Development of novel esomeprazole-loaded pharmaceutical formulation for GERD treatment using controlled release system

국문 초록 (Abstract)

양성자 펌프 억제제인 에스오메프라졸은 위궤양, 역류성 식도염, 졸링거-엘리슨 증후군 및 미란성 식도염 치료를 위해 단독 혹은 비스테로이드성 항염증제와 같은 약물과 함께 주로 사용되고 있다. 에스오메프라졸은 양성자 펌프를 직접적으로 억제함으로 역류성 식도염 치료에 더 강하고 빠른 효과를 보이는 것이 특징이다. 그러나 에스오메프라졸을 함유하고 있는 대부분의 제품은 장용코팅된 펠렛 형태로 위에서 바로 흡수되지 않고 소장에서 용해되어 흡수되도록 설계되어, 복용 후 즉각적인 치료가 필요한 환자에게는 적합하지 않다. 또한, 에스오메프라졸의 짧은 반감기로 인해 야간 산 분비 돌파가 자주 발생하여 환자의 수면을 방해한다. 이러한 약물 제형적인 단점을 극복하고 역류성 식도염의 효과적인 치료를 위해, 제어방출시스템이 적
용된 신규 에스오메프라졸 함유 제형개발을 수행하였다.
1장. 수산화마그네슘이 함유된 속방성 방출 이층정 연구
이 연구에서는 시판제품보다 약효 시간이 빠르고, 생체이용률이 개선된, 산중화제 함유 신규 에스오메프라졸 이층정을 개발하였다. 산중화제 종류 별 산 중화능, pH 완충능 및 배합적합성을 통해, 복약순응도가 향상된 수산화마그네슘 및 비율 (350mg/T)을 선정하였다. 위산에 분해되는 에스오메프라졸 특성을 고려, 시간 차 속방출이 가능한 이층정 제형으로 선정하여 모의 위 내 환경에서 에스오메프라졸 방출패턴 및 pH 변화를 관찰하였다. 또한 에스오메프라졸 층의 부형제 양별 평가를 통해, 산중화제층 보다 빨리 방출될 수 있는 최적 비율 연구를 수행하였다. 생체 내 약물동태학 실험에서는 이층정 정제가 시판제품과 유사한 생체이용률이 확인되었으며, 약 3.5배 빠르게 흡수되는 것을 입증했다.

2장. 이중방출 미니 정제 폴리캡 연구
이 연구에서는 야간 산 분비 돌파 예방하기 위해, 약효 지속시간을 연장하며 개선된 생체이용률을 나타내는 신규 이중방출 미니정제 폴리캡을 개발하였다. 에스오메프라졸을 함유하는 미니정제 코어 연구를 통해 신속한 약물 방출이 확인되었으며, 내부 코팅 후, 유드라짓®L30D-55 수분산 코팅으로 1차 방출 미니정제를 제조하였다. 또한 동일하게 코어에 내피코팅 후 유드라짓®S100/유드라짓®L100 혼합액으로 코팅하여 2차 방출 미니정제를 확보하였다. 코팅된 미니정제는 시험관 내 용해 및 현미경으로 특성화 하였으며, 각 10개 미니정제를 경질캡슐에 충전하여 이중방출 미니정제 폴리캡을 완성하였다. 미니정제의 조합은 시험관 내 방출패턴 및 생체 내 약물동태학 연구를 통해 최적화하였다. 이중방출 미니정제 폴리캡의 생체이용률은 시판제품와 유사하였으며, 최고약물혈중농도는 약 50 % 낮아졌고, 약 1.7배 약물 흡수 지연효과가 확인되었다. 추가 약물동력학 결과에서도 위내 pH 4이상 유지함으로서 야간 산 분비가 개선되었음을 확인하였다.
본 연구에서 비글견을 대상으로 한 생체 내 약물동태학 연구를 통해, 에스오메프라졸 함유 이층정과 이중방출 미니정제 폴리캡의 생체이용률은 시판제품과 유사하였으며, 치료효과를 위해 제형적으로 약효시간 조절이 가능함을 입증하였다. 결론적으로 제어방출시스템을 통해, 약효 문제를 극복하고 효과적인 최적의 치료옵션을 제공할수 있음이 확인되었다.

다국어 초록 (Multilingual Abstract)

Esomeprazole (EMP), a proton pump inhibitor (PPI), It is used for the prevention and treatment of gastrointestinal symptoms by anti-inflammatory analgesics, and for the treatment of Helicobacter pylori infection and gastroesophageal reflux disease (GERD). Unlike other mechanisms of action, PPI, such as EMP, directly inhibit the proton pump, so they have the characteristic of showing a slightly stronger and faster effect on GERD treatment. However, most products containing EMP are provided as delayed-release tablets designed with an enteric-coated multiunit pellet systems (MUPS), and are not suitable for the treatment of diseases that require immediate therapeutic effects after administration. In addition, EMP has a short plasma half-life (about 1.3 h), resulting in nocturnal acid breakthrough (NAB) occurs frequently, disturbing a patient’s nighttime comfort and sleep. In order to overcome these shortcomings, it is development of novel EMP-loaded novel pharmaceutical formulation for GERD treatment using controlled release system and provide various treatment options.

Chapter I. EMP-loaded bi-layer tablet with magnesium hydroxide for immediate release
In this study, a novel EMP-loaded bi-layer tablet containing an acid-neutralizing agent with faster onset time and improved bioavailability than a commercial product was developed. Magnesium hydroxide, an acid-neutralizing agent, was selected because of its acid-neutralizing capacity, pH-buffering capacity, and compatibility. It was found to be the most suitable acid-neutralizing agent for products with improved patient compliance (350 mg/T). Considering the characteristics of EMP that decompose in gastric acid, a bi-layer tablet formulation capable of time-dependent release was selected. Through the simulated conditions in the stomach release test, fast release and pH profiles were confirmed and compared with those of EMP-loaded commercial products. In addition, the amount of ingredients in the proven acceptance range was determined such that the acid-neutralizing agent layer could disintegrate faster than the drug layer. In vivo pharmacokinetic (PK) studies showed that the drug concentration-time curve (AUC) of the bi-layer tablet was similar to that of a comparable EMP-loaded commercial product and that Tmax was rapidly absorbed approximately 3.5-fold.

Chapter II. EMP-loaded mini-tablet polycap for dual-release
In this study, to develop a novel EMP magnesium-loaded dual-release mini-tablet polycap (DR polycap) with prolonged onset time and improved bioavailability to prevent NAB. Different types and amounts of diluents were evaluated to obtain EMP-loaded mini-tablet core preparations capable of rapid drug release. Inner coating was performed using a fluidized bed, and 1st release mini-tablet conting was achieved by coating with Eudragit®L30D-55 (ELD-55) aqueous dispersion. In addition, it was coated with an aqueous dispersion of Eudragit®S100 (ES-100) and Eudragit®L100 (EL-100) to realize optimal 2nd delayed release mini-tablet characteristics according to each coating thickness and polymer blend ratio. Each mini-tablet was characterized by SEM-EDS, light microscopic and in vitro dissolution test, and then ten mini-tablets were encapsulation in hard capsule to prepared a DR polycap. The combination of mini-tablets were optimized using in vitro release testing and in vivo PK studies. The AUC of the DR polycap was similar to that of a commercial product and that Cmax was lower by about 50 %, Tmax was extended by about 1.7-fold. Additional PD results also confirmed that NAB was improved by prolonged the maintenance of intragastric pH above 4.

The results of in vivo PK studies in beagle dogs, AUC of the bi-layer tablet and DR polycaps were similar to that of a comparable commercial product, and it was possible that Tmax can be controlled for therapeutic effects. The DR polycap was confirmed to improve NAB by prolonged onset time through PD results. In conclusion, we developed a controlled-release system to overcome drug efficacy concerns and provide optimal treatment options.

목차 (Table of Contents)

• Chapter 1. Novel esomeprazole magnesium-loaded bi-layer tablet with magnesium hydroxide as an acid-neutralizing agent: shortened onset time and improved bioavailability in beagle dogs １
• 1. Introduction 2
• 2. Materials and method 10
• 2.1. Materials 10
• 2.2. Acid neutralizing capacity & buffering capacity 11
• 2.3. Compatibility test of acid-neutralizing agent 13
• 2.4. Preparation and characterization of bi-layer tablet 15
• 2.5. In vitro evaluation of bi-layer tablet 18
• 2.6. Long-term stability 19
• 2.7. In vivo PK study in beagle dog 20
• 3. Results and discussion 23
• 3.1. Comparison of acid-neutralizing agents 23
• 3.2. Evaluation of EMP-loaded bi-layer tablet 28
• 3.3. Long-term stability of EMP-loaded bi-layer tablet 36
• 3.4. In vivo evaluation 38
• 4. Conclusion 41
• 5. References 42
• Chapter 2. Novel esomeprazole magnesium-loaded dual-release mini-tablet polycap: formulation, optimization, characterization, and in vivo evaluation in beagle dogs 50
• 1. Introduction 51
• 2. Materials and method 58
• 2.1. Materials 58
• 2.2. Preparation and evaluation of EMP mini-tablet core 59
• 2.3. Preparation of coated EMP mini-tablet 63
• 2.4. Preparation of EMP loaded dual release mini-tablet polycap 67
• 2.5. Morphology of the coated EMP mini-tablets 69
• 2.6. In vitro evaluation of DR polycaps 70
• 2.7. In vivo PK study of DR polycaps 76
• 2.8. Statistical Analysis 79
• 3. Results and discussion 80
• 3.1. Flow ability test of EMP mini-tablet core granule 80
• 3.2. Dissolution test of EMP mini-tablet core 82
• 3.3. Dissolution test of coated EMP mini-tablet 84
• 3.4. Morphology charaterization of coated EMP mini-tablet 89
• 3.5. Dissolution test of DR polycap 92
• 3.6. In vivo evaluation of DR polycaps 94
• 4. Conclusion 102
• 5. References 103
• 국문초록 110
• 감사의 글 113

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