(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.

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.

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

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).

(The) functional roles of microRNA-6126 during lung fibrosis induced by polyhexamethylene guanidine phosphate in human alveolar epithelial A549 cells

Jang, Eunhye Sungkyunkwan university 2019 국내석사

Polyhexamethylene guanidine-phosphate (PHMG-p), one of the major ingredients in the humidifier disinfectants, has been proven in many studies to cause pulmonary fibrosis. Recently, epithelial‐mesenchymal transition (EMT)-induced by PHMG-p has been reported in human lung alveolar epithelial A549 cells. Many studies has shed light on the role of dysregulation of microRNAs (miRNAs) in the regulation of EMT as one of the mechanisms of lung fibrosis, in which epithelial cells gain a mesenchymal phenotype. Although the previous study investigated mRNA-miRNA regulatory networks induced by PHMG-p exposure in vitro, the role of specific miRNA in the PHMG-p-induced fibrogenic mechanism was not studied. Thus, the aim of this study was to elucidate the functions of miR-6126, particularly up-regulated in A549 cells and rats by PHMG-p exposure. Moreover, the comparison of miR-6126 expression with three chemicals capable of inducing EMT, paraquat, transforming growth factor-β and bleomycin was implemented to check for specificity. Overexpression of miR-6126 elevated the expression of α-smooth muscle actin (α-SMA), a characterized marker of myofibroblast, whereas inhibition of miR-6126 repressed PHMG-p-induced α-SMA activation during EMT. Interestingly, phospho-kinase array revealed that miR-6126 acted in a concerted manner to regulate the numerous signaling pathways-activated by PHMG-p. Specially, the MAPK and Akt/GSK-3β pathways which have been known to be involved in the pathogenesis of fibrotic response, were regulated by miR-6126 modulation. Additionally, protocadherin9 (PCDH9), a mediator of cell adhesion, was predicted as a target of miR-6126 by multiple bioinformatics analyses and identified through target validation assays. Consistently, PCDH9 expression was significantly reduced by PHMG-p treatment. In conclusion, miR-6126 could play a pivotal role in PHMG-p-induced EMT regulating multiple signaling pathways including MAPK and Akt/GSK-3β pathway via targeting PCDH9. This study first elucidated the role of miR-6126 in PHMG-p-induced pulmonary fibrosis and indicated the potential of miR-6126 as a novel diagnostic marker for PHMG-p-induced pulmonary fibrosis.

Estrogen deficiency potentiates thioacetamide-induced hepatic fibrosis

Lee, Yonghee Sungkyunkwan university 2019 국내석사

Liver fibrosis is characterized by persistent deposition of extracellular matrix proteins which occurs in most types of chronic liver disease, such as fibrosis or cirrhosis. The protective role of estrogen on liver fibrosis has been studied extensively, but the molecular mechanism remains unclear. The goal of this study was to investigate the effect of estrogen deficiency on thioacetamide (TAA)-induced liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of TAA (150 mg/kg/day) for 1 week in ovariectomized (OVX) female rats, normal female rats, and male rats. Estrogen deficiency considerably increased the activity of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase in TAA-treated OVX female rats compared with TAA-treated female rats. Estrogen deficiency markedly reduced total glutathione levels and catalase and superoxide dismutase activity in TAA-treated OVX rats. In contrast, malondialdehyde levels were markedly increased in the livers of OVX rats treated with TAA. Particularly, estrogen deficiency significantly increased alpha smooth muscle actin, collagen I, and vimentin in the livers of TAA-treated OVX female rats, and further aggravated fibrosis through the transforming growth factor-β/Smad pathway. In conclusion, our findings reveal that estrogen deficiency potentiates the risk of hepatic fibrosis. 간 섬유화는 간경화와 같은 대부분의 유형의 만성 간 질환에서 발생하는 세포 외 기질 단백질의 지속적인 축적을 특징으로 합니다. 간에서 에스트로겐의 역할은 광범위하게 연구되어 왔지만 분자 메커니즘은 불분명하다. 본 연구의 목적은 thioacetamide (TAA)에 의한 간 섬유화 모델에서 에스트로겐 결핍이 간성상세포에 미치는 영향과 에스트로겐의 항 섬유화 신호 전달 경로를 연구하는데 있었다. 1 주간 TAA (150 mg / kg / day)를 복강 내 주사하여 간 섬유화를 유도 하였다. 에스트로겐 결핍은 TAA 처리 쥐에서 AST, ALT, ALP 및 r-GTP의 활성과 간 중량을 상당히 증가시켰다. 에스트로겐 결핍은 TAA 처리 쥐에서 총 GSH, CAT 및 SOD의 활성을 현저히 감소시켰고 MDA 수준은 현저하게 증가시켰으며, 에스트로겐 결핍은 간세포의 세포 사멸을 증가시켰다. 특히, 에스트로겐 결핍은 TAA 처리 된 래트에서 α - SMA, conllagen I, vimentin의 단백질 발현을 유의하게 증가시켰고 Hydroxyproline 함량을 유의하게 증가시켰다. 또한 TGF – β 신호 전달 경로의 활성화를 유의하게 증가시켰다. 따라서 에스트로겐 결핍은 간 섬유화의 위험을 증가시킬 수 있으며, 에스트로겐은 간 손상을 억제하여 항 섬유화의 효과를 암시 할 수 있음을 증명하였다.

Development of gastroretentive tablets containing pregabalin

Kim, Seongkyu Sungkyunkwan university 2019 국내박사

The main purpose of this study was to develop gastroretentive tablets with floating and swelling properties for once-daily administration of Pregabalin. The non-effervescent floating and swelling tablets were prepared using the wet granulation and compaction, which are widely used and easily accessible. The optimized PGRT300 formulation showed a sustained drug release patterns with the non-Fickian release behavior, began to float within 3 min, floated completely within 10 min, maintained buoyancy for over 24 h, and expanded above the fed-state pyloric sphincter diameter, 12.8 mm, in three dimensions. The amount of hydroxypropyl methylcellulose and crospovidone were found to be critical factors affecting in vitro dissolution and floating properties of the prepared tablets. The optimized tablets containing 300 mg of Pregabalin started to float within 3 min and swelled above 12.8 mm, the reported pyloric sphincter diameter during the fed state, in all dimensions including length, width, and thickness. In vivo results in beagle dogs indicated that the optimized formulations are suitable as once-daily dosage forms, and dose proportionality was observed in doses ranging from 75 to 300 mg. In addition, the dogs administered with the formulation having poor in vitro gastroretentive properties showed highly variable and reduced extent of absorption, signifying the necessity of the gastroretentive drug delivery system. In conclusion, the developed non-effervescent floating tablets are promising candidates for once-daily delivery of Pregabalin.

Dendropanax ameliorates nephrotoxicity by upregulating SIRT-1 in streptozotocin-induced diabetic rats

Sachan, Richa Sungkyunkwan university 2019 국내박사

The aim of this study is to identify the protective effect of Dendropanax (DP) against kidney injury in streptozotocin (STZ)-induced diabetic male wistar rats. Diabetes was induced by single intraperitoneal injection of streptozotocin (40 mg/kg). Two days after STZ treatment, development of diabetes in two experimental groups was confirmed by measuring blood glucose levels in a tail vein blood samples. Rats with blood glucose levels of 250 mg/dl or higher were considered to be diabetic. Dendropanax (200 mg/kg, DP) was administered orally for 28 days to rats with STZ-induced diabetic nephropathy. Metformin was used as a positive control and administered orally for 28 days. At the end of administration, fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), HDL-c, LDL-c, urinary or serum BUN and creatinine levels were subsequently examined. Diabetic rats expressed elevated blood glucose levels and altered lipids profiles. Treatment with DP and metformin significantly reduced blood glucose, total cholesterol (TC), triglycerides (TG), and HDL-c. Treatment of DP and metformin markedly reduced the urinary excretion of nephrotoxicity biomarkers (KIM-1, SBP-1, PKM2 & NGAL) as compared with diabetic untreated group. Moreover, the DP-treated group showed improvements in renal function and morphometry. In diabetic group, kidney SIRT (1, 3, or 4), catalase (CAT) and superoxide dismutase (SOD) activities were significantly lower than diabetic control group. DP and metformin caused significant increase in the SIRT1, SOD and CAT activities in kidney tissues compared to diabetic control group. Administration of DP extract significantly reduced in proinflammatory cytokines, cleavage caspase-3 and cleavage caspase-9 in the kidney tissue of diabetic rats. In conclusion, this study strongly suggests Dendropanax extract exerts a protective role against diabetesix induced renal injury by ameliorating oxidative stress, inflammation and apoptosis. DP extract significantly prevented diabetic-induced oxidative stress, inflammation, and apoptosis in the kidney tissues.

ATF3 stimulates IL-17A-mediated streptococcus pneumoniae clearance by regulating Ca2+/ROS-dependent IL-1β activation

Lee, Seungyeop Sungkyunkwan university 2019 국내박사

Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1β secretion. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1β production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca2+ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in gamma delta T cells to rapidly induce host defenses during early S. pneumoniae infection. 소포체 스트레스 반응에 의히여 유도된 활성 전사 인자 3 (Activating transcription factor 3, ATF3)는 그람양성균 감염 시 사이토카인 분비를 촉진시킴으로서 면역시스템을 강화하여 숙주의 생존에 기여한다. 특히, 폐렴구균 감염 시 초기 방어에 중요한 사이토카인인 IL-17A의 수준을 증가시켜 생쥐의 생존율을 향상시켰다. 현재까지 IL-17A와 폐렴구균과의 정확한 메커니즘이 밝혀지지 않았다. 따라서, 그에 따른 연구가 필요한 실정이다. ATF3는 폐렴구균 초기 감염 시 대식세포 내에서 NLRP3 인플라마좀을 구축을 도와서 IL-1β를 분비를 증가시킨다. 이렇게 분비된 IL-1β는 선천면역계의 γδ T 세포를 자극하여 폐렴구균 방어를 위한 IL-17A를 유도한다. 이를 증명하기 위하여 야생형과 ATF3 유전자 결핍 생쥐의 IL-17A를 중립화(Neutralization) 시킨 후 생존율을 측정하였으며 또한 FACS를 통하여 γδ T 세포를 통하여 ATF3가 IL-17A의 생산에 관여한다는 사실을 알 수 있었다. 더욱이, ATF3 유전자 결핍 생쥐에서 IL-17A의 단백질과 mRNA 수준이 야생형에 비해 통계적으로 유이하게 감소하였으며 생존율 역시 낮았다. 더욱이 야생형 및 ATF3 유전자 결핍 생쥐의 골수에서 추출하여 분화시킨 골수 세포성 대식세포에서는 ATF3 유전자 결핍 마우스의 IL-1β의 생산이 야생형에 비해 현저하게 낮았다. 또한 ATF3 유전자 결핍 마우스의의 대식세포가 폐렴균에 의한 숙주세포 감염 시 활성산소와 Ca2+의 항상성이 쉽게 붕괴되는 것을 관찰할 수 있었다. 특히 ATF3 결핍 마우스는 항산화 기능이 야생형에 대비하여 급격히 떨어지게 되어 폭발적인 ROS의 증가와 그에 따른 세포 내 ATP 고갈이 빠르게 일어났다. 그 결과 ATF3 유전자 결핍 생쥐는 선천 면역 기능이 감소하여 폐렴구균의 집락 형성에 대한 저항이 현저하게 감소하였다. 결과적으로 이 실험을 통해 ATF3가 폐렴구균의 방어에 중요한 사이토카인인 IL-17A의 메커니즘에 관여하여 선천면역계를 향상시킨다는 것을 알 수 있었다.

Application of solid fraction prediction method for atorvastatin calcium dry granules

Choi, Hyeongseok Sungkyunkwan university 2019 국내석사

The feasibility of the roller compaction and the current approach to development and scaleup use a considerable amount of material for the experiment. Material wasteful roller compaction process has been simulated in a single compressor to improve product development efficiency. Compaction simulators were used to simulate the manufacture of ribbons such as roller compactors. Compared to roller compression, simulation can use a limited amount of material (~10x reduction) and screening can be performed quickly by evaluating simulated compacts. The solid fraction of the ribbon is known to be the most important factor in determining the characteristics of granules in the dry granulation method. In general, the solid fraction of the ribbon used as a key parameter of the product quality to compare the actual roller compression process with a simulation using a single compression. In this study, solid fraction prediction method was developed by using the simulator, and formulation study for dry granules was performed using atorvastatin calcium as a model drug. The correction factor K was introduced to considering the elastic recovery of the compact, and the solid fraction was successfully predicted at out-die. Formulation studies were conducted using solid fraction prediction method. Binder and MCC/Lactose ratios were investigated to achieve the proper ribbon strength (> 1 MPa at 70% solid fraction). The effect of the binder was not significant, and the proper ribbon strength was achieved at 66% MCC/Lactose ratio. Ribbons were milled into granules using a Fitz mill and morphology, flowability, tabletability, and particle size distribution was evaluated. The tablets were compressed using the simulator and evaluated content uniformity, dissolution, hardness. Formulation with a comparable dissolution profile to reference drug (>95% release at 30min) was selected. 60-80% solid fraction ribbons were evaluated to determine the optimal solid fraction with a balance of "improvement of flowability" and "loss of tabletability". Finally, granules from the 70% solid fraction ribbons showed "fair" grade flowability and their tablets had a hardness above 100 N. In conclusion, the solid fraction was successfully predicted at the out-die using the correction factor K and the target solid fraction ribblets could be produced. The solid fraction prediction method enables systematic formulation studies using a small amount of sample. This prediction method offers many advantages for efficient formulation studies and scale-up of dry granules.