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      Development of sustained-release microparticles containing ropinriole hydrochloride for orally disintegrating tablets

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      https://www.riss.kr/link?id=T15519044

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      다국어 초록 (Multilingual Abstract)

      The aim of this study is to develop a sustained-release microparticle containing ropinirole hydrochloride for orally disintegrating tablets. The main indication of ropinirole hydrochloride is Parkinson's disease. The patient group of Parkinson's disease has difficulty swallowing tablets due to geriatrics, dysphagia and dyskinesia. The sustained-release microparticles were prepared using a fluid bed coater for the application of ropinirole hydrochloride to orally disintegrating tablets as a patient friendly dosage forms.
      A drug-ion exchange resin complex of ropinirole hydrochloride and Amberlite™ IRP 69 was prepared to control the rapid release of ropinirole hydrochloride and to mask the bitter taste in the mouth. Ropinirole hydrochloride was loaded with the sustained-release ion exchange resin, Amberlite™ IRP 69, in a batch method. The prepared drug-ion exchange resin complex showed more sustained-release than the active coated particles of ropinirole hydrochloride on Amberlite™ IPR 69. This confirmed that the drug-ion exchange resin complex was suitable as the core of sustained-release microparticle coated with hydrophobic polymer, Eudragit® RL PO, for further release control. To be equivalent to the reference drug, REQUIP® XL, in in vitro release study, drug-ion exchange resin complex was coated with Eudragit® RL PO to prepare sustained-release microparticles. The size of the prepared sustained-release microparticles was 200 µm or less and the sustained-release microparticles were suitable for orally disintegrating tablets because particles.
      The sustained-release microparticles prepared were mixed with excipients and compressed into tablets for application to orally disintegrating tablets. The formulation and process parameters were optimized to produce sustained-release orally disintegrating tablets. The orally disintegrating tablets containing sustained-release microparticles of ropinirole hydrochloride were prepared by varying the ratio of diluent, tableting pressure, and the thickness of coating layer of the sustained-release microparticle and evaluated by hardness study, disintegration study, and in vitro release study. The final optimized formulation for sustained-release orally disintegrating tablet of ropinirole hydrochloride was consisting of the sustained-release microparticle coated with 25% Eudragit® RL PO and 240 mg mannitol as diluent. The sustained-release orally disintegrating tablet met the release criteria of USP for ropinirole sustained-release tablet and the bitter taste of ropinirole hydrochloride was successfully masked. This tablet had proper mechanical strength with hardness of 67.0 N and disintegration time of 55.58 seconds. Additionally, the tablet was equivalent with REQUIP® XL 4mg in comparative release study and the similarity factor(f2) with the value of 43.38 was more than 40 which the criteria of f2 value for sustained-release tablets.
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      The aim of this study is to develop a sustained-release microparticle containing ropinirole hydrochloride for orally disintegrating tablets. The main indication of ropinirole hydrochloride is Parkinson's disease. The patient group of Parkinson's disea...

      The aim of this study is to develop a sustained-release microparticle containing ropinirole hydrochloride for orally disintegrating tablets. The main indication of ropinirole hydrochloride is Parkinson's disease. The patient group of Parkinson's disease has difficulty swallowing tablets due to geriatrics, dysphagia and dyskinesia. The sustained-release microparticles were prepared using a fluid bed coater for the application of ropinirole hydrochloride to orally disintegrating tablets as a patient friendly dosage forms.
      A drug-ion exchange resin complex of ropinirole hydrochloride and Amberlite™ IRP 69 was prepared to control the rapid release of ropinirole hydrochloride and to mask the bitter taste in the mouth. Ropinirole hydrochloride was loaded with the sustained-release ion exchange resin, Amberlite™ IRP 69, in a batch method. The prepared drug-ion exchange resin complex showed more sustained-release than the active coated particles of ropinirole hydrochloride on Amberlite™ IPR 69. This confirmed that the drug-ion exchange resin complex was suitable as the core of sustained-release microparticle coated with hydrophobic polymer, Eudragit® RL PO, for further release control. To be equivalent to the reference drug, REQUIP® XL, in in vitro release study, drug-ion exchange resin complex was coated with Eudragit® RL PO to prepare sustained-release microparticles. The size of the prepared sustained-release microparticles was 200 µm or less and the sustained-release microparticles were suitable for orally disintegrating tablets because particles.
      The sustained-release microparticles prepared were mixed with excipients and compressed into tablets for application to orally disintegrating tablets. The formulation and process parameters were optimized to produce sustained-release orally disintegrating tablets. The orally disintegrating tablets containing sustained-release microparticles of ropinirole hydrochloride were prepared by varying the ratio of diluent, tableting pressure, and the thickness of coating layer of the sustained-release microparticle and evaluated by hardness study, disintegration study, and in vitro release study. The final optimized formulation for sustained-release orally disintegrating tablet of ropinirole hydrochloride was consisting of the sustained-release microparticle coated with 25% Eudragit® RL PO and 240 mg mannitol as diluent. The sustained-release orally disintegrating tablet met the release criteria of USP for ropinirole sustained-release tablet and the bitter taste of ropinirole hydrochloride was successfully masked. This tablet had proper mechanical strength with hardness of 67.0 N and disintegration time of 55.58 seconds. Additionally, the tablet was equivalent with REQUIP® XL 4mg in comparative release study and the similarity factor(f2) with the value of 43.38 was more than 40 which the criteria of f2 value for sustained-release tablets.

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      국문 초록 (Abstract)

      이 연구의 목표는 구강 붕해정에 적용 가능한 로피니롤 염산염의 서방형 미립자 개발이다. 로피니롤 염산염은 비-에르고린 도파민 작용제이며 도파인 D2 수용체를 자극함으로써 작용한다. 로피니롤 염산염의 주 적응증은 파킨슨병으로 파킨슨병 환자들은 고령이며 연하곤란, 운동 실조로 인하여 정제의 삼킴이 어려웠으며 환자군들을 위한 복용 편의성이 개선된 제형이 필요로 하였다. 로피니롤 염산염을 복용 편의 제형인 구강 붕해정에 적용하기 위해 유동층 코팅기를 이용하여 서방형 미립자를 제조했다.
      로피니롤 염산염은 133 mg/mL의 높은 수용해도를 갖는 BCS class Ⅲ 약물이며 입 안에서 용해되어 쓴 맛을 나타낸다. 로피니롤 염산염의 빠른 방출을 조절하고 입 안에서 쓴 맛을 차폐하기 위하여 로피니롤 염산염과 Amberlite™ IRP 69의 약물-이온교환수지 복합체를 제조하였다. 추가적인 방출 조절을 위해 소수성 폴리머인 Eudragit® RL PO로 복합체를 코팅하였다. 제조된 서방 미립자들은 24시간 동안 로피니롤 염산염을 서서히 방출하여 서방형 구강 붕해정에 적용하기 적합하였다. 또한 미립자들의 d(0.9) 값은 200 µm 이하였다. 구강 붕해정에 200 µm 이상의 입자를 적용했을 때는 나쁜 식미감을 나타내기 때문에 제조된 미립자들은 구강 붕해정에 적합하였다.
      제조된 서방형 미립자는 구강 붕해정에 적용하기 위하여 부형제들과 혼합을 거쳐 타정되었다. 이때 부형제는 필러이자 감미제로써 만니톨, 필러이자 붕해제로써 미결정셀룰로오스, 슈퍼 붕해제인 크로스포비돈, 활택제인 마그네슘 스테아레이트가 첨가되었고 혼합기를 이용한 혼합 과정을 거쳐 타정되었다. 이때 Eudragit® RL PO로 25% 코팅된 서방형 미립자를 함유하며 240 mg의 만니톨, 타정압은 5 kN의 조건으로 제조된 서방형 구강 붕해정이 USP의 로피니롤 염산염 서방정의 용출기준에 부합하며 비교용출평가에서 기존의 시장 제품인 REQUIP® XL 4 mg과 동등했으며 f2 값은 43.38였다. 또한 이 구강붕해정은 로피니롤의 쓴 맛을 차폐하여 파킨슨병 환자들을 위한 복용 편의제제의 기준을 만족하였다.
      번역하기

      이 연구의 목표는 구강 붕해정에 적용 가능한 로피니롤 염산염의 서방형 미립자 개발이다. 로피니롤 염산염은 비-에르고린 도파민 작용제이며 도파인 D2 수용체를 자극함으로써 작용한다. ...

      이 연구의 목표는 구강 붕해정에 적용 가능한 로피니롤 염산염의 서방형 미립자 개발이다. 로피니롤 염산염은 비-에르고린 도파민 작용제이며 도파인 D2 수용체를 자극함으로써 작용한다. 로피니롤 염산염의 주 적응증은 파킨슨병으로 파킨슨병 환자들은 고령이며 연하곤란, 운동 실조로 인하여 정제의 삼킴이 어려웠으며 환자군들을 위한 복용 편의성이 개선된 제형이 필요로 하였다. 로피니롤 염산염을 복용 편의 제형인 구강 붕해정에 적용하기 위해 유동층 코팅기를 이용하여 서방형 미립자를 제조했다.
      로피니롤 염산염은 133 mg/mL의 높은 수용해도를 갖는 BCS class Ⅲ 약물이며 입 안에서 용해되어 쓴 맛을 나타낸다. 로피니롤 염산염의 빠른 방출을 조절하고 입 안에서 쓴 맛을 차폐하기 위하여 로피니롤 염산염과 Amberlite™ IRP 69의 약물-이온교환수지 복합체를 제조하였다. 추가적인 방출 조절을 위해 소수성 폴리머인 Eudragit® RL PO로 복합체를 코팅하였다. 제조된 서방 미립자들은 24시간 동안 로피니롤 염산염을 서서히 방출하여 서방형 구강 붕해정에 적용하기 적합하였다. 또한 미립자들의 d(0.9) 값은 200 µm 이하였다. 구강 붕해정에 200 µm 이상의 입자를 적용했을 때는 나쁜 식미감을 나타내기 때문에 제조된 미립자들은 구강 붕해정에 적합하였다.
      제조된 서방형 미립자는 구강 붕해정에 적용하기 위하여 부형제들과 혼합을 거쳐 타정되었다. 이때 부형제는 필러이자 감미제로써 만니톨, 필러이자 붕해제로써 미결정셀룰로오스, 슈퍼 붕해제인 크로스포비돈, 활택제인 마그네슘 스테아레이트가 첨가되었고 혼합기를 이용한 혼합 과정을 거쳐 타정되었다. 이때 Eudragit® RL PO로 25% 코팅된 서방형 미립자를 함유하며 240 mg의 만니톨, 타정압은 5 kN의 조건으로 제조된 서방형 구강 붕해정이 USP의 로피니롤 염산염 서방정의 용출기준에 부합하며 비교용출평가에서 기존의 시장 제품인 REQUIP® XL 4 mg과 동등했으며 f2 값은 43.38였다. 또한 이 구강붕해정은 로피니롤의 쓴 맛을 차폐하여 파킨슨병 환자들을 위한 복용 편의제제의 기준을 만족하였다.

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      목차 (Table of Contents)

      • I. Introduction 1
      • 1 Parkinson’s disease 1
      • 1.1 Background of Parkinson’s disease 1
      • 1.2 Treatment of Parkinson’s disease 2
      • 1.2.1 Levodopa 2
      • I. Introduction 1
      • 1 Parkinson’s disease 1
      • 1.1 Background of Parkinson’s disease 1
      • 1.2 Treatment of Parkinson’s disease 2
      • 1.2.1 Levodopa 2
      • 1.2.2 Dopaminergic receptor agonist 3
      • 1.2.3 MAO-B inhibitor 4
      • 2 Ropinirole hydrochloride 6
      • 2.1 Physicochemical properties 6
      • 2.2 Indications and mechanism of action 9
      • 2.2.1 Parkinson’s disease 9
      • 2.2.2 Restless legs syndrome 10
      • 2.3 Pharmacokinetics 10
      • 2.3.1 Absorption 10
      • 2.3.2 Distribution 11
      • 2.3.3 Metabolism 11
      • 2.3.4 Excretion 12
      • 2.4 Adverse effects of ropinirole hydrochloride 12
      • 2.5 Necessity of sustained-release formulation with ease of administration 13
      • 3 Sustained-release microparticle consisting of ion exchange resin 14
      • 3.1 Drug-ion exchange resin complex 14
      • 3.2 Taste-masking 14
      • 3.3 Sustained-release 15
      • 4 Fluid-bed technology 17
      • 4.1 Coated multiparticulate system 17
      • 4.2 Granulation/Agglomeration 18
      • 4.3 Coating/Powder layering 18
      • 4.4 Pharmaceutical excipients for fluid-bed coating 21
      • 4.4.1 Ethylcellulose 21
      • 4.4.2 Acrylate 22
      • 4.4.3 Additional excipients 23
      • 5 Orally disintegrating tablet 26
      • 5.1 Advantages of orally disintegrating tablet 27
      • 5.2 Consideration of orally disintegrating tablet 28
      • 5.2.1 Taste of the dosage 28
      • 5.2.2 Mouth feel 28
      • 5.2.3 Hydroscopicity 28
      • II. Objectives 29
      • III. Experimental methods 30
      • 1 Materials 30
      • 2 Instruments 32
      • 3 Quantitative analysis of ropinirole HCl for in vitro study 33
      • 3.1 HPLC conditions 33
      • 3.2 HPLC system 33
      • 3.3 Preparation of stock solution 34
      • 3.3.1 Drug content study and purity study 34
      • 3.3.2 In vitro release study 34
      • 3.4 Preparation of standard solution 34
      • 3.4.1 Drug content and purity study 34
      • 3.4.2 In vitro release study 35
      • 3.5 Validation HPLC analysis 35
      • 3.5.1 Drug content and purity study 35
      • 3.5.2 In vitro release study 36
      • 4 Preparation of drug-ion exchange resin complex and sustained-release microparticle 38
      • 4.1 Ropinirole hydrochloride loading on ion exchange resin 38
      • 4.2 Fluid-bed coating process for sustained-release microparticle 39
      • 5 Characterization of microparticle 42
      • 5.1 Drug loading study 42
      • 5.2 Powder X-ray diffraction 42
      • 5.3 FT-IR 43
      • 5.4 In vitro release study 43
      • 6 Morphology 45
      • 6.1 Particle size distribution 45
      • 6.2 SEM images 45
      • 7 Preparation of sustained-release orally disintegrating tablet 46
      • 7.1 Tableting study of sustained-release orally disintegrating tablet 46
      • 7.2 Hardness test 46
      • 7.3 In vitro disintegration test of ODT 46
      • 7.4 In vitro release study 47
      • 8 In vitro taste-masking study 48
      • IV. Result 49
      • 1 Quantitative analysis of ropinirole hydrochloride 49
      • 2 Preparation of drug-ion exchange resin complex 53
      • 2.1 Loading of ropinirole hydrochloride on ion exchange resin 53
      • 2.2 In vitro release study of drug-ion exchange resin complex 55
      • 2.3 Characterization of DRC 58
      • 2.3.1 Powder X-ray diffraction (PXRD) study 58
      • 2.3.2 FT-IR 61
      • 2.4 Morphology of drug-ion exchange resin complex 63
      • 2.4.1 SEM images 63
      • 3 Preparation of sustained-release microparticle 65
      • 3.1 Dissolution study of sustained-release microparticle 65
      • 3.2 Morphology 73
      • 3.2.1 Size distribution of microparticles 73
      • 3.2.2 SEM images 79
      • 4 Preparation of SR ODT 81
      • 4.1 Screening of SR ODT formulation 81
      • 4.2 Optimization of SR ODT formulation 92
      • 5 Taste masking 110
      • 5.1 Taste masking of ropinirole hydrochloride 110
      • V. Conclusion 114
      • VI. References 116
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