초록 ▼

1. 본과제 1단계 (‘95-’98)에서 개발된 3가지 핵심기술들을 특허출원(#98-1441, 98-1442, 97-31407, 97-31100, 96-29798)을 완료하였으며, 이들을 이용한 지속성진통제, 지속성 항생제, 지속성고혈합치료제와 고효율골다공증치료제 연구결과가 당초 목표 이상의 결과를 얻어, 이들중 일부 결과를 KBS(’98. 6. 2. 저녁 9시 News, SBS 저녁 8시 News), 각종 신문에 보도된 바 있다. 이들을 실용화하기 위한 제반 필수기술을 2단계에서 개발 및 최적화시켜 개발기간중 3개이상의 약물을 기

1. 본과제 1단계 (‘95-’98)에서 개발된 3가지 핵심기술들을 특허출원(#98-1441, 98-1442, 97-31407, 97-31100, 96-29798)을 완료하였으며, 이들을 이용한 지속성진통제, 지속성 항생제, 지속성고혈합치료제와 고효율골다공증치료제 연구결과가 당초 목표 이상의 결과를 얻어, 이들중 일부 결과를 KBS(’98. 6. 2. 저녁 9시 News, SBS 저녁 8시 News), 각종 신문에 보도된 바 있다. 이들을 실용화하기 위한 제반 필수기술을 2단계에서 개발 및 최적화시켜 개발기간중 3개이상의 약물을 기업에서 제품화 함으로써 수입대체 및 수출가능성 효과를 얻고자 함.
2. 개발된 3가지 핵심기술은 1) 생분해성 고분자 PLGA를 이용한 약물의 미립구제제 기술로서, 이를 지속성 진통제 fentanyl에 응용하여 실험실적 방출실험에서 14여일간 지속적으로 방출되었으며, 또한 S.D rat에 대한 실험에서도 그 효능이 3일 이상 지속됨이 입증되었고, 또한 지속성 항생제 Gentamycin에 대한 실험실적 방출실험에서 8주이상 약물이 방출됨과 항균성 test에서도 그 효능이 6주이상 지속됨이 입증되었다.
그리고 2) 고분자 반투막 제조기술과 삼투압 원리를 이용한 삼투성 tablet 제제 제조 기술을 개발하여 이를 지속성 고혈압 치료제 Nifedipine로 개발하여 ‘96. 세계 주요의약품 순위 7위인 기존 외국산품 Adalat과 비교실험을 실험실적 방출조절 성능 test 및 beagle dog 에 대한 혈압강하 실험결과 상호대등한 결과를 얻었으며, 3) 난용성 약물의 생체이용률을 높이기 위하여 수용성 고분자 matrix내에 난용성 약물을 분자상태 또는 극세입자로 분산시키는 제제기술을 개발하여 이를 이용하여 고효율 골다공증 치료제 Ipriflavone을 개발하여 본 결과 S.D rat에서 생체이용률이 기존 제품보다 7배 이상 높은 것으로 나타남. 이와 같이 3가지 핵심기술을 이용한 4가지 다른 특성 약물에 적용한 결과들을 실용화 시키기 위한 제반 필요기술을 2단계에서 개발하고자 함.
3. 실용화 기술개발 상세내용은 다음과 같다.
1) 생분해성 고분자 PLGA 제조기술 확립 - 재현성있는 분자량 조절과 대량생산 공정 개발
2) 지속성 진통제 fentanyl 미립구 제제기술 확립 - 미립구의 크기분포 조절과 재현성 있는 생산공정 확립과 약물의 투여량에 따른 각종 실험 data 구축에 따른 동물 실험확대 및 응용분야 확대.
3) 지속성 항생제 Gentamycin 제제기술 - 약물방출조절을 위한 미립구 또는 입자의 크기분포 조절과 재현성있는 약물제제 pilot 생산공정 확립과 이에 따른 각종 test 및 data 구축을 위한 동물실험 및 응용분야 확대.
4) 지속성 Nifedipine tablet 제제기술 - 삼투성 tablet의 크기 소형화 제제기술과 tablet 양산에 따른 재현성 있는 반투막 도포기술과 미세공(orifice) 최적화에 따른 각종 실험 data 구축과 동물실험 확대.
5) 고효율 Ipriflavone제제 기술 - Powder형 고분자 업자의 균일성 최적화를 위한 공정 process 확립, 생체이용률 확대실험과 생산공정에 적합한 formulation 최적화 현재까지의 연구결과를 근거로 약물별 실용화 시기 예측은 고효율 Ipriflavon과 지속성 Nifedipine은 1999년과 2000년, 지속성 항생제 Gentamycin과 지속성 진통제 Fentanyl은 2001 년과 2002년으로 예측하며 그외 2가지 이상 약물에 대한 개발도 병행하여 진행될 예정이다. 선택된 약물은 실수요자인 의사 및 약제학자들의 요구와, 기업으로 부터의 경제성, 제품의 시장성 및 기술의 진보성에 따른 산업재산권보호 등을 고려한 것으로 1단계에서 개발대상 상품에 대한 우수한 연구결과 및 많은 기술축적도를 바탕으로 2단계 개발기간중 일부 약물은 대량생산까지 이룩할 것을 목표로 함.

Abstract ▼

In order to improve the bioavailability and sustained release property of Ipriflavone, Gentamicin sulfate, Fentanyl citrate and Nifedipine for the treatment of osteoporosis, osteomyelities, pain (anesthesia), and hyperpressure of blood, respectively, we have been studied as follows.
(1) Improveme

In order to improve the bioavailability and sustained release property of Ipriflavone, Gentamicin sulfate, Fentanyl citrate and Nifedipine for the treatment of osteoporosis, osteomyelities, pain (anesthesia), and hyperpressure of blood, respectively, we have been studied as follows.
(1) Improvement in vivo Absorption of Ipriflavone by means of Spray drying ;
It has been widely applied that ipriflavone (3-phenyl-7-isopropoxy-4H-l-benzopyran-4-one), which was used in the treatment of osteoporosis, was water insoluble drug and showed extremely low the rate of absorption in the body. There have been several works which explained that water insoluble drugs were released slowly from solid type of pharmaceutical preparation and showed different releasing and/or absorbing behaviour depending on dosage form, particle a size, pharmaceutical preparation methods. In this work, we used a spray drying method to increase the rate of absorption in the body of ipriflavone. The difference of particle sizes which was obtained through a spray drying and a physical mixing of ipriflavone with polyvinylpyrrolidone(PVP, molecular weight; 40,000g/mol) was compared by scanning electron rnicroscopy(SEM). In vivo tests were carried out using Sprague Dawley rats and the concentration of ipriflavone in plasma with different time was analyzed by PHLC. From the result, it was clearly shown that ipriflavone formulated by spray drying increased the rate of absorption in vivo more than seven times that of control.
(2) Gentamicin sulfate-loaded PLGA micro spheres near zero order release over 60 days for the treatment of osteomeylilies;
Gentamicin sulfate(GS) is one of the most potent antibiotics for bone infection (osteomylitis). Prolonged parenteral and oral antibiotic trerapy for 4-6 weeks may be necessary for usual treatment. Some disadvantages of prolonged parenteral therapy by intravenenous or intramuscular antibiotic injections are the high cost of treatment, sysmetic toxicity and patient discomfort. Oral antibiotic delivery may also be asociated with patient compliance problems. In addition, GS is also well known for causing rather severe secondary effects such as nausea, vomiting, headache, skin eruption, nephrotoxity, and ototoxicity. Therefore, localized delivery of an antibiotic to the infected site was introduced to overcome the difficulties associated with parenteral and oral therapy. It would deliver the drug at a continuous rate, and would reduce the dose-dependent toxicity by minimizing the fluctuation in plasma concentration.
We prepared PLGA microsphers(MSs) with incorporated GS by using 0/0 solvent evaporation in order to increase encapsulation efficiency because the drug is highly water-soluble. It was also observed that the in vitro release profile was near zero-order release over 60 days through more large size(200-350,um) than small size. The in vitro antimicrobial activity of micro spheres were evaluated by using Staphylococcus aureus.
After the microspheres were sunk in pH 7.4 phosphate buffer solution, 10mg of GSIPLGA MSs were periodically taken out the microspheres.
The inhibitory zones around the MS that was located on the bacteria-seeded culture agar plate were observed after incubation for 24 hours in order to evaluate their drug release profile. The results of inhibition zone test were similar as those of in vitro release test obtained by HPLC.
(3) Preparation and Characterization of Fentanyl loaded PLGA micro spheres for local anesthesia;
The development of long-acting local anesthetics is needed for postoperative anesthesia and control of chronic pain as cancer patients.
Several attempts have been made to prolong the action of local anesthesia. Typical example is a trans dermal therapeutic system fentanyl as Durageic® (Alza Co.) which was introduces in the American in 1991.
It is indicated for the treatment for chronic pain requiring strong opioids, whereas it is not indicated for the treatment of . acute pain as postoperative pain since it is not possible to individualize and titrate the dose to an effective and safe level in painful conditions requiring short-term treatment, that is to say, it is difficult the precise control of fentanyl release rate through skin. One of the most significantcandidates for the study of biodegradable polymeric controlled release is the poly (lactide-co-glycolide)(PLGA) due to its controllable biodegradability and excellent biocompatibility.
In this study, we developed the fentanyl cirtate(FC) as water soluble drug loaded PLGA(mole ratio = 75:25 by lactide to glycolide, and MW :
87kg/mole, 55kg/mole, and 27kg/mole) microspheres(MSs) for with incorporated FC by using % solvent evaporation. In vitro releae studies showed that different release patterns and release rate can be achieved by simply modifying factors in the preparation procedure such as polymer molecular weigh, surfactant concentration, and drug initial loading.
(4) Elemental osmotic pump for Nifedipine;
A small osmotically-driven device which is consist of an osmotic core incorporating drug surrounded by a semi -permeable membrane with a delivery orifice (for examples, OROS^Ⓡ and Adalate^Ⓡ) was first developed by Theeuwees on 1970s. In the drug absorption window as small and large gastrointestinal tract, the active ingredient passes, resulting in the generation of osmotic pressure, is slowly release through an exit port of drug core in the membrane at a zero-order rate. Nifedifine(ND) is a well known and most widely used vasodilatory substance from the group of dihydropyrine derivatives. In addition to different polymorphic forms it can also exist in glassy state. Since it is porrly water-soluble (62.mg/L at 26.5 DC) its bioavailability is expected to be dissolution rate-limited.
In this study, the release rate of ND varied with molecular weight of PEO (0, 100, 300, and 900kg/mol) and the concentration of potassium chloride as osmogant (0, 36, 53, and 68% of total volume as 700mg) from ND-loaded elemental osmotic pumpCEOP) was observed. In the case of PE~, it was observed the highest of ND release rate at the 300kg/mol.
Also, the highest of ND release rate was observed at the 53% concentration of KCl. It can be concluded that the viscosity of the ingradients in EOP is an important role for release rate of ND.
(5) Transdennal therpentic system for fentanyl;
Systemic delivery of drugs via the transdermal route has several potential advantages over conventional route: avoidence of the first-pass elimination by the liver, stable drug level in blood, rapid termination of drug delivery, and improved patient complience. Reservoir device has been used for transdermal drug delivery. For reservoir devices, a rate controlling polymeric membrane is placed between the skin and the drug reservoir. The release rate can be controlled by varying the chemical composition of the membrane or by incorporating fluids in the membrane struture. For hydrogels, release rate can be controlled by varying the hydration of the membrane. In addition, it has been shown that the movement of solvent from the reservoir across the membrane depends on the properties of the membrane and may influence drug release rate.
The aim of the present work is to evaluate the possibility of using EVA(ethylene-co-vinylacetate) membranes as rate-controlling membranes for reservoir devices. The additives-free EVA films with 12, 15 and 21% of vinylacetate content (40um thickness, Hanyang chemical Co., Korea) were a nonporous sheet membranes which were manufactured by T-die blow molding. The result was shown that drug permeability increased with increasing as the content of vinylacetate. This might be atrributed to creating a higher free volume permeation of ethanol and fentanyl.

목차 Contents

• 표지 ... 1
• 연구개발 최종보고서 ... 3
• 제출문 ... 4
• 최종보고서 요약 (초록) ... 5
• 목차 ... 7
• 요약문 ... 10
• SUMMARY ... 21
• CONTENTS ... 26
• PART I. 골다공증 치료제인 Ipriflavone의 생체활성을 증가시킨 제제에 관한 연구 ... 28
• 제1장 서론 ... 29
• 제2장 실험 재료 및 방법 ... 36
• 제3장 결과 ... 40
• 제4장 결론 ... 43
• 제5장 참고문헌 ... 44
• PART II. 생분해성 고분자를 이용한 항생제와 마취제의 서방화에 관한 연구 ... 55
• 제1장 서론 ... 56
• 제2장 수용성의약을 함유한 PLGA미립구 제조의 최근동향 ... 59
• 제3장 연구배경 ... 61
• 제4장 본 연구의 연구동향 ... 63
• 제5장 실험 및 결과고찰 ... 64
• 제6장 결론 ... 76
• 제7장 참고문헌 ... 77
• PART III. 지속성 항고혈압제 Nifedipine의 삼투압 타블렛 제제화 ... 97
• 제1장 서론 ... 98
• 제2장 삼투압 현상의 이론적고찰 ... 99
• 제3장 삼투압 Tablet 연구의 최근동향 ... 104
• 제4장 연구결과 및 향후연구계획 ... 130
• PART IV. 본 연구의 결과와 향후계획 ... 133
• 제1장 연구성과 ... 134
• 제2장 후속연구에서의 활용계획 ... 136
• 끝페이지 ... 138