에서 제조된 용액의 pH를 7.2-7.5로 조절하는 단계를 포함하는 투명 점안액 조성물의 제조방법을 제공한다.
The present invention also provides a method for preparing a composition, comprising the steps of: adding a surfactant to cyclosporin and dissolving the same (step 1); Adding polyethylene glycol 400 to water and dissolving (step 2); Adding the solution prepared in step 1 to the solution prepared in step 2 (step 3); And adjusting the pH of the solution prepared in step 3 to 7.2-7.5.
상기 제조방법에 사용되는 각 성분의 종류 및 함량은 앞서 설명한 부분과 동일하다.
The kind and content of each component used in the above production method are the same as those described above.
본 발명의 일실시예에 따른 투명 점안액 조성물은, 외관상 투명하여 무균제제의 전수검사에 적합하고, 눈에 이물감 및 자극이 없음을 확인하였으며, 이에 따라 안구건조증의 예방 또는 치료에 유용하게 사용할 수 있다.
Transparent eye drop composition according to an embodiment of the present invention, apparently transparent, suitable for the full test of the aseptic preparation, confirmed that there is no foreign body and irritation in the eye, and thus can be usefully used for the prevention or treatment of dry eye syndrome. .
본 발명에 따른 투명 점안액 조성물은, 외관상 투명하고 눈에 이물감 및 자극이 없어, 안구건조증의 예방 또는 치료에 유용하게 사용할 수 있다.
INDUSTRIAL APPLICABILITY The transparent ophthalmic solution composition according to the present invention can be used for preventing or treating dry eye syndrome, which is apparently transparent and has no foreign body sensation and irritation to eyes.
도 1은, 본 발명의 일실시예에 따른 투명 점안액의 외관을 나타낸 것이다.
도 2는, 시판되고 있는 사이클로스포린 점안액의 외관을 나타낸 것이다.Figure 1 shows the appearance of a transparent eye drop according to an embodiment of the present invention.
2 shows the appearance of commercially available cyclosporine eye drops.
이하，본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 더욱 쉽게 이해하기 위하여 제공되는 것일 뿐，실시예에 의하여 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred embodiments of the present invention will be presented to assist in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.
실시예Example 1 One
사이클로스포린에 폴리옥실40경화피마자유와 폴리소르베이트80을 넣고 용해시켰다. 따로 주사용수(증류수)에 폴리에틸렌글리콜400을 넣어 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 1과 같다.Polyoxyl 40 hardened castor oil and polysorbate 80 were dissolved in cyclosporine. Separately, polyethylene glycol 400 was dissolved in water for injection (distilled water), and then the cyclosporine solution prepared above was stirred and adjusted to pH 7.3 using sodium hydroxide, and the total volume was adjusted with water for injection (distilled water). The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered, and then filled in a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 1 below.
실시예Example 2 2
사이클로스포린에 폴리소르베이트80과 폴리에틸렌글리콜400을 넣고 용해시켰다. 주사용수(증류수)에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 2와 같다.Polysorbate 80 and polyethylene glycol 400 were added and dissolved in cyclosporine. The cyclosporin solution prepared above was added to the water for injection (distilled water), followed by stirring. The pH was adjusted to 7.3 using sodium hydroxide, and the total volume was adjusted to the water for injection (distilled water). The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered and then filled into a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 2 below.
실시예Example 3 3
사이클로스포린에 폴리소르베이트60과 폴리에틸렌글리콜400을 넣고 용해시켰다. 주사용수(증류수)에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 3과 같다. Polysorbate 60 and polyethylene glycol 400 were added and dissolved in cyclosporine. The cyclosporin solution prepared above was added to the water for injection (distilled water), followed by stirring. The pH was adjusted to 7.3 using sodium hydroxide, and the total volume was adjusted to the water for injection (distilled water). The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered, and then filled in a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 3 below.
실시예Example 4 4
사이클로스포린에 폴리옥실40경화피마자유와 폴리소르베이트80을 넣고 용해시켰다. 따로 주사용수(증류수)에 폴리에틸렌글리콜400과 카르복시메틸셀룰로오스나트륨을 넣어 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후 수산화나트륨을 사용하여 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후, 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 4와 같다.Polyoxyl 40 hardened castor oil and polysorbate 80 were dissolved in cyclosporine. Separately, dissolve polyethylene glycol 400 and sodium carboxymethylcellulose in water for injection (distilled water), add the cyclosporine solution prepared above, stir and dissolve with sodium hydroxide, and then dissolve the cyclosporine solution prepared above. After stirring, the pH was adjusted to 7.3 using sodium hydroxide and the total volume was adjusted with water for injection (distilled water). The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered and then filled into a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 4 below.
실시예Example 5 5
사이클로스포린에 폴리옥실40경화피마자유를 넣고 용해시켰다. 따로 주사용수(증류수)에 폴리에틸렌글리콜400과 히알루론산 나트륨을 넣어 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후, 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 5와 같다.Polyoxyl 40 hardened castor oil was dissolved in cyclosporine. Separately, dissolve polyethylene glycol 400 and sodium hyaluronate in water for injection (distilled water), add cyclosporine solution prepared above, and stir, adjust pH to 7.3 using sodium hydroxide, Adjusted volume. The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered, and then filled in a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 5 below.
실시예Example 6 6
사이클로스포린에 오메가 3 지방산 및 폴리옥실40경화피마자유를 넣고 용해시켰다. 따로 주사용수(증류수)에 폴리에틸렌글리콜400을 넣어 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후, 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 6과 같다.Omega 3 fatty acid and polyoxyl 40 hardened castor oil were dissolved in cyclosporine. Separately, polyethylene glycol 400 was dissolved in water for injection (distilled water), and then the cyclosporine solution prepared above was stirred, and then the pH was adjusted to 7.3 using sodium hydroxide and the total volume was adjusted with water for injection (distilled water). . The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered, and then filled in a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 6 below.
실시예Example 7 7
사이클로스포린에 폴리옥실40경화피마자유와 폴리소르베이트80을 넣고 용해시켰다. 따로 주사용수(증류수)에 폴리에틸렌글리콜400과 프로필렌글리콜을 넣어 용해시킨 다음, 여기에 앞서 제조한 사이클로스포린 용액을 넣어 교반한 후 수산화나트륨을 사용하여 pH를 7.3으로 맞추고 주사용수(증류수)로 전체부피를 맞추었다. 제조된 용액을 고압미세유화기에 통과시켜 얻어진 용액을 여과한 다음, 용기에 충전하여 사이클로스포린 투명 점안액을 제조하였으며, 각 성분은 하기 표 7과 같다.Polyoxyl 40 hardened castor oil and polysorbate 80 were dissolved in cyclosporine. Separately, dissolve polyethylene glycol 400 and propylene glycol in water for injection (distilled water), add cyclosporine solution prepared above, and stir, adjust pH to 7.3 using sodium hydroxide, and adjust the total volume with water for injection (distilled water). Fit. The solution obtained by passing the prepared solution through a high pressure microemulsifier was filtered, and then filled in a container to prepare a cyclosporin clear eye drop, and each component is shown in Table 7 below.
실험예Experimental Example
상기 실시예에서 제조된 사이클로스포린 투명 점안액과, 일반적으로 시판되고 있는 사이클로스포린 점안액(레스타시스 점안액; 삼일앨러간)의 외관을 관찰하였으며, 그 결과를 각각 도 1 및 2에 나타내었다.
The appearance of the cyclosporin clear eye drops prepared in the above examples, and commercially available cyclosporin eye drops (Restasis eye drops; three days allergan) were observed, and the results are shown in FIGS. 1 and 2, respectively.
도 1은 실시예 2의 외관을 관찰한 것으로, 본 발명에 따른 사이클로스포린 투명 점안액은 투명한 제형으로 제조됨을 확인하였다. 반면, 도 2에 나타난 바와 같이 일반적으로 시판되고 있는 사이클로스포린 점안액은 불투명함을 확인하였다. 따라서, 본 발명에 따른 사이클로스포린 투명 점안액은 폴리에틸렌글리콜400과 계면활성제를 포함함으로써, 투명 점안액의 형태로 제조할 수 있음을 확인할 수 있었다.1 is an observation of the appearance of Example 2, it was confirmed that the cyclosporin clear eye drops according to the present invention was prepared in a transparent formulation. On the other hand, as shown in Figure 2 it was confirmed that the commercially available cyclosporine eye drops are opaque. Therefore, it was confirmed that the cyclosporin transparent eye drops according to the present invention can be prepared in the form of transparent eye drops by including polyethylene glycol 400 and a surfactant.
Claims (8)
1 part by weight of cyclosporine, 20 to 50 parts by weight of polyethylene glycol 400, 5 to 20 parts by weight of polyoxyl 40 hardened castor oil, 2 to 10 parts by weight of polysorbate 80, 20 to 40 parts by weight of propylene glycol and water Transparent eye drop composition.
The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of sodium carboxymethylcellulose based on 1 part by weight of cyclosporin.
The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of sodium hyaluronate per part by weight of cyclosporine.
The composition of claim 1, wherein the composition further comprises 1 to 10 parts by weight of omega-3 fatty acid relative to 1 part by weight of cyclosporine.
The composition of claim 1, wherein the composition is from pH 7.2 to pH 7.5.
6. The composition of claim 5, wherein the pH is adjusted with sodium hydroxide, sodium chloride or a combination thereof.
A pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising the composition of any one of claims 1 to 6.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210012346A (en) | 2019-07-25 | 2021-02-03 | 심낙범 | Fine dust lid cleansing stick |
| CN114246935A (en) * | 2020-09-23 | 2022-03-29 | 上海现代药物制剂工程研究中心有限公司 | Composition containing cyclosporine and application of composition in preparation of medicine for treating xerophthalmia |
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| JPH0558906A (en) * | 1991-09-06 | 1993-03-09 | Sankyo Co Ltd | Cyclosporin eye-lotion |
| KR20010112315A (en) * | 1999-03-09 | 2001-12-20 | 항조우 쫑메이화동 파마수티컬 컴퍼니 리미티드 | Pharmaceutical composition containing cyclosporin |
| JP2010540671A (en) * | 2007-10-08 | 2010-12-24 | フォベア、ファルマスティカル、ソシエテ、アノニム | Aqueous ophthalmic formulation |
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| JPH0558906A (en) * | 1991-09-06 | 1993-03-09 | Sankyo Co Ltd | Cyclosporin eye-lotion |
| KR20010112315A (en) * | 1999-03-09 | 2001-12-20 | 항조우 쫑메이화동 파마수티컬 컴퍼니 리미티드 | Pharmaceutical composition containing cyclosporin |
| JP2010540671A (en) * | 2007-10-08 | 2010-12-24 | フォベア、ファルマスティカル、ソシエテ、アノニム | Aqueous ophthalmic formulation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210012346A (en) | 2019-07-25 | 2021-02-03 | 심낙범 | Fine dust lid cleansing stick |
| CN114246935A (en) * | 2020-09-23 | 2022-03-29 | 上海现代药物制剂工程研究中心有限公司 | Composition containing cyclosporine and application of composition in preparation of medicine for treating xerophthalmia |
| CN114246935B (en) * | 2020-09-23 | 2023-12-26 | 上海现代药物制剂工程研究中心有限公司 | Cyclosporin-containing composition and application thereof in preparation of dry eye treatment drugs |
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