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Park J.W.,Seoul National University | Park J.W.,Amore Pacific | Jeon O.C.,Mediplex Corporation | Kim S.K.,Seoul National University | And 4 more authors.
Molecular Pharmaceutics | Year: 2010

The need for an efficacious and safe oral anticoagulant that does not require monitoring has been largely unmet. Many efforts have centered on preparing orally available heparin to improve patient compliance. In this study, novel orally active heparin derivatives (LHD), i.e. low molecular weight heparin (LMWH) conjugated with deoxycholic acid (DOCA), were evaluated in vitro and in vivo for their enhancement effect of oral heparin absorption. After oral administration of 10 mg/kg of water-soluble LHD, Ws-LHD1.5 showed optimum oral efficacy and its bioavailability was about 24% in rats. The oral absorption of LHD1.5 was also enhanced by several solubilizers, among which Poloxamer 407 provided the best results. When 5 mg/kg of LHD1.5 with Poloxamer 407 was orally administered to monkeys, the maximum anti-FXa activity in plasma was 0.26 ± 0.04 IU/mL and its bioavailability was 17.4%. In a rat thrombosis model, 5 mg/kg of orally administered LHD1.5 formulated with Poloxamer reduced thrombus formation by 63.9 ± 16.6%, which was higher than the efficacy of clinically used enoxaparin (49.4 ± 17.8% at 100 IU/kg, sc). Considering the oral absorption efficacy and therapeutic effect, the conjugation ratio was optimized as about 1.5 molecules of DOCA per mole of heparin. Therefore, LHD1.5 with Poloxamer 407 can be further formulated as a solid oral anticoagulant drug. © 2010 American Chemical Society.


Park J.W.,Seoul National University | Park J.W.,Amore Pacific | Jeon O.C.,Mediplex Corporation | Kim S.K.,Seoul National University | And 5 more authors.
Thrombosis and Haemostasis | Year: 2011

This study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of 131I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the anti-thrombotic effect of the subcutaneously injected LMWH (100 IU/ kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin. © Schattauer 2011.


Jeon O.-C.,Sungkyunkwan University | Jeon O.-C.,Mediplex Corporation | Hwang S.R.,Seoul National University | Al-Hilal T.A.,Seoul National University | And 5 more authors.
Pharmaceutical Research | Year: 2013

Purpose: Since the absorption of ceftriaxone (CTO) in the intestine is restricted by its natural physiological characteristics, we developed a series of small synthetic compounds derived from bile acids to promote the absorption of CTO in the gastrointestinal tract. Methods: Several bile acid derivatives were screened by measuring water solubility and partition coefficient of their complexes with CTO. The pharmacokinetic parameters of the selected CTO/HDCK ionic complex in monkeys were evaluated. The absorption pathway of CTO/HDCK complex was evaluated using Caco-2 cells and MDCK cells transfected with ASBT gene. Results: HDCK enhanced the apparent membrane permeability of CTO 5.8-fold in the parallel artificial membrane permeability assay model. CTO/HDCK complex permeated Caco-2 cell via transcellular pathway, and interaction of the HDCK complex with ASBT was important to enhance uptake. When CTO/HDCK (equivalent to 50 mg/kg of ceftriaxone) formulated with lactose, poloxamer 407 and Labrasol was orally administered to monkeys, its maximum plasma concentration was 19.5 ± 1.8 μg/ml and oral bioavailability 28.5 ± 3.1%. Conclusions: The CTO/HDCK formulation could enhance oral bioavailability of CTO in non-human primates. This oral formulation could be an alternative to injectable CTO with enhanced clinical effects. © 2012 Springer Science+Business Media New York.


Patent
MEDIPLEX Corporation, Snu R&Db Foundation and St Pharm Co. | Date: 2012-11-29

The present invention relates to a method for preparing an end site-specific macromolecule-bile acid oligomer conjugate, comprising conjugating a bile acid oligomer which is prepared by oligomerization of two or more bile acid monomers to the terminal site of a macromolecule; a method for body absorption of an end site-specific macromolecule-bile acid oligomer conjugate, comprising administering the macromolecule-bile acid oligomer conjugate prepared by the above method to a subject orally; an end site-specific macromolecule-bile acid oligomer conjugate wherein the bile acid oligomer is conjugated to the terminal site of macromolecule; a composition comprising the conjugate; an oral formulation for macromolecule comprising the conjugate, a solubilizer, an excipient, a disintegrant, a binder, and a lubricant; a pharmaceutical composition comprising a heparin-bile acid oligomer conjugate wherein the bile acid oligomer is conjugated to the terminal site of heparin; and a method for treating thrombosis using said composition.


Kim J.S.,Chungbuk National University | Cho K.J.,Catholic University of Korea | Tran T.H.,Chungnam National University | Nurunnabi M.,Chungbuk National University | And 3 more authors.
Journal of Colloid and Interface Science | Year: 2011

Luminescent near-infrared (NIR) CdTe/CdSe QDs were synthesized and encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres to prepare stable and biocompatible QDs-loaded nanospheres for in vivo imaging. QDs were encapsulated with PLGA nanospheres by a solid dispersion method and optimized to have high fluorescence intensity for in vivo imaging detection. The resultant QDs-loaded PLGA nanospheres were characterized by various analytical techniques such as UV-Vis measurement, dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Finally, we evaluated toxicity and body distribution of QDs loaded in PLGA nanospheres in vitro and in vivo, respectively. From the results, the QDs loaded in PLGA nanospheres were spherical and showed a diameter range of 135.0-162.3. nm in size. The QD nanospheres increased their stability against photooxidation and photobleaching, which have the high potential for applications in biomedical imaging. We have also attained non-invasive in vivo imaging with light photons, representing an intriguing avenue for obtaining biological information by the use of NIR light. © 2010 Elsevier Inc.


Li L.,Chungnam National University | Moon H.T.,Mediplex Corporation | Park J.-Y.,National Cancer Center | Heo Y.J.,National Cancer Center | And 5 more authors.
Macromolecular Research | Year: 2011

Novel heparin-based self-assembled nanoparticles were developed for photodynamic cancer therapy. A heparin-poly(β-benzyl-L-aspartate) (HP) amphiphilic copolymer was synthesized for effective delivery of a hydrophobic photosensitizer, pheophorbide a (Pheo). The anti-coagulant activity of the HP copolymer decreased significantly, as measured by an anti-FXa chromogenic assay. Pheo was effectively incorporated into the HP nanoparticles using a dialysis technique. A good drug-loading content was obtained by altering the composition of the HP copolymer and Pheo/HP feed ratio. The Pheo-loaded HP nanoparticles had an average diameter of 117-189 nm, a negatively charged surface, and a sustained drug release pattern. These properties may allow them to passively target the tumor site through an enhanced permeability and retention (EPR) effect. Furthermore, the Pheo-loaded HP nanoparticles demonstrated marked photocytotoxicity and minimal darktoxic without a light treatment. The 6HP-Pheo15 nanoparticles were internalized into SCC7 cancer cells and damaged the cells after a light treatment. This suggests that HP nanoparticles have potential as an effective delivery system for clinical PDT. [Figure not available: see fulltext.] © 2011 The Polymer Society of Korea and Springer Netherlands.


Kim S.K.,Seoul National University | Lee S.,Seoul National University | Jin S.,Seoul National University | Moon H.T.,Mediplex Corporation | And 3 more authors.
Molecular Pharmaceutics | Year: 2010

Oral insulin therapy has great potential benefits over conventional therapy for diabetic patients as well as mimicking the physiological fate of insulin. Here we evaluated the characteristics of insulin and deoxycholate-based synthetic Nα-deoxycholyl-l-lysyl-methylester (DCK) complex, and diabetes correction in pancreatectomized canines after oral administration. After the insulin/DCK complexation was made, the insulin's folding structure, stability against digestive enzymes, lipophilicity and permeability to Caco-2 monolayer were evaluated in vitro. Diabetic canines were kept under fasting conditions, and Eudragit-coated gelatin capsules containing insulin or insulin/DCK powder were singly or triply administered. Evaluation of glucodynamics, pharmacokinetics, oral glucose tolerance test (OGTT) and reproducibility were carried out. After complexation with DCK, the folding structure of insulin did not become denatured and the resistance against digestive enzymes was powerfully improved. The lipophilicity and permeability of insulin/DCK (coupling ratio up to 1:10) were also highly increased. The insulin/DCK complex, administered orally into diabetic canines at the doses of 21, 42, and 81 IU/kg, reduced the plasma glucose levels by about 28%, 44% and 67%, respectively, while the plasma insulin concentrations increased. During OGTT, insulin/DCK nearly maintained the normoglycemic state in the diabetic canines, whereas the hyperglycemic state of placebo-treated controls was not corrected. During oral administration of insulin/DCK, it repetitively showed similar therapeutic efficacy in diabetic canines for 3 days. The therapeutic efficacy of insulin/DCK was exhibited in its digestive enzyme resistance, deoxycholate-based lipophilicity for enhancing permeability and intact insulin delivery without chemical modification, providing potential oral therapeutic remedy as an alternative to injectable insulin medication. © 2010 American Chemical Society.


Park J.W.,Seoul National University | Park J.W.,Amoprepacific Corporation R and nter | Kim S.K.,Seoul National University | Al-Hilal T.A.,Seoul National University | And 3 more authors.
Biotechnology and Bioprocess Engineering | Year: 2010

Advances in biotechnology, gene manipulation, and protein engineering for macromolecule drugs, such as insulin, parathyroid hormone (PTH), calcitonin, human growth hormone, erythropoietin (EPO), and peptide YY (PYY) allow commercial production in large scale for diverse therapeutic uses. Other macromolecules, such as mucopolysaccharide heparin, have expanded markets through improvements in their pharmacokinetic and pharmacological effects. However, most products are available only as injectable forms and are limited to patients with no alternative therapeutic choices. Orally available macromolecule formulations are still unmet needs for improving patient compliance and expanding administration paradigms and indications. Oral delivery technologies including carrier systems, absorption enhancers, protease inhibitors, and modification by conjugating transporter or receptor recognition molecules have been developed and some are undergoing clinical studies. In this review, we discuss major obstacles for oral absorption of macromolecule drugs and summarize recent strategies to overcome the huddles related to enhancing intestinal permeation. © KSBB.


Krishna O.D.,Seoul National University | Jeon O.C.,Mediplex Corporation | Jeon O.C.,Kyung Hee University | Kim K.,Korea Institute of Science and Technology | And 2 more authors.
Journal of Biomaterials Science, Polymer Edition | Year: 2010

We have prepared a covalently-grafted phsopholipid/PEG mixed monolayer onto drug-loaded polymercoated stainless-steel stents by in situ polymerization. To introduce a biocompatile surface on the stent surface, AcPC (1-palmitoyl-2-[12- (acryloyloxy)dodecanoyl]-sn-glycero-3-phosphocholine) and AcPEG (12-(acryloyloxy)dodecanoyl-poly(ethylene glycol)) were synthesized by modifying phospholipid and PEG with 12-(acryloyloxy)-1-dodecanoic acid and 12-(acryloyloxy)-1-dodecanol, respectively. Also, an acrylated co-polymer was synthesized by the acrylation of poly(octadecyl acrylate-co-hydroxybutyl acrylate, poly(OA-co-HA)) with acryloyl chloride, and poly(OA-co-HA) loaded with a hydrophobic drug, echinomycin, was coated on the stent surface using a spray coating system. In situ polymerization was carried out at the interface between a pre-assembled AcPC/AcPEG mixture and the enchinomycin-loaded acrylated co-polymer-coated stainless steel (Pol-SS). The physicochemical properties of a covalently-grafted phsopholipid/PEG mixed monolayer onto the drug-loaded polymer-coated stainless-steel stents were evaluated using water contact angle, field-emission scanning electron microscopy (FE-SEM) and X-ray photoelectron spectroscopy (XPS). The data confirmed a successful phsopholipid/PEG monolayer grafting on the stents surface. The drug-release profile showed a sustained and controllable release pattern by the top-coated stents, achieved by adjusting the amount of loaded drug. © 2010 Koninklijke Brill NV, Leiden.


Alam F.,Seoul National University of Science and Technology | Chung S.W.,Seoul National University | Hwang S.R.,Chosun University | Kim J.-Y.,Seoul National University | And 5 more authors.
Journal of Applied Toxicology | Year: 2015

In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight heparin derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg-1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg-1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg-1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg-1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. © 2014 John Wiley & Sons, Ltd.

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