SMEDDS를 이용한 난용성 약물의 흡수율 개선에 관한 연구 = Study on bioavailability assessment of poorly water soluble drug with self-microemulsifying drug delivery system (SMEDDS)

다국어 초록 (Multilingual Abstract)

PATR 1
Formulation Design and Bioavailability Assessment of SMEDDS Formulation of Simvastatin
Simvastatin, a highly effective cholesterol-lowering agent, has been widely used for the treatment of hypercholesterolemia. As all lactone prodrug administered orally, it hydrolyzes in vivo to simvastatin acid, which a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin, a white to off-white, nonhygroscopic, highyl crystalline powder with a melting point of 135-138'C, is practically insoluble in water and poorly absorbed from the GI tract.
To overcome many problems (poorly water solubility and the oral delivery of such drug is associated with implications of low bioavailability et al.), various formulation strategies are reported in the literature including the use of surfactants, cyclodextrins, nanoparticles, solid dispersions, micronization, lipids, and permeation enhancers. In order to improve the bioavailability efficiency of simvastatin, several ways have been explored: freezing mill, spray dry and alginate beads.
Much attention has been paid to the application of microemulsions as drug delivery systems. Because of their high solubilizing capability, thermodynamic stability and spontaneously formation by simple mixing of the various components. Their advantages over conventional emulsions are their stability and ease of manufacture.
SMEDDS are isotropic mixtures of an oil, surfactant, cosurfactant, and drug. They form fine oil-in-water emulsions when introduced into aqueous media under mild agitation. The digestive motility of the stomach and intestine provide the agitation necessary for self-emulsification in vivo. The spontaneous formation of an emulsion upon drug release in the GI tract advantageously presents the drug in a solubilised form, and the small droplet size provides a large interfacial surface area for drug absorption.
For selecting a suitable self-emulsifying vehicle, it is important to assess: (a) the drug solubility in various components; (b) the area of self-emulsifying region in the phase diagram; and (c) droplet size distribution following self-emulsification. Various types of self microemulsifying formulations were prepared using four types of oil (Capryol 90, Lauroglycol 90, Labrafil M 1944 CS and Labrafil M 2125), two surfactants (Cremophor EL and Tween 80), and three cosurfactants (Carbitol, PEG 400 and propylene glycol). The efficiency of emulsification was studied using a laser diffraction size analyzer to determine particle size distributions of the resultant emulsions.
The objectives of the present study were to develop and characterize SMEDDS of simvastatin using propylene glycol monocaprylate (Capryol � 90) as solubilizers, polyoxyl 35 castor oil (Cremophor^� EL) as surfactants and diethylenglycol monoethyl ether (Carbitol) and to assess their bioavailability in beagle dogs.
The SMEDDS was optimized by the solubility of simvastatin and the microemulsion existence range after the preparation of microemulsion with varying compositions of Capryol^� 90 and S/CoS mixtures (Cremophor^� EL as surfactants (S) and the combination of Carbitol as cosurfactant (CoS)). The microemulsion existing range is increased proportional to the ratio of S/CoS, however, it decreased remarkable the solubilisity of drug.
SMEDDS is the mixtures of oils, surfactants, and cosurfactants, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal (GI) tract. Optimized formulations selected for bioavailability assessment were Carpryol 90 (40%), Cremophor EL (30%) and Carbitol (30%). SMEDDSs containing simvastatin 20 mg were compared to a conventional simvastatin tablet (Zorcoa^� , 20 mg/tab) by the oral administration as prefilled hard gelatin capsules to fasted beagle dogs for in vivo study. The area under the serum concentration-time curve from time zero to the last measured time in plasma, AUC_(0→24h), was significantly greater in SMEDDS, suggesting that bioavailability increase 158.90% and 142.85% by the SMEDDS-D form, SMEDDS-H form, respectively. The self-microemulsifying formulations of simvastatin afforded the improvement in absolute oral bioavailability relative to previous data of simvastatin tablet formulation.
PART 2
Formulation Design and Bioavailability Assessment of SMEDDS Formulation of Lovastatin
Poorly water solubility may be the harbinger of poor oral absorption, profound food effects, site-specific absorption, and extreme sensitivity to salt or polymorphic form, formulation composition, or process variables. The suitability of formulating with organic solvents, oils and emulsions, surfactant systems, complexing agents and even particle size reduction to submicron size then may be evaluated within the context of known properties of the compound.
The potential for lipidic SMEDDS to improve the oral bioavailability of a poorly absorbed was investigated through many studies within the past decade. The use of lipid formulations to solubilize drugs can provide the means to delivery insoluble agents via either injectable or oral routes. Lipid-based vehicles are typically considered when the property responsible for the poor aqueous solubility of a given compound is its hydrophobicity. The physicochemical properties of these molecules generally dictate that their dissolution in the gastrointestinal (GI) tract is poor and in many cases limits the extent of drug absorption, oral bioavailability and consequently clinical utility.
Lovastatin is a kinds of cholesterol-lowering drugs that are potent inhibitors of the enzyme HMG-CoA reductase. This enzyme is responsible for the conversion of HMG-CoA to mevalonate, which is the major rate-limiting step in the synthesis of cholesterol. After oral administration, lovastatin is hydrolyzed to the active β -hydroxy acid form and produce significant lowering of serum cholesterol in normal human volunteers and in patients with heterozygous familial hypercholesterolemia. Lovastatin is isolated from a strain of Aspergillus terreus and a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in alcohol and acetonitrile. The absorption of lovastatin in gastrointestial is averaged 30% of oral dose and its serum concentration through systemic circulation is less than 5%.
Optimized formulations selected for bioavailability assesment were transqutol, polyethylene glycol, propylene glycol, dimethylether isosorbide, and propylene glycol monocaprylate (Capryol^� 90) as solubilizers and polyoxyl 35 castor oil (Cremophor^� EL) as a surfactant. The multi-component delivery systems were optimized by evaluating their ability to self-emulsifying when introduced to an aqueous medium and gentle agitation, and by determination of particle size of the resulting emulsion. The potential for SMEDDS to improve the oral bioavailability of poorly absorbed, hypercholesterolemia drug (lovastatin) was investigated in fasted beagles by the oral administration. The area under the serum concentration-time curve from time zero to the last measured time in plasma, AUC_(0→24h), was significantly greater in SMEDDS, suggesting that bioavailability increase 130% and 192% by the SMEDDSs, respectively. The self-emulsifying formulations of lovastatin afforded the improvement in absolute oral bioavailability relative to previous data of lovastatin tablet formulation. These data indicate the utility of dispersed self-microemulsifying formulations for the oral delivery of lovastatin and potentially other poorly absorbed drugs.

목차 (Table of Contents)

• 목차
• List of Tables = iv
• List of Figures = v
• Abstract = vii
• 제1장 서론 = 1
• 1. 약물전달 시스템 = 1
• 2. 약물전달시스템의 분류 = 2
• 2-1. 흡수 촉진형 = 2
• 2-2. 약효지속형 = 3
• 2-3. 표적지향형(Targeting Drug Delivery System) = 4
• 2-4. 인공지능형 = 5
• 3. 참고문헌 = 7
• 제2장 난용성 약물인 심바스타틴의 흡수율 개선 = 8
• 1. 서론 = 8
• 1-1. 고지혈증 = 9
• 1-2. 심바스타틴의 특성 = 10
• 1-3. 약물 전달시스템의 설계 = 11
• 1-3-1. 심바스타틴의 제형 = 11
• 1-3-2. SMEDDS 제형의 성분 = 13
• 1-3-2-1. 오일 및 용해제 선택 = 13
• 1-3-2-2. 계면활성제 = 14
• 1-3-2-3. 공계면활성제 = 15
• 1-4. 생체이용률 = 15
• 2. 실험 = 16
• 2-1. 시약 및 재료 = 16
• 2-2. SEM 관찰과 XRD 측정 = 17
• 2-3. 심바스타틴과 로바스타틴의 대사체 제조 = 17
• 2-3-1. 심바스타틴산의 제조 = 18
• 2-3-2. 로바스타틴 산의 제조 = 18
• 2-3-3. 심바스타틴/로바스타틴 salt 제조 = 18
• 2-4. 용해도 측정 = 19
• 2-5. 상평형도(Pseudo-ternary phase diagram)의 작성 = 20
• 2-6. 심바스타틴 SMEDDS의 제조 = 20
• 2-7. 에멀젼의 형성 및 입자경의 크기 측정 = 21
• 2-8. 안정성 측정 = 21
• 2-9. 쥐에서의 약물동태 실험 = 21
• 2-9-1. 실험동물의 처치 = 21
• 2-9-2. 약물 투여, 혈액채취 및 혈장의 분리 = 22
• 2-9-3. 시료의 전처리 = 22
• 2-9-4. 검량선 작성 및 HPLC 분석 = 22
• 2-10. 비글견에서의 약물동태 실험 = 23
• 2-10-1. 실험동물 = 23
• 2-10-2. 투여방법 및 투여 용량 = 23
• 2-10-3. 혈액 채취 및 혈장의 분리 = 23
• 2-10-4. 시료의 전처리 = 24
• 2-10-5. 검량선 작성 = 24
• 2-10-6. HPLC 분석 = 25
• 2-10-7. 약물속도론적 분석 = 25
• 3. 결과 및 고찰 = 26
• 3-1. SEM 및 XRD 분석 = 26
• 3-2. 대사체의 분석 = 27
• 3-3-1. EA 분석 결과 = 27
• 3-3-2. 1H-NMR(CDC13, ppm) 분석결과 = 27
• 3-3-3. HPLC 결과 = 28
• 3-3-4. FT-IR 분석결과 = 28
• 3-3. 용해도 측정 및 오일과 계면활성제의 결정 = 29
• 3-4. 상평형도 = 30
• 3-5. 마이크로에멀젼의 형성 및 입자경의 분포 = 30
• 3-6. 약물의 안정성 = 31
• 3-7. 쥐에서의 약물동태 = 32
• 3-8. 비글견에서의 약물동태 = 32
• 4. 결론 = 33
• 5. 참고문헌 = 34
• 제3장 난용성 약물인 로바스타틴의 흡수율 개선 = 70
• 1. 서론 = 70
• 2. 실험 = 71
• 2-1. 시료 및 시약 = 71
• 2-2. SEM, XRD 분석 = 72
• 2-3. 대사체 제조 = 73
• 2-4. 용해도 측정 = 73
• 2-5. 로바스타틴 SMEDDS의 제조 = 73
• 2-6. 입자경 및 입도분포 측정 = 74
• 2-7. 안정성 평가 = 74
• 2-8. 시료의 전처리 및 검량선 작성 = 74
• 2-9. HPLC 분석 = 75
• 2-10. 비글견에서의 약물동태 = 75
• 3. 결과 및 고찰 = 76
• 3-1. SEM, XRD = 76
• 3-2. 오일 및 계면활성제의 결정 = 77
• 3-3. 미세유화형성 및 입도크기 = 78
• 3-4. 약물의 안정성 = 79
• 3-5. 비글견에서의 약물동태 = 79
• 4. 결론 = 80
• 5. 참고 문헌 = 81
• List of Publications = 96
• List of Presentations = 98
• 감사의글