부유 기술을 이용한 위체류 이중정의 개발

박준범(Park, Jun-Bom) 한국산학기술학회 2015 한국산학기술학회논문지 Vol.16 No.11

본 이 연구의 목적은 부유 기술을 이용하여 제형이 위에 더 오래도록 머무르면서 약물을 지속적으로 방출하는 이중정 을 개발하는 것이다. 실험방법으로는 메트포르민을 주 약물로 선정하였는데, 그 이유는 메트포르민은 주로 소장 상부에서만 흡수되는 좁은 흡수 영역 대를 가지고 있는 점, 용해도가 매우 높아 약물 방출을 조절하는 것이 쉽지 않은 점 등 때문이다. 정제의 부유를 위한 가스를 생성하는 부분과 약물의 방출을 조절하는 부분의 간섭을 최소화하기 위해 이중정 타정 기를 사용 해 이중정으로 제조하였으며, 정제의 모양, 질량 및 경도를 측정하였고, 부유정의 중요한 요소인 부유 촉발시간과 부유유지 시간을 평가하였다. 또, 약물의 방출 조절을 평가하기 위해 용출시험을 시행하였으며, 그 결과를 시판되고 있는 메트포르민 서방성 제제인 Glucopharge XR® 과 비교평가 하였다. 그 결과, 부유 촉발제인 NaHCO₃ 및 약물 방출 조절제인 hydroxypropyl methylcellulose (HPMC)의 사용량에 따라 13초의 부유 촉발시간, 10시간 이상의 부유 유지시간 및 시판 제제와 매우 유사한 약물 방출 거동을 확인할 수 있었다 (f2: 89.6). 결론적으로 메트포르민을 함유한 위 체류 이중정을 성공적으로 개발할 수 있었으며, 그로 인해 메트포르민의 치료효과도 극대화 할 수 있을 것으로 예상된다. The aim of this study was to develop gastric retentive bi-layered tablet using floating drug delivery technique. Metformin was selected as a model drug due to its narrow absorption window as well as very highly water solubility. These properties of metformin led to be difficult controlling the drug release. The bi-layered tablet was prepared with bi-layered compression machine to minimize interference between floating part and controlling part. The tablet weight, appearance and hardness were evaluated after compression process. The times of 'time to floating' and 'Floating duration' were tested for floating ability and drug release study was also carried out to understand drug release behavior. Furthermore, the drug release of bi-layered tablet was compared with marketed metformin tablet with sustained release pattern (Glucopharge XR®).The floating ability and drug release behaviors were well controlled by changing amounts of NaHCO₃ (floating substance) and hydroxypropyl methylcellulose (HPMC; release control material). Bi-layered tablet had 13s of time to float, over 10h of floating duration and very similar drug release behavior compared with Glucopharge XR®(f2: 89.6). Consequently, the bi-layered tablet with floating ability was successfully prepared and these properties can maximize the efficacy of metformin.

이중 고온용융 압출 성형된 이중 방출능을 가지는 제형의 개발

김동욱(Dong-Wook Kim),강진양(Chin-Yang Kang),강창민(Changmin Kang),박준범(Jun-Bom Park) 한국산학기술학회 2016 한국산학기술학회논문지 Vol.17 No.9

본 이 연구의 목적은 이중 고온용융 압출법을 이용하여 기존의 방법으로 가지기 어려운 이상성의 약물방출 양상을 가지는 제형을 개발하는 것이다. 이 고온용융 압출물은 동회전 능을 가지는 두 개의 스크류가 장착된 압출기를 이용하여 제조되었다. Hydroxpropylmethylcellulose(HPMC) 같은 상대적으로 유리전이 온도가 높은 고분자를 이용하여 1차로 고온용융 압출물이 제조되었고, 이 1차 압출물과 상대적으로 유리전이 온도가 낮은 HPMC-AS(Acceate succinate)나 PEO(polyethylene oxide)를 이용하여 2차로 고온용융 압출물이 제조되었다. 또한 이중 고온용융 압출물과의 비교시험을 위해 같은 조성과 같은 조건하에서 일반적인 한 번의 고온용융 압출물도 제조되었다. 시차주사 열량계를 통해 물리적인 성질이 평가되었고, 미국약전의 제 1법에 따라 37 ± 0.5°C와 100 rpm의 조건에서 약물방출 시험이 진행되었으며 그 약물방출은 유사성인자(f2)를 이용하여 평가되었다. 시차주사 열량계 결과는 이부프로펜의 결정성이 이중 고온용융 압출법에서나 한번 고온용융 압출법 모두에서 무정형으로 변화된 것을 확인할 수 있었으며, 용출시험에서는 이중 고온용융 압출법에서 더욱 더 이상적인 이부프로펜의 방출을 인공위액(pH 1.2)에서 2시간, 0차 방출을 인공장액(pH 6.8)에서 6시간 동안 확인할 수 있었다. 빠른방출이 요구되는 글리메피라이드의 경우는 이중 고온용융 압출물에서는 60분에 80% 이상의 빠른 약물 방출을 보인 반면, 한번 고온용융 압출물에서는 약물방출이 HPMC와의 상호작용 때문에 느려져서 기준을 만족하지 못했다. 유사성 인자(f2) 값도 28.5로 매우 다른 방출을 보여주고 있음이 통계적으로 확인되었다. 이상의 결과들을 종합해 볼 때, 이중 고온용융 압출법은 완건성이 좋은 또 원하는 약물방출을 얻을 수 있는 방법이라 할 수 있다. The aim of this study was to develop pharmaceutical dosage forms with a bi-phasic drug using a double extrusion approach. Hot melt extrusion was performed using a co-rotating twin-screw extruder. The. 1st melt extrusion was performed using polymer with a relatively higher Tg, such as HPMC and the 2nd melt extrudate was obtained using the 1st extrudate and polymers with a lower Tg, such as HPMC-AS and PEO. In addition, the formulation with all the content in the same proportion as the double extudate was produced using single extrusion for comparison. Physical characterization was performed on the formulations employing differential scanning calorimetry (DSC). In vitro release tests were studied using a USP Type-I apparatus at 37 ± 0.5°C and 100 rpm. The similarity factor (f2) was also used to check the difference statistically. The DSC results indicated that the crystallinity of ibuprofen was changed to an amorphous state after extrusion in both double and single melt extrusion. Double melt extrudate with ibuprofen showed the desired release in acidic media (pH 1.2) in the first two hours and basic (pH 6.8) during six hours. Double melt extrudate with glimepiride showed faster release in 60 min of over 80%, whereas the single extrudate with glimepiride showed retarded release due to the interaction with HPMC. The similarity factor(f2) value was 28.5, which demonstrates that there were different drug release behavior between the double and single extrusion. Consequently, the double melt extrudated formulation was robust and gave the desired drug release pattern.

친수성 기제와 소수성 기제를 이용한 Sarpogrelate hydrochloride 서방정의 제조 및 평가

채유병(Yu-Byoung Chae),김성엽(Sung-Yeop Kim),강진양(Chin-Yang Kang),박준범(Jun-Bom Park) 대한약학회 2020 약학회지 Vol.64 No.6

The purpose of this study was to develop a sustained-release (SR) matrix tablet containing sarpogrelatehydrochloride (SH) and investigate the effect of hydrophilic and/or hydrophobic polymers on SH release. SH was selectedas a water-soluble drug, Hypromellose (HPMC) and Polyethylene oxide (PEO) as hydrophilic matrix-forming agents, andglyceryl behenate (GB; Compritol 888 ATO) as a hydrophobic agent. SR tablets with varying compositions of theaforementioned agents were prepared using wet granulation and tablet compression. Dissolution tests were performed usingthe paddle method per the US Pharmacopeia Apparatus II. Tablets containing only HPMC did not retard the initial releaseof SH easily, whereas those containing only PEO did not maintain the late-stage sustained-release profiles well. Hydrophobic GB polymer alone did not facilitate tailored drug release. However, a formulation comprising a mixture ofhydrophilic PEO and hydrophobic GB exhibited swelling and erosion that resulted in a zero-order, ideal drug-releasepattern for 12 h, with an R2 value of 0.914. Therefore, these results demonstrated that a combination of hydrophilic andhydrophobic polymers can form a matrix system that is more effective for the sustained release of SH compared to thematrix system formed using a single polymer.

고온용융압출 기술을 적용한 난용성 약물의 가용화 및 용출시험에서의 계면활성제의 농도의 영향

최성민(Sung-min Choi),전용구(Yong-Koo Jeon),이주현(Ju-Hyun Lee),강진양(Chin-Yang Kang),박준범(Jun-Bom Park) 대한약학회 2019 약학회지 Vol.63 No.6

Solid dispersions (SDs) were manufactured by hot-melt extrusion (HME) technology to enhance the solubility of the poorly soluble drugs (fenofibrate, celecoxib and cilostazol). Soluplus and Kollidon VA64 were selected as polymers due to their thermoplastic and hydrophilic behaviors. The SDs with three types of active pharmaceutical ingredients (APIs) were prepared using a twin-screw HME system, at three processing temperatures. To check drug release behaviors and solubility of poorly water-soluble drugs, a dissolution test was performed using the paddle method per the US Pharmacopeia Apparatus II. Distilled water with 0.5% sodium lauryl sulfate (SLS) was used as dissolution media. The extrudates containing fenofibrate and celecoxib showed enhanced drug release profiles compared to the APIs alone. However, in case of cilostazol, the extrudate had a lower dissolution rate than the API. To solve this phenomenon, the dissolution test was continuously performed by changing the amount of SLS. As a result, the drug release from the extrudate with cilostazol was higher than cilostazol alone in the dissolution media containing 0.1% SLS. Based on this result, the dissolution medium containing 0.1% SLS or less was considered as more suitable media than containing 0.5% SLS solution, which is mentioned in the cilostazol US Pharmacopeia (USP) monograph.