쿠에티아핀 푸마르산을 함유하는 방출제어 캡슐제의 용해특성

김필윤(Pil Yun Kim),정준재(Jun Jae Jung),김남영(Nam Yeong Kim),김진우(Jin Woo Kim),최정민(Jeong Min Choi),이원찬(Won Chan Lee),송정은(Jeong Eun Song),강길선(Gilson Khang) 한국고분자학회 2020 폴리머 Vol.44 No.5

쿠에티아핀 푸마르산(quetiapine fumarate, QF)은 낮은 용해도와 높은 투과성을 갖는 BCS CLASS Ⅱ로 생체이용률이 낮은 문제가 있다. 또한 쿠에티아핀은 2개의 수산화기를 보유하여, 산성 조건 하에서 더 높은 용해도를 갖는다고 보고되어 있다. 즉, pH 4 이상의 범위에 대해서는 용해도가 낮고, pH 2에서 높은 용해도를 보이며, pH 2 미만에서는 이온 효과로 인하여 용해도가 감소한다. 따라서 QF의 용해도를 향상시키고 pH의 변화에도 일정한 방출을 유도하기 위해 속방 및 서방성 과립물을 이용한 캡슐을 제조하였다. XRD와 DSC를 사용하여 약물의 결정성과 포접을 평가, SEM을 통해 형태학적인 분석, FTIR 분석을 수행하여 화학적 변화를 분석하였다. 또한 습식과립공정을 통해 유동성이 개선된 것을 확인하기 위해 유동성 평가를 하였으며 최종적으로, 용해도 시험으로 고체 분산체 및 캡슐제의 용해도 패턴을 분석하였다. Quetiapine fumarate (QF) is a BCS CLASS II with low solubility and high permeability, which has a problem of low bioavailability. It has also been reported that Quetiapine possesses two hydroxyl groups, so it has a higher solubility under acidic conditions. The solubility is low in the range of pH 4 or higher and it is high when pH is 2, and it decreases when the pH is lower than 2 which is due to ion effect. Therefore, capsules were prepared using immediate-release and sustained-release granules to improve the solubility of QF and induce constant release even with a change in pH. XRD and DSC were used to evaluate the crystallinity and inclusion of drugs, SEM was used for morphological analysis, and FTIR was used to analyze chemical changes. In addition, fluidity was evaluated to confirm that it was improved by granulation process. Finally, the solubility patterns of solid dispersions and capsules were analyzed by a solubility test.

아시아인의 제2형 당뇨병 치료를 위한 친수성 고분자를 사용한 메트포르민 염산염-리나글립틴 방출제어형 정제 개발

박선재,김필윤,김나은,송영은,전가영,투무르수흐너밍에르덴,송정은,강길선 한국고분자학회 2022 폴리머 Vol.46 No.2

제2형 당뇨병 치료제 메트포르민 염산염은 생물약제학적 분류체계 III에 속하는 약물로 물에 대한 용해도가높다. 따라서 초기 방출이 급격하게 일어나기 때문에 서구인에 비해 낮은 체중과 체지방을 가진 아시아인들에게는저혈당증이 발생한다. 이에 급격한 약물 혈중농도 증가에 의한 저혈당증 위험의 발생률을 낮출 수 있도록 친수성고분자를 사용하였고, 습식과립공정을 통하여 메트포르민 염산염과 리나글립틴 고정 용량 조합 삼중층 정제를 제조하였다. X-ray diffractometer(XRD)를 통해 약물의 결정성 및 포접을 평가했고, Fourier transform infrared spectroscopy(FTIR)을 통해 물리·화학적 변화를 확인하였다. 최종적으로, 본 연구의 서방정제와 트라젠타듀오정과의 비교용출 시험을 수행하여, 아시아인들에 적합한 제2형 당뇨병 치료제로 개발 가능함을 확인하였다.

Substitution effect of white radish (Raphanus sativus L.)’ by-product and tunic of sea squirt (Halocynthia rorentzi, von Drasche) for Undaria pinnatifida in feed of abalone (Haliotis discus, Reeve 1846)

이기욱,김희성,김필윤,정해성,김준,윤아영,조성환 한국수산과학회 2018 Fisheries and Aquatic Sciences Vol.21 No.2

Substitution effect of white radish’ by-product (WRB) and tunic of sea squirt (TSS) for Undaria in feed on growth and carcass composition of abalone was determined. Eight-hundred forty juveniles were distributed into 12 containers. Three formulated diets were prepared in triplicate. A 15% Undaria was included in the control diet. The 15% Undaria was substituted with a same amount of WRB and TSS, referred to as the DRG and TSS diets, respectively. Finally, dry Undaria was also prepared to compare effect of the formulated diets on performance of abalone. The experimental diets were fed to abalone once a day at a satiation level with a little leftover. The feeding trial lasted for 16 weeks. Crude protein, crude lipid, and ash content of the experimental diets changed over all period of time. Higher crude protein and lipid and ash contents retained in all formulated diets compared to the Undaria were observed at 24 and 48 h after seawater immersion. Survival of abalone was not affected by the experimental diets. Weight gain and specific growth rate (SGR) of abalone fed the TSS diet was greater than all other diets. Weight gain and SGR of abalone fed the control diet was not different from those of abalone fed the WRB diet. Proximates of the soft body of abalone was affected by the diets. In conclusion, WRB and TSS are the promising feed ingredients to replace Undaria in abalone feed; especially, TSS is superior to either Undaria or WRB. The formulated diets produced improved growth performance of abalone over the single Undaria.

Release Behavior of Telmisartan/Amlodipine Combination Drug According to Polymer Type

빈수영,최정민,김필윤,김원경,Alessio Bucciarelli,송정은,강길선 한국고분자학회 2021 Macromolecular Research Vol.29 No.3

Patients at risk for hypertension with comorbidities such as diabetes and metabolic syndrome often require two or more antihypertensive drugs to lower their blood pressure. Telmisartan and amlodipine are widely known drugs to treat hypertension. However, telmisartan suffer of poor solubility in water that makes necessary to increase its dosage to reach a sufficient therapeutic concentration. In this study, a solid dispersion containing a water-soluble polymer was prepared to make the absorption rate of telmisartan similar to that of amlodipine, a water soluble drug. As water-soluble polymers, polyvinylpyrrolidone K30, polyethylene glycol 6000, and poloxamer 407 were used. The encapsulation of the solid dispersion was analyzed by differential scanning calorimetry, Xray diffraction, and high-performance liquid chromatography. The reduced flowability of the solid dispersion was improved by a wet granulation. Scanning Electron Microscopy was used to study the morphology and the flowability was verified by measuring the angle of repose, bulk density, and tap density, and expressed by Hausner ratio and Carr index. The release behavior was confirmed by dissolution test and high-performance liquid chromatography. As result we proved that telmisartan a higher release rate when encapsulated with PVP K30. Finally, we designed a drug formulation in which amlodipine and telmisartan could be absorbed at a similar rate.

Improvement of Medication Adherence and Controlled Drug Release by Optimized Acetaminophen Formulation

빈수영,최정민,이영훈,김필윤,김원경,조훈휘,이지은,Alessio Bucciarelli,이대훈,송정은,강길선 한국고분자학회 2021 Macromolecular Research Vol.29 No.5

Acetaminophen (paracetamol, APAP) is a major component of Tylenol, Penzal Q, and Panpyrin, and is the most commonly used antipyretic analgesic in children. The conventional oral drug delivery systems of APAP are pills and tablets. However alternative drug delivery methods are desirable in case of pediatric or geriatric patients, especially for drugs like APAP that must be taken in large doses at once. Another requirement for a good drug delivery system is the rapid dissolution to ensure a rapid therapeutic action as pain reliever. In this study Acetaminophen (paracetamol, APAP) was encapsulated in a water-soluble polymer. After the preparation of the solid dispersion by encapsulating acetaminophen in polyvinylpyrrolidone, the resultant granules were used in three formulations: tablets, chewable tablets, and oral dissolving films (ODF). Solid dispersions and prepared formulations were evaluated by Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffractometer (XRD), and universal tensile machine (UTM), and the release behavior was compared. As a result, it was confirmed that the oral dissolving films can be taken easily because it has the advantages of both tablet and liquid dosage form accurate dosage, easy administration, easy swallowing, and fast bioavailability. Furthermore, the drug absorption rate can be effectively increased by changing the formulation.

젖당과 미결정 셀룰로오스 함량에 따른 니자티딘 속방정 방출 거동

정준재(Jun Jae Jung),김진우(Jin Woo Kim),김필윤(Pil Yun Kim),김원경(Won Kyung Kim),송정은(Jeong Eun Song),강길선(Gilson Khang) 한국고분자학회 2020 폴리머 Vol.44 No.4

최근 불규칙한 식습관, 잦은 스트레스, 지나친 음주로 인해, 위궤양과 역류성 식도염같은 만성질환으로 고통받는 환자가 증가하고 있다. 니자티딘은 히스타민 수용체(histamine-2 receptor, H2)와 국소적으로 결합하여 위산 생성을 억제하는 히스타민 수용체 길항제로 주로 위궤양과 역류성 식도염 치료제로 사용된다. 젖당을 이용하여 제형제조 시 제형의 부피를 증가시키고 우수한 수용성의 장점이 있지만 제형의 경도가 좋지 않아 쉽게 분해되는 단점이 있다. 젖당과 미결정 셀룰로오스를 적절한 비율로 혼합하여 고체분산체 제조 시 미결정 셀룰로오스에 의해 제형의 경도가 증가되고, 경도가 증가됨에 의해 제형의 안정성도 증가한다는 것을 확인하고자 니자티딘과 젖당/미결정 셀룰로오스를 메탄올/디클로로메탄 공용매 조건에서 회전증발기를 이용하여 고체분산체를 제조하였다. 고체분산체의 특성분석을 위해, SEM, DSC, XRD, FTIR을 실시하였고, 이 후 생체 외 용출거동을 통해 약물 방출을 확인하였다. 젖당과 미결정 셀룰로오스의 비율이 3:7인 고체분산체에서 상대적으로 우수한 포접률을 확인하였으며, 이를 이용한 속방정의 약물방출 거동으로 이상적인 속방정 약물방출 거동을 확인하였다. 이러한 결과로 니자티딘과 젖당/미결정 셀룰로오스를 이용한 속방정은 역류성 식도염 치료제로 사용 가능함을 확인할 수 있다. Recently, patients suffering from unexpected chronic diseases such as gastric ulcer and reflux esophagitis are increasing due to irregular eating habits, frequent stress, and excessive drinking. Nizatidine is a histamine receptor antagonist that inhibits gastric acid production by locally binding to the histamine H2 receptor and is mainly used as a treatment for gastric ulcer and reflux esophagitis. Lactose can increase drug volume and provide moderate water solubility, but it decreases hardness. To confirm the increase of hardness and stability of drug when lactose is blended with microcrystalline cellulose to make solid dispersion, nizatidine, lactose and microcrystalline cellulose solid dispersion was manufactured by rotary evaporator in methanol/dichloromethane cosolvent condition. For characterization of the solid dispersion, SEM, DSC, XRD and FTIR were performed, and then drug release was confirmed through an in vitro dissolution test. A relatively good inclusion rate was confirmed in a solid dispersion having a ratio of lactose and microcrystalline cellulose of 3:7, and an ideal behavior of immediate release tablet was confirmed by this. As the result of this, it can be confirmed that nizatidine and lactose/microcrystalline cellulose can be used as immediate release tablet for reflux esophagitis.

습식 과립을 통해 용해도가 개선된 나프록센 나트륨 제형 설계

이성원(Seong Won Lee),조훈휘(Hun Hwi Cho),김진우(Jin Woo Kim),김남영(Nam Yeong Kim),김필윤(Pil Yun Kim),송철의(Cheol Ui Song),이원찬(Won Chan Lee),최정민(Jeong Min Choi),송정은(Jeong Eun Song),강길선(Gilson Khang) 한국고분자학회 2021 폴리머 Vol.45 No.3

최근 유전 및 노화로 인해 관절염(류마티스, 퇴행성 관절염 등)으로 고통받는 환자들이 증가하고 있으며, 이들 대부분의 환자들은 지속적인 통증으로 인해 건강 관련 삶의 질(HQRL)이 저하되고 있다. 통증 치료를 위해서는 비스테로이드성 항염증제(NSAIDs)가 널리 사용되고 있으며, 대표적인 치료제로 나프록센 나트륨(NAP)이 사용된다. NAP는 발열, 염증, 통증을 일으키는 프로스타글란딘(PG)의 생성에 관여하는 효소인 사이클로옥시게나제 1과 2(COX-1, COX-2)를 억제하는 장점이 있으며, 상대적으로 반감기가 12시간이다. 그러나 NAP는 하루에 2번 275-550 mg의 경구 투여에 의해 용해도가 낮고 흡수도가 높은 생물약제학적 분류체계 c la ss 2 약물이다. 나프록센 나트륨의 낮은 용해도를 개선하기 위해 수용성 고분자인 폴리비닐피롤리돈(PVP-K30), 폴리비닐알콜(PVA), 전분과 NAP를 습식과립법으로 과립을 제조하였다. 이후 NAP의 향상된 형태와 용해도를 확인하고자 주사전자현미경(SEM), 시차주사 열량분석법(DSC), X선 회절분석법(XRD), 푸리에 변환 적외선 분광학(FTIR) 및 고성능 액체 크로마토그래피(HPLC)를 통해 확인하였다. 이러한 결과를 바탕으로 습식 과립 형성을 통해 NAP의 용해도가 향상되었음을 보여주었고, 즉시 방출 효과인 속방정으로써 관절염에 대한 치료제로 응용 가능하다는 것을 보여주었다. Recently, many patients are suffered from arthritis including osteoarthritis, rheumatoid arthritis due to increment in genetic disease and aging. Most patients with arthritis have a relatively low health-related quality of life (HRQL) due to persistent pain. For the treatment of pain, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and among them, naproxen sodium (NAP) is typically applied. NAP has merits in inhibiting cyclooxygenases 1 and 2 (COX-1, COX-2), enzymes involved in the production of prostaglandin (PG) which cause fever, inflammation, and pain, and has a relatively long half-life of 12 h. However, NAP is a biopharmaceutics classification system (BCS) class 2 drugs with low solubility and high absorption by oral administration of 275~550 mg per time, twice a day. Herein, the low solubility of NAP was improved by wet granulation of the water-soluble polymer polyvinylpyrrolidone (PVP-K30), polyvinyl alcohol (PVA), starch, and NAP. The improved morphology and solubility of NAP was confirmed by scanning electron microscope (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC). Overall results showed enhanced solubility of NAP through the wet granule formation and showed promising treatment for arthritis as immediate release medicinal effects.