KR0185215B1 - 서방성 안구삽입용 약제 - Google Patents
서방성 안구삽입용 약제 Download PDFInfo
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- KR0185215B1 KR0185215B1 KR1019910020940A KR910020940A KR0185215B1 KR 0185215 B1 KR0185215 B1 KR 0185215B1 KR 1019910020940 A KR1019910020940 A KR 1019910020940A KR 910020940 A KR910020940 A KR 910020940A KR 0185215 B1 KR0185215 B1 KR 0185215B1
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- 238000013268 sustained release Methods 0.000 title claims abstract description 19
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 19
- 239000003889 eye drop Substances 0.000 title 1
- 229940012356 eye drops Drugs 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 53
- 229940079593 drug Drugs 0.000 claims abstract description 51
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 24
- 239000004626 polylactic acid Substances 0.000 claims abstract description 23
- 238000003780 insertion Methods 0.000 claims abstract description 11
- 230000037431 insertion Effects 0.000 claims abstract description 11
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 14
- RPBJOYICBFNIMN-RDWMNNCQSA-M dexamethasone sodium m-sulfobenzoate Chemical class [Na+].O=C([C@]1(O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)COC(=O)C1=CC=CC(S([O-])(=O)=O)=C1 RPBJOYICBFNIMN-RDWMNNCQSA-M 0.000 claims description 8
- 238000001356 surgical procedure Methods 0.000 claims description 8
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- 229920002988 biodegradable polymer Polymers 0.000 claims description 7
- 239000004621 biodegradable polymer Substances 0.000 claims description 7
- 229960002949 fluorouracil Drugs 0.000 claims description 7
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims description 6
- 229960001048 fluorometholone Drugs 0.000 claims description 5
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 claims description 5
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- 239000005557 antagonist Substances 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 208000017442 Retinal disease Diseases 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000824 cytostatic agent Substances 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
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- 230000004663 cell proliferation Effects 0.000 claims 1
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
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- 238000005266 casting Methods 0.000 description 1
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- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/0051—Ocular inserts, ocular implants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
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Abstract
항염제 또는 세포증식길항제를 특정 폴리락트산에 균일하게 분산시키고 특정형상으로 형성함으로써 제조되는, 망막/초자체 질환 또는 녹내장의 수술후 안구내에 적용되는 안구내 삽입용 서방성 약제 및 수술후 상기 질환 또는 녹내장의 재발을 방지하는 방법에 관한 것이다.
Description
본 발명은 안과분야에 있어서 생분해성 고분자를 이용하는 약물 서방성의 삽입용 약제에 관한 것이다. 좀더 구체적으로는 망막/초자체의 질환 또는 녹내장의 수술후에 적용되는 생분해성 고분자인 폴리락트산에 항염제 또는 세포증식길항제를 균일하게 분산시키고 혼합물을 특정한 형상으로 형성시켜 이루어지는 서방성 안구내 삽입용 약제에 관한 것이다.
막 절제술 및 실리콘오일 탐폰삽입법 등의 외과치료기술로 인하여 증식성 초자체망막증의 치료효과는 현저하게 개선된어 왔다. 그러나, 외과적 수술만을 실시한 경우에는 대부분 수술 4 내지 6주후에 재발되는 것으로 보고되어 왔다(Machemer, R. et al., Ophthalmology, 85 584-593(1978)). 그러므로, 수술후 재발방지를 위하여 약물치료에 대한 다양한 실험이 시도되어 왔다.
예컨대, 스테로이드, 5-플루오로우라실 등의 초자체내 주입이 증식성 초자체망막증에 효과가 있는 것으로 밝혀졌으며(Tano, Y. et al., Am. J. Ophthalmol., 89, 131-136(1980) 및 Blumenkranz, M.S. et al., Am. J. Ophthalmol. 94, 458-467(1982)), 또한 수술후 제1주동안은 1일 1회, 제2주동안은 2일 1회 5-플루오로우라실을 결막하부에 주사하여 약물이 안구내로 이송될 수 있도록 함으로써 안구내 조직의 회복을 조절하여 녹내장의 여과수술효과를 유지할 수 있음이 보도된 바 있다(Nakano et al., Rinsho Ganka, 43, 1929-1933(1989)).
그러나 스테로이드 및 5-플루오로우라실 등의 약제를 단순히 초자체내 주입하는 것은 안구내 조직이 일시에 고농도의 약제에 노출되기 때문에 투여량에 따라서는 안구내 조직을 손상시킬 위험이 있는 것으로 밝혀졌다(Shimada et al., Acta Soc. Ophthalmol. Jpn., 93, 501-510(1989). 더욱이, 녹내장 수술후 반복되는 결막하부 주사는 환자에게 정신적으로 뿐만 아니라 육체적으로 과도한 고통을 주게된다.
이러한 문제점들을 해결하기 위하여, 예컨대, 약물 효과를 발휘하는데 필요한 수준으로 안구내 약물농도를 일정기간 유지하기 위하여 약물을 미세구 입자에 담지시킨 특정 형태의 약제에 대한 연구가 행해져 왔다(Moridera et al., Acta Soc. Ophthalmol. Jpn., 94, 508-513(1990)). 또한 현탁액 제제로서 스테로이드도 유사한 효과가 기대되고 있다.
그러나, 이들 약제를 안구내 예컨대 초자체내에 주입할 경우, 미세구 입자 및 현탁액 입자들이 이물질로서 수정체낭 또는 각막대피 등의 조직표면에 접촉 및 축적되거나 또는 이들로부터 용출된 약물이 수정체 또는 각막내에 축적되어 이들투명 조직을 혼탁시키는 등의 심각한 부작용을 일으킬 위험성이 매우 높다. 따라서 아직 그 안정성은 확립되지 않았다.
이러한 상황에서 안구내 1회 투여후 소정기간동안 안구내 약물 농도를 유지할 수 있도록 약물을 지속적이고 서서히 방출시키는 안전한 약제 형태가 요망되고 있다.
이와 같은 배경하에, 본 발명자들은 안구내 사용을 위한 서방성 약제를 개발하기 위하여 많은 연구를 하여 왔다. 그 결과, 생분해성 고분자인 특정 분자량 Mn(수평균 분자량) 범위의 폴리락트산에 약물을 균일하게 분산시키고 이 혼합물을 특정한 형상으로 형성함으로써 제조된 안구내 삽입용 약제에 의하여 상기 요망사항들이 만족됨을 발견하였다. 그리하여 거듭된 연구결과의 축적으로 본 발명이 완성되기에 이르렀다.
즉, 본 발명은 항염제 또는 세포증실길항제와 생분해성 고분자인 폴리락트산으로 이루어지고, 폴리락트산은 약 2000 내지 약 4000, 바람직하게는 약 2500 내지 약 3500, 가장 바람직하게는 약 3200의 Mn, 또는 약 5000 내지 약 7000, 바람직하게는 약 5500 내지 약 6500, 가장 바람직하게는 약 5900의 Mn을 가지는 폴리락트산 또는 소정 중량비의 두 폴리락트산의 혼합물이 사용되어, 일정한 소망 기간동안에 약물이 안구내에 계속적으로 방출되게 할 수 있는 것을 특징으로 하는 안구내 삽입용 서방성 약제에 관한 것이다.
본 발명의 서방성 안구내 삽입용 약제에 사용되는 약물을 항염제 및 세포증식길항제이며, 그 예로서는 덱사메타손 m-술포벤조에이트 나트륨염, 히드로 코르티손 아세테이트, 플루오로메톨론 등의 스테로이드 및 5-플루오로우라실등의 피리미딘 대사 길항제 등이 있다.
본 발명의 서방성 안구내 삽입용 약제에 사용되는 생분해성 고분자는 약 2000 내지 약 4000, 바람직하게는 약 2500 내지 약 3500, 가장 바람직하게는 약 3200의 Mn을 가지는 폴리락트산 및 약 5000 내지 약 7000, 바람직하게는 약 5500내지 약 6500, 가장 바람직하게는 약 5900의 Mn을 가지는 폴리락트산으로서, 약물의 소망 방출 지속시간에 따라서 10부/90부 내지 90부/10부 범위, 바람직하게는 30부/70부 내지 70부/30부의 중량비 범위의 혼합물 형태로 사용되거나 또는 단독으로 사용된다.
본 발명의 서방성 안구내 삽입용 약제는 약물과 폴리락트산의 균일한 혼합물로 이루어진 특정한 형상의 약제로서, 약물의 함량은 약제의 전체 중량에 대하여 10 내지 70중량%, 바람직하게는 40 내지 60중량% 이다.
본 발명의 서방성 안구내 삽입용 약제는 짧은 막대형, 바늘형 또는 필름형일 수 있으며, 용매를 이용한 주형법, 용융법, 가압법 또는 가압가열용융법등의 일반적 방법에 의하여 제조될 수 있다.
본 발명의 서방성 안구내 삽입용 약제에 따라 약물은 장기간에 걸쳐 안구내 조직에 서서히 계속적으로 투여된다. 더욱이, 실험 실시예 1에 도시된 바와 같이, Mn이 다른 두 종류의 폴리락트산의 혼합비를 변경함으로써 약물의 방출속도를 용이하게 조절할 수 있다. 따라서 약물이 짧은 시간 또는 더 장기간의 소망기간 예컨대 2주 또는 8주간 계속적으로 방출되도록 약제를 설계하는 것도 가능하다.
그러므로, 본 발명에 따라서 (1)수정체 및 각막 등의 안구조직에 심각한 부작용을 유발할 위험성이 없고, (2)반복적인 결막하부주사로 인하여 야기되는 과도한 고통을 환자에게 주지 않고, (3)환자의 상태에 따라 적당한 약물방출 지속시간의 설정이 가능하기 때문에 약물의 효과를 최대로 발휘시키는 것이 가능하고 (4)비독성 생분해 고분자를 사용하기 때문에 잔류물로 인한 문제점을 결코 야기시키지 않는 등의 많은 장점들을 가지는, 증식성 초자체망막증 또는 녹내장의 수술후 재발방지를 위해 매우 유용한 서방성 약제가 제공된다.
이하 실시예를 통하여 본 발명을 구체적으로 설명하고자 한다.
[실시예 1]
덱사메타손 m-술포벤조에이트 나트륨염을 함유하는 안구내 삽입용 서방성약제
덱사메타손 m-술포벤조에이트 나트륨염 및 폴리락트산을 하기 표 1에 제시된바 대로의 각 성분비가 되도록 기계적으로 혼합하고 내경 0.8㎜의 테프론 튜브에 충전한 다음 약 80℃까지 가열하면서 스테인레스스틸 막대로 양 끝을 가압하여 직경 0.08㎜ 및 길이 5㎜의 짧은 막대형을 형성하였다.
덱사메타손 m-술포벤조에이트 나트륨염 및 폴리락트산을 하기 표 1에 제시된 각 성분비로 혼합하고 메탄올/아세토니트릴(4/1)의 혼합용액 50㎖에 용해하였다. 혼합물을 테프론 용기에 부어 퍼지게 하고 상온에서 건조하여 시이트를 형성하였다. 그 다음, 형성된 시이트를 압연하여 두께 약 600㎛의 필름을 형성하였다.
[실시예 2]
히드로코르티손 아세테이트를 함유하는 안구내 삽입용 서방성 약제
히드로코르티손 아세테이트 0.1g 및 Mn 3200의 폴리락트산 0.1g을 기계적으로 혼합하고 내경 0.8㎜의 테프론 튜브에 충전한 후 약 80℃까지 가열하면서 스테인레스스틸 막대로 양 끝을 가압하여 직경 0.8㎜ 및 길이 5㎜의 짧은 막대형을 형성하였다.
[실시예 3]
플루오로메톨론을 함유하는 안구내 삽입용 서방성 약제
플루오로메톨론 0.1g 및 Mn 3200의 폴리락트산 0.1g을 기계적으로 혼합하고 내경 0.5㎜의 테프론 튜으에 충전한 후 약 80℃까지 가열하면서 스테인레스스틸 막대로 양끝을 가압하여 직경 0.8㎜ 및 길이 5㎜의 짧은 막대형을 형성하였다.
[실시예 4]
5-플루오로우라실을 함유하는 안구내 삽입용 서방성 약제
5-플루오로우라실 0.1g 및 Mn 5900의 폴리락트산 0.1g을 기계적으로 혼합하고 내경 0.8㎜의 테프론 튜브에 충전한 후 약 80℃까지 가열하면서 스테인레스스틸 막대로 양끝을 가압하여 직경 0.8㎜ 및 길이 5㎜의 짧은 막대형을 형성하였다.
[실험 실시예 1]
실시예 1에서 제조된 제제의 방출성능실험
실시예 1에서 제조된 덱사메타손 m-술포벤조에이트 나트륨염을 함유하는 짧은 막대형 약제를 하기의 pH7.4 완충용액 100㎖에 침윤시키고 37℃에서 교반하여 약물의 방출성능을 평가하였다.
염화 나트륨 0.7959g
염화 칼륨 0.036g
염화 칼슘 0.018g
시트르산 나트륨 0.1g
아세트산 나트륨 0.06g
멸균 정제수 100㎖
평가 결과, 실험개시 4주후 제제중의 덱사메타손 m-술포벤조에이트 나트륨염의 잔류량은 초기량에 대하여 샘플 No.1에서는 50%, 샘플 No.5에서는 83%였다.
이어서, 실시예 1에서 제조된 짧은 막대형 약제 각각을 토끼의 초자체에 삽입하여 약물 방출성능을 평가하였다. 평가 결과, 실험개시 4주후 제제중의 덱사메타손 m-술포벤조에이트 나트륨염의 잔류량은 샘플 No.1, 2, 3, 4 및 5 각각에 대하여 초기량의 0%, 13%, 15%, 50% 및 82%이었다.
이러한 결과로부터 본 발명은 매우 장기간에 걸쳐 지속적으로 안구내에 약물을 투여할 수 있다는 것을 알 수 있다. 더욱이, Mn 5900의 폴리락트산의 비율이 높으면 높을수록 약물의 방출속도가 낮아진다. 그러므로, 각 Mn 3200 및 5900의 폴리락트산 함유비율을 변화시킴으로써 약물의 방출속도를 변화시킬 수 있다.적용되는 약물 본래의 수용성을 고려하여 각 폴리락트산 함량비를 전체 폴리락트산 함량에 대하여, 0% 내지 100% 범위내에서 조절함으로써 치료목적 및 환자의 중증도에 따라 단기간에서부터 장기간에 걸친 소망 기간동안 안구내 조직에 지속적으로 약물을 적용시키는 것이 용이하게 달성될 수 있다.
[실험 실시예 2]
실시예 2에서 제조된 제제의 방출성능실험
실시예 2에서 제조된 히드로코르티손 아세테이트를 함유하는 짧은 막대형 약제를 토끼의 초자체에 삽입하고 약물의 방출성능을 평가하였다. 평가 결과, 실험개시 4주후 제제중의 히드로코르티손 아세테이트 잔류량은 초기량의 20%이었다.
[실험 실시예 3]
실시예 3에서 제조된 제제의 방출성능실험
실시예 3에서 제조된 플루오로메톨론을 함유하는 짧은 막대형 약제에 대하여 실험 실시예 2와 동일하게 평가하였다. 평가 결과, 실험개시 4주후 제제중의 약물의 잔류량은 56%이었다.
Claims (3)
- 적어도 하나의 항염제 또는 하나의 세포증식길항제를 생분해성 고분자로서 약 2000 내지 약 4000의 수평균 분자량을 가지는 폴리락트산, 또는 약 5000 내지 약 7000의 수평균 분자량을 가지는 폴리락트산, 또는 혼합물에 균일하게 분산시키고 이것을 막대형, 바늘형 또는 필름형으로 형성함으로써 제조되는 것을 특징으로 하는, 망막/초자체 질환의 수술 또는 녹내장 수술후 안구의 내부에 적용되는 안구내 삽입용 서방성약제.
- 제1항에 있어서, 상기 항염제 또는 상기 세포증식길항제는 덱사메타손 m-술포벤조에이트 나트륨염, 히드로코르티손 아세테이트 및 플루오로메톨론 등의 스테로이드, 그리고 5-플루오로우라실 등의 피리미딘 대사 길항제로 구성되는 군으로부터 선택되는 것을 특징으로 하는 안구내 삽입용 서방성 약제.
- 제1항 또는 제2항에 있어서, 상기 생분해성 고분자는 약 2000 내지 약 4000의 수평균 분자량을 가지는 폴리락트산과 약 5000 내지 약 7000의 수평균 분자량을 가지는 폴리락트산의 중량비 10부/90부 내지 90부/10부 범위의 혼합물인 것을 특징으로 하는 안구내 삽입용 서방성 약제.
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| Application Number | Priority Date | Filing Date | Title |
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| JP33885390 | 1990-11-30 | ||
| JP90-338853 | 1990-11-30 |
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| KR920009385A KR920009385A (ko) | 1992-06-25 |
| KR0185215B1 true KR0185215B1 (ko) | 1999-05-01 |
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| KR1019910020940A KR0185215B1 (ko) | 1990-11-30 | 1991-11-22 | 서방성 안구삽입용 약제 |
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| EP (1) | EP0488401A1 (ko) |
| JP (1) | JP3116489B2 (ko) |
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| WO2024054436A1 (en) | 2022-09-06 | 2024-03-14 | Alexion Pharmaceuticals, Inc. | Diagnostic and prognostic biomarker profiles in patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy (hsct-tma) |
| WO2024238421A1 (en) | 2023-05-12 | 2024-11-21 | Alexion Pharmaceuticals, Inc. | Use of biomarkers for the identification and treatment of complement-mediated disorders |
| WO2024238422A1 (en) | 2023-05-12 | 2024-11-21 | Alexion Pharmaceuticals, Inc. | Use of a panel of lectins for detection of complement biomarkers in urine extracellular vesicles |
| WO2025015317A2 (en) | 2023-07-13 | 2025-01-16 | Kriya Therapeutics, Inc. | Complement pathway inhibitor fusions and methods of using the same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4135514A (en) * | 1974-12-23 | 1979-01-23 | Alza Corporation | Osmotic releasing system for administering ophthalmic drug to eye of animal |
| EP0108661A1 (en) * | 1982-10-04 | 1984-05-16 | Merck & Co. Inc. | Stabilized hydroxypropyl cellulose ophthalmic inserts and process to sterilize the same |
| US4853224A (en) * | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
| US5164188A (en) * | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
-
1991
- 1991-11-22 KR KR1019910020940A patent/KR0185215B1/ko not_active IP Right Cessation
- 1991-11-26 JP JP03337591A patent/JP3116489B2/ja not_active Expired - Fee Related
- 1991-11-27 US US07/799,249 patent/US5501856A/en not_active Expired - Lifetime
- 1991-11-28 CA CA002056513A patent/CA2056513A1/en not_active Abandoned
- 1991-11-29 EP EP91120586A patent/EP0488401A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CA2056513A1 (en) | 1992-05-31 |
| KR920009385A (ko) | 1992-06-25 |
| EP0488401A1 (en) | 1992-06-03 |
| JPH0517370A (ja) | 1993-01-26 |
| US5501856A (en) | 1996-03-26 |
| JP3116489B2 (ja) | 2000-12-11 |
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