(The) viability of online pharmacies and safety regulations : globally and in South Korea

Song, Hyunsue Sungkyunkwan university 2020 국내박사

This study examines the characteristics of online pharmacies and possible policy directions for countries in which online pharmacies are not yet permitted. Factors governing physical and online pharmacies, pharmacy and e-commerce related regulations, and drug classification systems—particularly the United States Government Accountability Office (GAO)—in fourteen countries were surveyed based on e-commerce indices and the number of internet users. The regulatory environments, distribution systems, and industrial ecosystems related to online medicine sales in South Korea were also analyzed to determine why online pharmacies are not yet permitted. The survey results show that eleven of the fourteen countries permit online pharmacies. A survey of the scales of the e-commerce, health/beauty, and online pharmacy markets by country showed that the United States has the highest share in the entire e-commerce and online pharmacy market. However, China’s share in the business to consumer (B2C) market and the health/beauty market are first globally. Despite the rapid growth of the online pharmacy market, markets in the surveyed countries had a B2C market share of less than 2%. When classifying individual countries according to the sales restrictions imposed by the US GAO, South Korea’s classification system was shown to be similar to that of China. If countries where online pharmacies are not yet permitted such as South Korea prepare response systems similar to the structures of countries in the GAO classification system, they may be able to contribute to the maintenance of stable medicine management systems once online pharmacies are permitted. Therefore, it is time for the South Korean government to consider seriously allowing online pharmacies in the trend of allowing global online pharmacies. To enhance the competitiveness of the nation`s pharmaceutical market, the Korean government must address the challenges required to minimize the threat posed by allowing online pharmacies.

Development of orally disintegrating tablet containing dapoxetine

Kim, Sangjoon Sungkyunkwan University 2015 국내석사

Abstract Development of Orally Disintegrating Tablet containing Dapoxetine The Graduate School of Sungkyunkwan University Department of Pharmacy Sang-Joon Kim The aim of this study was to develop taste-masked orally disintegrating tablet (ODT) containing dapoxetine (DPX). In this study, dapoxetine freebase (DPX-FB) was used as active pharmaceutical ingredient (API) due to less bitter taste than dapoxetine hydrochloride (DPX-HCl). DPX-FB was achieved by salt-alteration of DPX-HCl. DPX-FB had different structural, physicochemical properties with DPX-HCl and showed improvement in taste-masking efficiency. Taste-masked granules containing DPX-FB and taste-masking excipients; Compritol ATO 888, Precirol ATO 5 and Eudragit EPO were prepared at three different API to excipient ratios (1:0.5, 1:1, 1:2). Particle size distribution, in vitro release test and taste-masking efficiency of granules were evaluated. Among them, granules with drug to Eudragit EPO ratio of 1:2 had the highest in vitro taste-masking efficiency and were chosen as the optimized granules. ODTs containing optimized granules, sugar excipients and superdisintegrants were prepared by direct compression method. Hardness, disintegration time and taste-masking efficiency of ODTs were evaluated. ODT of optimum disintegrated within 10 s in a disintegration tester and had hardness of higher than 50 N. In conclusion, taste-masked ODTs were developed and optimum formulation was selected based on hardness, disintegration time and taste-masking efficiency. Keywords: Dapoxetine, Electronic-tongue system (E-tongue system), Orally disintegrating tablet (ODT), Taste-masking, Sugar excipients

Design, synthesis and structure-activity relationship studies of bioactive ligands with heterocyclic scaffolds

Duy-Viet Vo Kangwon National University 2020 국내석사

Design, Synthesis and Structure-Activity Relationship Studies of Bioactive Ligands with Heterocyclic Scaffolds Duy-Viet Vo Department of Pharmacy Graduate School, Kangwon National University Abstract SECTION 1 Drug Development with Flavonol Scaffold as Chemotherapy-induced Peripheral Neuropathy (CIPN) Modulators Currently, no sufficient treatment options are available for treatment CIPN; hence it is essential to find other safe and effective treatments. Natural products such as plant secondary metabolites are still important molecules of interest in the treatment of various pain conditions. The known in vitro and in vivo studies of CIPN therapeutics have shown flavonoids as the promising agents for the treatment of CIPN. The present research will focus on investigating the flavonoids, mainly flavonols, flavonol analogues and their derivatives with effects on CIPN. We succeeded to design, synthesize a series of galangin analogues and their derivatives and evaluate their bioactivity against CIPN. We effectively developed a new method to synthesize the flavonol analogues via the nucleophilic substitution of the α-bromide compound and the Baker-Venkataraman rearrangement as key reactions with overall 6-8 steps and effective with high yield (~ 10%) from commercially available chemicals. In our efforts to discover pharmacologically superior analgesic effects for the treatment of CIPN, we operated an approach to design the structure requirements for activity on CIPN. From the present SAR studies that we have the preliminary conclusions for the analgesic effect of flavonol’s for treatment CIPN. The result of this study will be helpful to amplify and comprehend the development of flavonols analgesic effects on CIPN. Keywords: flavonol, galangin analogues, galangin derivaties, thioketones, nucleophilic substitution of α-ketone, Baker-Venkataraman rearrangement, analgesic effect, CIPN, SAR study, drug design. SECTION 2 Drug Development with 1,3,5-Triazine Scaffolds as GPR119 Agonists GPR119 is a G protein-coupled receptor (GPCR) expressed both in pancreatic β cells and enteroendocrine L cells. In vitro and in vivo studies show that GPR119 agonists can improve glucose homeostasis, proving GPR119 is a promising target for the treatment of type 2 diabetes. For the drug development study on GPR119, compound AR-231453 was chosen as the hit structure. The replacement of the 5-nitropyrimidine with less hepatotoxicity 1,3,5-triazine in parent rings was performed and assessed for their biological activity. Then two anilinos substituted by electron-withdrawing groups (EWG) were provided as tail moiety linked to the novel scaffold. Finally, replacement of the piperidine ring with conformationally controlled azabicyclic rings constructed a new series of 1,3,5-triazine analogues 2a-2l. We assessed the introduction of inflexible fragments like azabicyclic moieties to the ligands that decreased the conformational suppleness to create an ideal conformation and best recognized by the receptor. We have also investigated synthetic pathway as a novel and stereoselective method of a series of key intermediate azabicyclic alcohols or amines 3a-3f in the good to excellent yields. In the synthetic strategy, dechlorination reaction with H2 and TEA, using 10% Pd/C as a catalyst in Et2O:THF to afford the target compounds 2a-2l was also studied as the key reaction. Nevertheless, the yield of the dechlorination reaction was not agreeable. Hence, the optimal conditions will be researched in subsequent studies to support the discovery of the lead compounds on 1,3,5-triazine scaffold for GPR119 agonist activity. Keywords: GPR119 agonist, type 2 diabetes, 1,3,5-triazine, stereoselective of azabicyclic alcohols and amines, dechlorination, drug design.

Maternal opioid use during breastfeeding and the risk of adverse infant outcomes : a nationwide cohort study

Choi, Eunyoung Sungkyunkwan University 2025 국내박사

Analysis of factors affecting spontaneous adverse drug reaction reporting and completeness of reports by Korean community pharmacists

Lee, Mose Sungkyunkwan university 2020 국내박사

Since pharmacies in Korea have about 500 million outpatient prescriptions per year and also sell over-the-counter (OTC) drugs, monitoring Adverse drug reactions(ADRs) in pharmacies is very important, but the completeness of drug ADR reports and reporting data are still low. Therefore, in this study, it was analyzed the factors affecting ADR reporting by community pharmacists and the factors that influence their completeness in order to find an effective method for increasing the ADR reporting and improving the completeness of the reporting data. To analyze the factors influencing the ADR reporting, a survey was conducted with community pharmacists. In order to analyze the factors affecting the completeness of the report data, the KAERS (Korea adverse event reporting system) data of KIDS (Korea Institute of Drug Safety & Risk management) from January 1, 2016 to December 31, 2016 was analyzed. The survey was conducted online from community pharmacists throughout the country and analyzed 382 responses was analyzed. In the analysis of descriptive statistics for each response item, further analysis was conducted by dividing into three groups based on responses to the number of reports in the last three years. Logistic regression analysis was performed to determine the factors affecting ADR reporting and to evaluate statistically significant factors and their magnitudes. In addition, multiple linear regression analysis was conducted to identify factors that affect the completeness of reports at each reporting institution. As a result of logistic regression, the probability of reporting with a frequency is 10.5% lower with increasing age (p = 0.001), and about 32 times higher than without the ADR reporting program (p = 0.001). If you know how to report it, it's about 54 times higher than it would otherwise be (p <0.001). In community pharmacies, the probability of reporting frequent events increased by 4.1 times (p = 0.034). Regarding attitudes, there were significantly fewer reports of those who said, `I have no time and can’t afford to psychologically to report ADRs.' and ‘It’s complicate ADR report format or report method’ In terms of the completeness of reports, three variables with the absolute value of the regression coefficient of more than 10 points in both models were identified as the variables that have high influence on the completeness confirmed by reporting groups by affiliation and reporting groups by profession. The analysis results by reporting groups by affiliation and reporting groups by profession are as follows. 'Indication for use in the case' (Regression coefficient = -12.99, -12.29), 'Date of start of drug' (Regression coefficient = -12.06, -12.18), 'Date of start of reaction/event' (Regression coefficient = -11.42,- 11.59).

Development of benzothiazole derivatives as PI3KC2γ inhibitor for rheumatoid arthritis

Yoo, Jaeho Sungkyunkwan university 2020 국내박사

Rheumatoid arthritis (RA) is a major disease of modern humans, and numerous studies have sought to find a therapeutic agent against RA. At present, the main treatment modalities of RA are disease-modifying anti-rheumatic drugs DMARD and biologics. To find out the new target for RA treatment, in the present study, I have suggested PI3K class2 gamma inhibitor. 6-(pyridin-4-yl)benzo[d]thiazol-2-amine was also evaluated in the RA tissue and in the RA animal model. An amino benzothiazole derivative was reported to inhibit PI3K kinase. Therefore, based on this evidence, in the present study, I demonstrated the relevance of amino benzothiazole to rheumatoid arthritis. To demonstrate the viability of MH7A (rheumatoid arthritis synovial cell) and raw 264.7 cell line, as well as the effect of rheumatoid arthritis model, 6-(pyridin-4-yl)benzo[d]thiazol-2-amine was evaluated RA tissue and in vivo model. Using a sample of tissue in the CIA model, I experimentally demonstrated that the target is effective in the rheumatoid arthritis by confirming the expression level of the target; the effect was also demonstrated in the rheumatoid arthritis model through the compound which is benzothiazole derivative. Amino benzothiazole derivatives are well known for their anti-inflammation effect. This compound was reported to have the effect of blocking TNF-α in MH7A cells; in vivo changes in physiological activity in cells were also demonstrated. The 6-(pyridin-4-yl)benzo[d]thiazol-2-amine compound was a PI3K class2 gamma inhibitor with druglikeness and inhibited by the cell. It was also effective in the model of CIA of rheumatoid arthritis disease. The present study demonstrates the 6-(pyridin-4-yl)benzo[d]thiazol-2-amine compound will be new RA treatment.

Development of iFRET probe for the detection of p73 binding to MDM2

Han, Aro Sungkyunkwan university 2020 국내석사

p73 acts as a transcription factor resulting in tumor suppression. MDM2 and Bcl-XL, to oncogenic proteins can negatively influence p73-mediated apoptosis by binding to p73 transactivation domains (TAD). The inhibition of protein-protein interaction between p73 and oncogenic proteins is an attractive strategy to promote p73-mediated apoptosis. Here, we describe the use of a modified p73-TAD peptide to construct a FRET based binding assay of p73-TAD to MDM2 and Bcl-XL. The FRET-probe equipped with 1-naphthylamine (λex = 330 nm, λem = 445 nm) serves as a FRET acceptor and tryptophan residues of the proteins act as the FRET donor (Trp, λex = 280 nm, λem = 340 nm). Sensitized emission of the FRET probe is observed upon excitation of the protein-FRET probe complex at Trp excitation wavelength. Furthermore, addition of the MDM2 inhibitor nutiln-3, the FRET signal was drastically reduced indicating that the FRET-probe binds competitively to MDM2. Our developed FRET binding assay may be applicable in high throughput screening of novel drugs which inhibit interactions between p73 and MDM2.

Development of sustained-release microparticles containing ropinriole hydrochloride for orally disintegrating tablets

Im, Jaehyeok Sungkyunkwan university 2020 국내석사

The aim of this study is to develop a sustained-release microparticle containing ropinirole hydrochloride for orally disintegrating tablets. The main indication of ropinirole hydrochloride is Parkinson's disease. The patient group of Parkinson's disease has difficulty swallowing tablets due to geriatrics, dysphagia and dyskinesia. The sustained-release microparticles were prepared using a fluid bed coater for the application of ropinirole hydrochloride to orally disintegrating tablets as a patient friendly dosage forms. A drug-ion exchange resin complex of ropinirole hydrochloride and Amberlite™ IRP 69 was prepared to control the rapid release of ropinirole hydrochloride and to mask the bitter taste in the mouth. Ropinirole hydrochloride was loaded with the sustained-release ion exchange resin, Amberlite™ IRP 69, in a batch method. The prepared drug-ion exchange resin complex showed more sustained-release than the active coated particles of ropinirole hydrochloride on Amberlite™ IPR 69. This confirmed that the drug-ion exchange resin complex was suitable as the core of sustained-release microparticle coated with hydrophobic polymer, Eudragit® RL PO, for further release control. To be equivalent to the reference drug, REQUIP® XL, in in vitro release study, drug-ion exchange resin complex was coated with Eudragit® RL PO to prepare sustained-release microparticles. The size of the prepared sustained-release microparticles was 200 µm or less and the sustained-release microparticles were suitable for orally disintegrating tablets because particles. The sustained-release microparticles prepared were mixed with excipients and compressed into tablets for application to orally disintegrating tablets. The formulation and process parameters were optimized to produce sustained-release orally disintegrating tablets. The orally disintegrating tablets containing sustained-release microparticles of ropinirole hydrochloride were prepared by varying the ratio of diluent, tableting pressure, and the thickness of coating layer of the sustained-release microparticle and evaluated by hardness study, disintegration study, and in vitro release study. The final optimized formulation for sustained-release orally disintegrating tablet of ropinirole hydrochloride was consisting of the sustained-release microparticle coated with 25% Eudragit® RL PO and 240 mg mannitol as diluent. The sustained-release orally disintegrating tablet met the release criteria of USP for ropinirole sustained-release tablet and the bitter taste of ropinirole hydrochloride was successfully masked. This tablet had proper mechanical strength with hardness of 67.0 N and disintegration time of 55.58 seconds. Additionally, the tablet was equivalent with REQUIP® XL 4mg in comparative release study and the similarity factor(f2) with the value of 43.38 was more than 40 which the criteria of f2 value for sustained-release tablets. 이 연구의 목표는 구강 붕해정에 적용 가능한 로피니롤 염산염의 서방형 미립자 개발이다. 로피니롤 염산염은 비-에르고린 도파민 작용제이며 도파인 D2 수용체를 자극함으로써 작용한다. 로피니롤 염산염의 주 적응증은 파킨슨병으로 파킨슨병 환자들은 고령이며 연하곤란, 운동 실조로 인하여 정제의 삼킴이 어려웠으며 환자군들을 위한 복용 편의성이 개선된 제형이 필요로 하였다. 로피니롤 염산염을 복용 편의 제형인 구강 붕해정에 적용하기 위해 유동층 코팅기를 이용하여 서방형 미립자를 제조했다. 로피니롤 염산염은 133 mg/mL의 높은 수용해도를 갖는 BCS class Ⅲ 약물이며 입 안에서 용해되어 쓴 맛을 나타낸다. 로피니롤 염산염의 빠른 방출을 조절하고 입 안에서 쓴 맛을 차폐하기 위하여 로피니롤 염산염과 Amberlite™ IRP 69의 약물-이온교환수지 복합체를 제조하였다. 추가적인 방출 조절을 위해 소수성 폴리머인 Eudragit® RL PO로 복합체를 코팅하였다. 제조된 서방 미립자들은 24시간 동안 로피니롤 염산염을 서서히 방출하여 서방형 구강 붕해정에 적용하기 적합하였다. 또한 미립자들의 d(0.9) 값은 200 µm 이하였다. 구강 붕해정에 200 µm 이상의 입자를 적용했을 때는 나쁜 식미감을 나타내기 때문에 제조된 미립자들은 구강 붕해정에 적합하였다. 제조된 서방형 미립자는 구강 붕해정에 적용하기 위하여 부형제들과 혼합을 거쳐 타정되었다. 이때 부형제는 필러이자 감미제로써 만니톨, 필러이자 붕해제로써 미결정셀룰로오스, 슈퍼 붕해제인 크로스포비돈, 활택제인 마그네슘 스테아레이트가 첨가되었고 혼합기를 이용한 혼합 과정을 거쳐 타정되었다. 이때 Eudragit® RL PO로 25% 코팅된 서방형 미립자를 함유하며 240 mg의 만니톨, 타정압은 5 kN의 조건으로 제조된 서방형 구강 붕해정이 USP의 로피니롤 염산염 서방정의 용출기준에 부합하며 비교용출평가에서 기존의 시장 제품인 REQUIP® XL 4 mg과 동등했으며 f2 값은 43.38였다. 또한 이 구강붕해정은 로피니롤의 쓴 맛을 차폐하여 파킨슨병 환자들을 위한 복용 편의제제의 기준을 만족하였다.

Development of a 3D-printed gastroretentive system for riboflavin by applying design of experiment approach

Jeong, Hyeonmyeong Sungkyunkwan university 2020 국내석사

This study aims to develop a new device-based gastroretentive system that consists of a 3D-printed capsular device and conventional tablets. The gastroretentive system was designed to be expandable in the gastric cavity to prevent passage through a pylorus during the drug release from the inner tablet, and to be back to its original shape to escape the stomach after completing drug release. The device was printed with poly lactic acid by using a fused deposition modeling printer. A sustained release (SR) tablet containing riboflavin 20 mg was inserted inside of the device. Definitive screening design and Box-Behnken design were used to design a gastroretentive device for desired drug release characteristics and gastric retention time. The in vitro dissolution was determined by the paddle method. Concentrations of riboflavin in the dissolution medium were determined by high-performance liquid chromatography. Following oral administration in Beagle dogs, the in vivo gastric retention was monitored by X-ray images, and the pharmacokinetics was evaluated. Plasma concentrations of riboflavin was determined by a validated liquid chromatography-tandem mass spectrometry method. The abdominal X-ray images showed the extended gastric residence of more than 12 h and the transit of the gastroretentive device as its original form to the intestine. Compared to the reference SR tablet, the gastroretentive system showed the higher maximum plasma concentration (Cmax) and the area under the plasma concentration (AUC) by 1.96 and 3.19 folds, respectively. Taken together, this study suggested that the oral bioavailability of SR tablets of a drug with a narrow absorption window could be improved by combining gastroretentive device. This approach may provide a promising approach for various drugs to develop gastroretentive systems. 본 연구의 목표는 3D 프린팅 된 캡슐형태의 장치와 내부 정제로 구성된 새로운 장치 기반 위체류 시스템을 개발하는 것이다. 개발된 위체류 시스템은 위내에서 팽창하여 내부 정제의 약물이 방출되기 전까지 위의 유문을 통과하지 못하게 하고 약물 방출이 완전히 방출된 후 원래 형태로 되돌아가 위장관을 통과할 수 있도록 설계되었다. 위체류 장치는 융합적층모델링 (FDM) 방식의 프린터를 사용하여 poly lactic acid (PLA) 재질로 제작되었다. 리보플라빈 20 mg의 서방정제를 장치 내부에 삽입하였다. 확정선별설계 및 Box-Behnken 설계는 약물방출 특성 및 위체류 시간을 설계하는 데 사용되었다. 시험관 내 용출시험은 패들 법을 이용하여 측정하였으며 용출액 중 리보플라빈의 농도는 고성능액체크로마토그래피 (HPLC)를 이용하여 정량하였다. 위체류 시스템은 비글견에 경구로 투여한 후 위에 머무는 시간과 방출되는 리보플라빈의 약물동태를 확인하였다. 복부 X-선 촬영을 퉁해 위체류 시스템이 12 시간 이상 위내에 머무는 것을 확인하였으며 약물이 완전히 방출된 이후 위체류 시스템의 구조변화를 통해 소장으로 배출되었다. 대조 SR 정제와 비교할 때, 위체류 시스템의 최대혈중농도 (Cmax)와 혈중농도곡선하면적 (AUC)은 각각 1.96 및 3.19 배 더 높아졌다. 종합하면, 개발된 위체류 시스템을 이용하여 좁은흡수 부위를 갖는 약물의 생체이용률과 혈중농도의 지속성을 개선할 수 있었으며 이는 개발된 위체류 시스템을 다양한 약물에 적용하여 새로운 위체류 제형을 개발할 수 있는 가능성을 보여준다.

Design and synthesis of Diosgenin derivatives for SHP2 inhibitors

Hwang, Yeongyo Sungkyunkwan university 2020 국내석사

The non-receptor type 11 tyrosine phosphatase (PTPN11), better known as Src homology region 2-domain containing phosphatase-2 (SHP2), has been recognized as a potential anti-cancer target. SHP2 regulates various signaling pathway and is reported to act as either a tumor suppressor or promoter. Hence, in the battle against cancer, the inhibition of SHP2 may prove to be vital. Diosgenin, a naturally occurring phytosteroid sapogenin has been shown to inhibit tumor proliferation and induce apoptosis in a variety of cancer cells. Unfortunately, the low water solubility of diosgenin hampers its bio-availability thereby diminishing its therapeutic usefulness. In this study, we focused on improving the water solubility of diosgenin through the chemical modification of diosgenin backbone. To this end, we have designed several diosgenin analogues which incorporate structure similarities to polyphyllin D, a known natural product with anti-cancer activity. Next, the biological profile of the freshly synthesized diosgenin derivatives was assessed revealing that the improved solubility of our diosgenin analogues resulted in an increased inhibitory profile towards SHP2. The developed and synthesized diosgenin derivatives with improved biological properties may be applicable as new anti-cancer therapeutics.