Dopa-Empowered Schiff Base Forming Alginate Hydrogel Glue for Rapid Hemostatic Control

송충길,김민경,이정한,DAVAA ENKHZAYA,Rengarajan Baskaran,양수근 한국고분자학회 2019 Macromolecular Research Vol.27 No.2

In this study we prepared tissue-adhesive hemostatic glue and assessed hemostatic effects on hepatic bleeding animal model. Alginate was used as primary polymer for the fabrication of hemostatic glue, oxidized for the introduction of the tissue-adhesive Schiff base forming aldehyde and then encoded with mussel-inspired dopa. In addition, polyallylamine (PAA) was selected for as an intra-structuring polymer which ensures the gel strength and allows instantaneous glue formation on the bleeding spot. Primary glue (OA glue) was quickly formed within 5 to 10 seconds after the mixing oxidized alginate (OA) with PAA. The degree of oxidation and the mixing ratio of OA and PAA were precisely determined based on glue formation time and gel strength. And the extend of dopa conjugation on OA was determined by the tissue adhesion force and the elasticity of the glue (Dopa-OA glue). Especially, elasticity of Dopa-OA glue was significantly enhanced after introduction of dopa to OA. Functional assay of Dopa-OA glue on hepatic bleeding animal model showed much enhanced hemostatic action. Dopa-OA glue is expected to provide novel injectable tissue adhesives for the treatment of hemorrhage caused by clinical procedures or trauma.

신규 합성 당지질 함유 리포솜의 In Vitro 안정성

송충길,정순화,성하수,조선행,신병철,Song, Chung-Kil,Jung, Soon-Hwa,Seong, Ha-Soo,Cho, Sun-Hang,Shin, Byung-Cheol 대한화학회 2007 대한화학회지 Vol.51 No.1

리포솜은 수십~수백 나노미터 크기의 소포체(small vesicle)로서 약물전달에 유용한 구조체이나 체내 혈류 순환계(blood circulatory system)에서 구조적 불안정성에 의해 체내 순환시간이 짧고 세망내피계(reticuloendothelial system)에 의해 소실되어 이를 개선하기 위한 다양한 연구가 시도되고 있다. 본 연구에서는 이당류(disaccharide)로서 락토오스와 슈크로스가 1,2-디스테아로일-sn-글리세로-3-포스포에탄올아민(1,2-Distearoylsn-glycero-3-phosphoethanolamine, DSPE)과 공유결합된 새로운 당-DSPE 유도체를 합성하고 이를 리포솜의 구성성분으로 하는 리포솜을 제조함으로써 리포솜의 표면이 이당으로 수식된 리포솜을 제조하였다. 제조된 리포솜의 입자크기는 대략 100 nm였으며, 표면전하 값은 당이 수식되지 않은 대조군 리포솜이 -10 mV를 나타내었으나 당-DSPE 유도체를 함유한 리포솜의 경우 리포솜 표면에 존재하는 당의 수산화기에 의하여 표면전하의 값은 -25 mV를 나타내었다. 리포솜 내부에 모델약물인 독소루비신(doxorubicin)의 로딩효율은 약 90%를 나타내었다. 당-DSPE 유도체 함유 리포솜의 in vitro 안정성은 혈청 내에서 단백흡착량의 변화 및 리포솜의 입자크기를 관찰하여 평가하였다. 당-인지질 유도체를 함유한 리포솜은 당-인지질 유도체를 함유하지 않은 리포솜 또는 폴리에틸렌글리콜(PEG) 수식 리포솜에 비해 단백흡착의 양과 혈청 내 입자크기의 변화가 적은 것으로 관찰되었다. 이당이 결합된 DSPE와 이를 함유한 리포솜은 혈액내 안정성이 향상되어 체순환계 내에서 장시간 순환이 가능한 약물전달체로서 유용할 것이라 사료된다. Liposomes having particle size from several tens to hundreds nanometers are efficient carriers for injectable drug delivery. Enhancement of liposome stability in bloodstream has been studied because of its relatively short circulation time and fast clearance from human body by reticuloendothelial system (RES) in blood vessel. In this study, new disaccharide-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) derivatives in which lactose or sucrose as the disaccharide molecule was conjugated covalently to DSPE were synthesized. Liposomes of which surface had disaccharide molecules were prepared by incorporating the disaccharide-DSPE into liposomes as one of their lipid components. Particle size of the prepared liposomes was approximately 100 nm. The liposomes of which surface were modified with the disaccharide-DSPE showed -25 mV of zeta potential value due to the presence of hydroxyl groups on their surface, while the unmodified control liposomes showed -10 mV of zeta potential value. Loading efficiency of model drug, doxorubicin, into liposomes was about 90%. Stability of the disaccharide-modified liposomes in vitro was evaluated by monitoring the amount of protein adsorption and particle size of the liposomes in serum. Disaccharide-modified liposomes were more stable in serum than unmodified control liposomes or polyethyleneglycol (PEG)-modified liposomes due to less adsorption of serum protein and hence less increase of their particle size. The liposomes of which surface was modified with disaccharide-DSPE conjugate can be used as long-circulating carriers for drugs having high toxicity or short half-life time due to their enhanced stability in blood circulatory system.

Cyclosporin A가 봉입된 nanostructured Lipid carriers의 물리적 특성연구

송충길 ( Chung Kil Song ),정석재 ( Suk Jae Chung ),심창구 ( Chang Koo Shim ),김대덕 ( Dae Duk Kim ) 한국약제학회 2008 Journal of Pharmaceutical Investigation Vol.38 No.1

혈류 내 안정성 향상을 위한 빗 모양 고분자로 개질된 리포솜

신병철,송충길,황태원,성하수,박은석,Sin, Byeong-Cheol,Song, Chung-Gil,Hwang, Tae-Won,Seong, Ha-Su,Park, Eun-Seok 대한화학회 2006 대한화학회지 Vol.50 No.3

혈류 내에서 리포솜의 안정성을 향상시키기 위해 지질-고분자 유도체를 지질 이중층에 도입하거나 친수성 고분자를 리포솜에 결합시켜 리포솜의 표면을 개질하는 방법이 개발되어왔다. 본 연구에서는 비닐 단량체로서 히드록시에틸메타크릴레이트(HEMA)와 히드록시폴리옥시에틸렌메타크릴레이트(HPOEM)를 자유 라디칼 중합하여 측쇄에 다수의 폴리에틸렌옥사이드를 갖는 빗(Comb) 모양 공중합체인 poly(HEMA-co-HPOEM)를 제조하였다. Poly(HEMA-co-HPOEM)를 리포솜의 표면에 결합시키고 혈장 용액 내에서 개질된 리포솜의 특성을 살펴보았다. Poly(HEMA-co-HPOEM)으로 개질된 리포솜의 입자크기는 대조군 리포솜에 비해 약 30 nm 증가하였고 리포솜 표면의 음전하를 차폐하여 제타 포텐셜의 절대값은 감소하였다. 리포솜 내부에 모델약물인 독소루비신(Doxorubicin)의 로딩효율은 ~ 90%로서 리포솜 표면에 결합된 poly(HEMA-co-HPOEM)는 약물의 로딩효율에 영향을 주지 않았다. 혈장 내에서 리포솜의 안정성을 평가한 결과, 빗 모양 고분자로 수식한 리포솜의 입자크기는 증가하지 않았고 단백질 흡착은 대조군 리포솜 또는 폴리에틸렌옥사이드-지질 유도체가 도입된 리포솜(PEG-리포솜)에 비해 감소되어 빗 모양 고분자인 poly(HEMA-co-HPOEM)이 혈류 내 리포솜의 안정성 향상에 효과적임을 확인하였다. To increase the stability of liposomes in blood circulation, surface modification of liposomes by incorporating a lipid-polymer derivative in the lipid bilayer or conjugating a hydrophilic polymer to the liposomal surface has been developed. In this study, the comblike copolymer, poly(HEMA-co-HPOEM), having multiple polyethyleneoxide side chains was prepared by free radical polymerization of hydroxyethylmethacrylate (HEMA) and hydroxypolyoxyethylenemethacrylate (HPOEM) as vinyl monomers. Poly(HEMA-co-HPOEM) was conjugated to the liposomal surface and the characteristics of the modified liposomes in serum were investigated. Conjugation of poly(HEMA-co-HPOEM) to liposomes increased the particle size of the liposomes by 30 nm and decreased the absolute value of zeta potential of the liposomes by shielding the negative charge of liposomal surface. Loading efficiency of model drug, doxorubicin, in liposomes was about 90% and the efficiency was not affected by conjugation of poly(HEMA-co-HPOEM) to liposomes. The particle size of poly(HEMA-co-HPOEM)-conjugated liposomes in serum did not changed and the protein adsorption was lower than that of control liposomes or liposomes containing polyethyleneoxide-lipid derivative (PEG-liposomes). These results suggest that poly(HEMA-co-HPOEM) is efficient for the stabilization of liposomes in blood circulation.

항암제를 함유한 키토산 코팅 리포솜과 DNA 복합체의 제조

한희동,서동환,송충길,성하수,신병철,Han, Hee-Dong,Seo, Dong-Hoan,Song, Chung-Kil,Seong, Ha-Soo,Shin, Byung-Cheol 대한화학회 2005 대한화학회지 Vol.49 No.6

Physicochemical Characterization and Skin Permeation of Liposome Formulations Containing Clindamycin Phosphate

Srinivasan Shanmugam,송충길,Santhoshkumar Nagayya-Sriraman,Rengarajan Baskaran,용철순,최한곤,Dae-Duk Kim,우종수,유봉규 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.7

This study was undertaken to evaluate the physicochemical properties and skin permeation of liposome formulations containing clindamycin phosphate (CP), especially when charge was imparted to the liposome. Five different liposome formulations were prepared using Phospholipon 85G (PL) and cholesterol (CH) by conventional lipid film hydration technique. Molar ratio of CH to PL was varied in the range of 0.16-1.0. Charged liposomes were prepared in the same way with addition of 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and 1,2-dimyristoyl-sn-glycero-3-phosphate monosodium salt (DMPA) as charge carrier lipid for cationic or anionic charge of the liposome, respectively. Fresh full-thickness mice skin was taken and used for skin permeation study using Keshary-Chien diffusion cell with 1.77 ㎠ diffusion area at 37℃. All liposome formulations prepared showed homogeneous size distribution with mean particle size of about 1 μm or less. Among the five liposome formulations prepared, formulation with the molar ratio of 0.5 showed the best result in the physicochemical properties such as polydispersity index, entrapment efficiency, size evolution, and ability of the liposome to retain CP as of entrapped in the vesicles. Charge-impartation of the formulation with cationic charge carrier lipid resulted in additional benefit in terms of inhibition of size evolution, the ability of the liposome to retain CP in the vesicles, and skin permeation. Steady state flux of the drug through the mice skin in the cationic liposome vesicles was 0.75 ± 0.01 μg/㎠h while that in the control (dissolved into mixed alcohol solution) was 0.17 μg/㎠h. One half molar ratio of CH to PL was optimal in terms of physicochemical properties of the liposome formulation containing CP, and incorporation of cationic charge carrier lipid appeared to provide additional benefits for the stability of the liposome formulation and skin permeation of the drug.

음이온성 리포솜이 결합된 키토산 겔의 항암효과

최민수,한희동,김태우,송충길,박은석,신병철 한국약제학회 2005 Journal of Pharmaceutical Investigation Vol.35 No.1

Depot system for local drug delivery using chitosan hydrogel has been developed to enhance the therapeutic efficacy and to prevent the severe side effect in whole body. Thus, we have prepared an injectable chitosan hydrogel containing liposomes to treat cancers clinically. Anionic liposomes incorporated to improve sustained release efficiency within chitosan hydrogel. The chitosan solution containing liposomes was designed to form a hydrogel complex at body temperature. The released behavior of doxonibicin from liposomes in chitosan hydrogel showed sustained-release caused by diffusion of doxorubicin from temperature responsive liposome into chitosan hydrogel. The chitosan hydorgel containing liposomes enhanced the therapeutic potency for the solid tumor in vivo system. Our results indicate that the liposomes in chitosan hydrogel represent a depot system for local drug delivery.

Inclusion Complex Effect on the Bioavailability of Clotrimazole from Poloxamer-based Solid Suppository

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.

이중 가교제 또는 알긴산에 의해 물리적인 안정성이 향상된 히알루론산 마이크로입자의 제조

김동환(Dong-Hwan Kim),최애진(Ae-Jin Choi),박충근(Chun-Geon Park),Prabagar Balakrishnan,송충길(Chung Kil Song),심창구(Chang-Koo Shim),김대덕(Dae-Duk Kim),정석재(Suk-Jae Chung) 大韓藥學會 2011 약학회지 Vol.55 No.1

Hyaluronic acid (HA) is a natural polymer consisting of disaccharide units of D-glucuronic acid and N-acetyl- D-glucosamine. It has a great potential and success in cosmetic and biomedical applications. However, native HA is highly soluble and easily metabolized by enzymes such as hyaluronidase. Thus, various studies have been reported on modifying the physicochemical properties of HA, while maintaining its biocompatibility. For controlled drug delivery, many trials for fabricating HA microspheres were achieved under chemical reaction. The HA microspheres fabricated to improve the physical stability of HA using adipic acid dihydrazide (ADH) by cross-linking reaction has been reported earlier, however it lacks the desired physical stability and rapidly decomposes by swelling or enzymes. Therefore, we prepared double cross-linked HA microspheres (DC-HA microspheres) and alginate containing HA microspheres (AC-HA microspheres) to enhance its physicochemical properties. DC-HA microspheres were prepared using trisodium trimetaphosphate (STMP) under crosslinking reaction after ADH cross-linking reaction. AC-HA microspheres were prepared by adding alginate as a networking polymer. These microspheres were characterized by morphology, particle size, zeta potential, stability against hyaluronidase. Results showed that the DC-HA and AC-HA microspheres are more stable than that of HA microspheres.