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좌제로부터의 약물의 방출제어에 관한 연구

Title
좌제로부터의 약물의 방출제어에 관한 연구
Other Titles
Studies on Release Control of Drugs from Suppository : Release Control of Propranolol·HCI and Indomethacin from hollow type suppository using Witepsol H-15
Authors
秦叔伶
Issue Date
1993
Department/Major
대학원 약학과
Keywords
약물 방출제어Witepsol 중공좌제Propranololindomethacin
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
具永順
Abstract
In order to study the release control of drugs from the suppository, several type of solid dispersion system (SDS) were prepared. In doing so, wiitepsol H-15 was utilized as the base, and indomethacin (IDM, poorly water-soluble) and propranolol·HCI(PPH, water-soluble) as the model drug. In addition, methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), lactose and polyvinylpyrrolidone (PVP) were used as the carrier for preparing SDS. Each type SDS was filled in the cavity of each hollow type suppository so as to produce two types of IDM hollow type suppositories and three types of PPH hollow type suppositories. An in vitro dissolution test on the SDS showed that in terms of 24-hour cumulative dissolved amount both IDM-lactose-SDS and IDM-PVP-SDS indicated a 30.2% and 70.3% increase respectively compared to IDM powder. On the other hand, it was shown that regarding 6-hour cumulative dissolved amount, both PPH-EC-SDS and PPH-MC-SDS indicated 40% and 22% decrease respectively compared to PPH powder. As a result of a powder X-ray diffraction experiment, both PPH-SDS and IDM-SDS showed a decrease in crystallinity. An in vitro release test on the suppository showed that in case of the PPH suppository, although the conventional suppository reached 80% in 6-hour cumulative released amount, both PPH-MC-SDS hollow type suppository and PPH-EC-SDS hollow type suppository reached 40% and 12%. According to the adding method, three different hollow type suppositories were prepared, based on the combination of SDS and PPH powder with three different ratios. One of the three suppositories was added 5mg of PPH powder to the base and SDS (equivalant to 15mg of PPH powder) to the cavity. Likewise, the rest two suppositories combined PPH powder and SDS at the ratio of 10:10 and 5:15 each. Following such a combination, an increase was found in initial release and 24-hour cumulative released amount. In case of the PPH-EC-SDS hollow type suppository, which is conspicuous in release control, the same phenomenon was shown by adding water-soluble polymer as a channeling agent. In case of the IDM suppository the IDM-PVP-SDS hollow type suppository reached 99% in 24-hour cumulative released amount whereas the conventional suppository reached 85%. An in vivo experiment with rabbits indicated that IDM-PVP(1:2)-SDS hollow type suppository caused a three times' delay, a 21.8% decrease and a 1.2 times' increase in terms of t_(max), C_(max) and AUC_(0→8) respectively. The IDM-PVP(1:2)-SDS hollow type suppository was expected to decrease in mucouse irritation due to the disturbed burst in the initial stage.;좌제로부터의 약물의 방출제어를 도모하기 위하여 Witepsol H-15를 기제로 사용하고 난용성 약물인 Indomethacin(IDM)과 수용성 약물인 Propranolol·HCl(PPH)을 model drug으로 사용하여 methylcellulose(MC), ethylcellulose(EC), hydroxypropylcellulose(HPC), hydroxypropylmethylcellulose(HPMC), lactose 및 polyvinylpyrrolidone(PVP)을 Carrier로 하여 Solid Dispersion System(SDS)을 제조하고 각각을 중공좌제의 중공부에 봉입하여 IDM의 중공좌제 2종과 PPH의 중공좌제 3중을 제조하였다. SDS의 용출 실험 결과에서 IBM-lactose-SDS는 24시간 누적용출량은 IDM 원말의 29%에 비해 30.2%가 증가되었고 IDM-PVP-SDS는 70.3%가 증가되었다. 그리고, PPH-EC-SDS는 6시간까지의 누적용출량이 PPH 원말의 100%에 비해 40%가 지연되었고, PPH-MC-SDS는 22%가 지연되었다. 분말 X-ray 회절 실험 결과 PPH-SDS 와 IDM-SDS는 모두 약물의 결정성 감소를 확인 할 수 있었다. 좌제로부터의 방출 실험 결과, PPH 좌제의 경우 통상형 좌제는 6시간까지의 누적방출량이 80%였으나 PPH-MC-SDS 봉입 중공좌제 및 PPH-EC-SDS 봉입 중공좌제는 각각 40% 및 12%로 방출 제어의 양상을 관찰할 수 있었다. 또한 약물 봉입 방법에 따라 dose 20mg 중 기제에 5mg, 10mg 및 15mg의 PPH 원말을 각각 분산시키고 중공부에 15mg, 10mg 및 5mg의 PPH에 상당하는 PPH-SDS를 각각 봉입한 중공좌제로 부터 초기 방출 및 24시간 누적방출량을 증대시킬 수 있었고 방출 제어가 현저한 PPH-EC-SDS 봉입 중공좌제의 경우 수용성 고분자를 channelling agent로 첨가함으로써 초기 방출 및 누적방출량을 증대시킬 수 있었다. 그리고 IDM좌제의 경우 24시간에서의 누적방출량이 통상형 좌제는 85%였고 IDM-PVP-SDS 봉입 중공좌제는 99%였으며 IDM-PVP(1:2)-SDS 봉입 중공좌제의 토끼직장 흡수 실험결과 통상형 좌제에 비하여 t_(max)는 3배 지연되었고, C_(max)는 21.8%저하되었으나 AUC_(0→8)는 1.2배 증대 되었으며 초기의 burst 현상이 감소되어 점막 자극성이 저하될 것으로 사료된다.
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