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( Prabagar Balakrishnan ),( Chung Kil Song ),( Hyun Ji Cho ),( Su Geun Yang ),( Dae Duk Kim ),( Chul Soon Yong ),( Han Gon Choi ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
To study the effect of β-cyclodextrin (βCD) inclusion complex on the bioavailability of clotrimazole frompoloxamer-based suppository, formulations composed of P 188, propylene glycol and different molar ratio of clotrimazole-βCD inclusion complex were prepared. Clotrimazole (1%) has been formulated in a suppository using the thermo sensitive polymer P188 (70%) together with propylene glycol (30%). To increase its aqueous solubility, clotrimazole was incorporated as its inclusion complex at various molar ratios with βCD (1:0.25, 1:0.5, 1:1, and 1:2). The inclusion complex was characterized by differential scanning calorimetry (DSC), XRD and phase solubility studies. It was observed that the complexation with βCD, particularly at high molar ratio (F3 (1:1) and F4 (1:2)) decreased the release profile of clotrimazole considerably. However, suppositories containing inclusion complex at low molar ratio (F1 (1:0.25) and F2 (1:0.5)) showed excellent release profile compared to control formulation. In vivo study in rats at 15 mg/Kg dose showed that the F1 and F2 (82.39 ± 15.40 and 67.05 ± 8.79, respectively) significantly increased the AUC compared to that of F3 (41.48 ± 11.51), F4 (23.34 ± 8.37) and control (46.7 ± 7.87) suppositories. Thus, the suppositories containing inclusion complexes prepared at low drug to βCD molar ratio (F1) could be a potential suppository formulation to increase the bioavailability of hydrophobic drugs such as clotrimazole.
Prabagar Balakrishnan,최한곤,송충길,Hyun-Jong Cho,양수근,Dae Duk Kim,용철순 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.7
To study the effect of β-cyclodextrin (βCD) inclusion complex on the bioavailability of clotrimazole from poloxamer-based suppository, formulations composed of P 188, propylene glycol and different molar ratio of clotrimazole-βCD inclusion complex were prepared. Clotrimazole (1%) has been formulated in a suppository using the thermo sensitive polymer P188 (70%)together with propylene glycol (30%). To increase its aqueous solubility, clotrimazole was incorporated as its inclusion complex at various molar ratios with βCD (1:0.25, 1:0.5, 1:1, and 1:2). The inclusion complex was characterized by differential scanning calorimetry (DSC), XRD and phase solubility studies. It was observed that the complexation with βCD, particularly at high molar ratio (F3 (1:1) and F4 (1:2)) decreased the release profile of clotrimazole considerably. However, suppositories containing inclusion complex at low molar ratio (F1 (1:0.25) and F2 (1:0.5)) showed excellent release profile compared to control formulation. In vivo study in rats at 15 mg/Kg dose showed that the F1 and F2 (82.39 ± 15.40 and 67.05 ±8.79, respectively) significantly increased the AUC compared to that of F3 (41.48 ± 11.51), F4 (23.34 ± 8.37) and control (46.7 ± 7.87) suppositories. Thus, the suppositories containing inclusion complexes prepared at low drug to βCD molar ratio (F1) could be a potential suppository formulation to increase the bioavailability of hydrophobic drugs such as clotrimazole.
Prabagar, Balakrishnan,Yoo, Bong-Kyu,Woo, Jong-Soo,Kim, Jung-Ae,Rhee, Jong-Dal,Piao, Ming Guan,Choi, Han-Gon,Yong, Chul-Soon 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2
Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with ${\beta}$-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of ${\beta}$-cyclodextrin concentration, resulting in A$_L$ type Phase solubility diagram Which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M$^{-1}$. The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.
Prabagar, M G,Do, Y,Ryu, S,Park, J-Y,Choi, H-J,Choi, W-S,Yun, T J,Moon, J,Choi, I-S,Ko, K,Ko, K,Young Shin, C,Cheong, C,Kang, Y-S Macmillan Publishers Limited 2013 Cell death and differentiation Vol.20 No.4
Complements, such as C1q and C3, and macrophages in the splenic marginal zone (MZMs) play pivotal roles in the efficient uptake and processing of circulating apoptotic cells. SIGN-R1, a C-type lectin that is highly expressed in a subpopulation of MZMs, regulates the complement fixation pathway by interacting with C1q, to fight blood-borne Streptococcus pneumoniae. Therefore, we examined whether the SIGN-R1-mediated classical complement pathway plays a role in apoptotic cell clearance and immune tolerance. SIGN-R1 first-bound apoptotic cells and this binding was significantly enhanced in the presence of C1q. SIGN-R1–C1q complex then immediately mediated C3 deposition on circulating apoptotic cells in the MZ, leading to the efficient clearance of them. SIGN-R1-mediated C3 deposition was completely abolished in the spleen of SIGN-R1 knockout (KO) mice. Given that SIGN-R1 is not expressed in the liver, we were struck by the finding that C3-deposited apoptotic cells were still found in the liver of wild-type mice, and dramatically reduced in the SIGN-R1 KO liver. In particular, SIGN-R1 deficiency caused delayed clearance of apoptotic cells and aberrant secretion of cytokines, such as TNF-α, IL-6, and TGF-β in the spleen as well as in the liver. In addition, anti-double- and single-stranded DNA antibody level was significantly increased in SIGN-R1-depleted mice compared with control mice. These findings suggest a novel mechanism of apoptotic cell clearance which is initiated by SIGN-R1 in the MZ and identify an integrated role of SIGN-R1 in the systemic clearance of apoptotic cells, linking the recognition of apoptotic cells, the opsonization of complements, and the induction of immune tolerance.
Enhanced Bioavailability of Poorly Water-Soluble Clotrimazole by Inclusion with β-Cyclodextrin
Balakrishnan Prabagar,Bong-Kyu Yoo,우종수,Jung-Ae Kim,이종달,Ming Guan Piao,최한곤,용철순 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2
Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with β-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of β-cyclodextrin concentration, resulting in AL type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M-1. The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.
MG Prabagar,Y Do,S Ryu,J-Y Park,H-J Choi,W-S Choi,TJ Yun,J Moon,I-S Choi,K Ko,K Ko,C Young Shin,C Cheong,Y-S Kang 한국당과학회 2013 한국당과학회 학술대회 Vol.2013 No.1
Complements, such as C1q and C3, and macrophages in the splenic marginal zone (MZMs) play pivotal roles in the efficient uptake and processing of circulating apoptotic cells. SIGN-R1, a C-type lectin that is highly expressed in a subpopulation of MZMs, regulates the complement fixation pathway by interacting with C1q, to fight blood-borne Streptococcus pneumoniae. Therefore, we examined whether the SIGN-R1-mediated classical complement pathway plays a role in apoptotic cell clearance and immune tolerance. SIGN-R1 first-bound apoptotic cells and this binding was significantly enhanced in the presence of C1q. SIGN-R1-C1q complex then immediately mediated C3 deposition on circulating apoptotic cells in the MZ, leading to the efficient clearance of them. SIGN-R1-mediated C3 deposition was completely abolished in the spleen of SIGN-R1 knockout (KO) mice. Given that SIGN-R1 is not expressed in the liver, we were struck by the finding that C3-deposited apoptotic cells were still found in the liver of wild-type mice, and dramatically reduced in the SIGN-R1 KO liver. In particular, SIGN-R1 deficiency caused delayed clearance of apoptotic cells and aberrant secretion of cytokines, such as TNF-α, IL-6, and TGF-β in the spleen as well as in the liver. In addition, anti-double- and single-stranded DNA antibody level was significantly increased in SIGN-R1-depleted mice compared with control mice. These findings suggest a novel mechanism of apoptotic cell clearance which is initiated by SIGN-R1 in the MZ and identify an integrated role of SIGN-R1 in the systemic clearance of apoptotic cells, linking the recognition of apoptotic cells, the opsonization of complements, and the induction of immune tolerance.
The role of SIGN-R1, a C-type lectin in apoptotic cell clearance in spleen marginal zone
Miglena G. Prabagar,Heoung-Jwa Choi,Jin-Yeon Park,Kyung-Hyun Kang,Eun-Hee Cho,Chae Gyu Park,Young-Sun Kang 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.07
SIGN-R1, a C-type lectin, is expressed on a subset of resident macrophages in spleen marginal zone. Recently, it was found that SIGN-R1 mediates complement activation pathway by interacting C1q. It is well known that C1q binds to apoptotic cells and has an important role in there clearance. Therefore, we assessed whether SIGN-R1 could be involved in the apoptotic cells clearance, too. In vitro binding assay reveals that soluble SIGN-R1 specifically bind to apoptotic thymocytes. Consistent with our in vitro results, intravenous injected apoptotic cells were uptaken by SIGN-R1-positive macrophages in the splenic marginal zone. To confirm the role of SIGN-R1, apoptotic cells were intravenously injected into control or SIGN-R1 knock-out mice(SR1KO). We observed that apoptotic cells was trapped in the marginal zone at early time point (10min) in both mice which might be due to the presence of other macrophage receptors such as MARCO or Dectin-2. However, as we expected, it was very clear that SIGN-R1 mediated C3 fixation on apoptotic cells in control mice, but not in SR1 KO. Moreover, at 1 hr time point, SR1 KO mice showed the dramatic delay of apoptotic cell clearance in spleen or liver, compared to the control mice. Considered together, our findings suggest that SIGN-R1 specifically mediates complement activation pathway in the splenic marginal zone and this leads to the efficient clearance of apoptotic cells.
조현종,Prabagar Balakrishnan,Hongxia Lin,Min-Koo Choi,김대덕 한국약제학회 2012 Journal of Pharmaceutical Investigation Vol.42 No.3
Transport studies of model drugs were conducted across the human nasal epithelial (HNE) and normal human bronchial epithelial (NHBE) cell monolayers cultured by air–liquid interface method. Physicochemical properties (e.g., molecular weight, calculated partition coefficient, dose number) of model drugs were quoted from literatures and apparent permeability coefficients (Papp)across the HNE and NHBE cell monolayers were directly measured. A linear relationship was observed between the Papp values of model drugs in the HNE and NHBE cell monolayers. As the molecular weight of model drugs increased, the Papp showed a decreasing pattern while the increase of partition coefficients resulted in the increment of Papp. These results indicated that the transport of model drugs across both cell monolayers followed mainly the passive diffusion mechanism, although substrates mediated by drug transporters showed a deviating pattern. It was also interesting to note that almost all model drugs could be grouped into the same biopharmaceutics classification system as that classified by the human intestinal permeability when the Papp was plotted as a function of dose number (D0) of each drug.