• Journal of Pharmaceutical Investigation
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• 제40권spc호
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• pp.75-82
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• 2010

Specific diseases like cancer and acquired immune deficiency syndrome (AIDS) occur at various organs including lymphatics and spread through lymphatic system. Thus, if therapeutic agents for such diseases are more distributed or targeted to lymphatic system, we can obtain several advantages like reduction of systemic side effect and increase of efficacy. For these reasons, much interest has been focused on the nature of lymphatics and a lot of studies for lymphatic delivery of drugs have been carried out. Because lymphatics consist of single layer endothelium and have high permeability compared with blood capillaries, especially, the studies using nano-sized carriers have been performed. Polymeric nano-particle, liposome, and lipid-based vehicle have been adopted for lymphatic delivery as carriers. According to the administration route and the kind of carrier, the extent of lymphatic delivery efficiency of nano-sized carriers has been changed and influenced by several factors such as size, charge, hydrophobicity and surface feature of carrier. In this review, we summarized the key factors which affect lymphatic uptake and the major features of carriers for achieving the lymphatic delivery. Lymphatic delivery of drug using nano-sized carriers has many fold improved ability of lymphatic delivery compared with that of conventional dosage forms, but it has not shown whole lymph selectivity yet. Even though nano-sized carriers still have the potential and worth to study as lymphatic drug delivery technology as before, full understanding of delivery mechanism and influencing factors, and setting of pharmacokinetic model are required for more ideal lymphatic delivery of drug.

• Journal of Pharmaceutical Investigation
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• 제25권1호
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• pp.55-62
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• 1995

W/O and O/W emulsions of tegafur (50 mg/5 ml/kg) were orally administered to rats to compare with their mesenteric lymphatic delivery effects. And also in order to demonstrate the lymph targeting associated to the oral route, it was deemed necessary to investigate the fate of solution after oral administration as a control. Lymph and plasma samples were periodically taken from each subject of mesenteric lymphatic duct cannulated rats. Then, lymph and plasma levels of tegafur and its active metabolite, 5-FU, were simultaneously observed. Also pharmacokinetic parameters were compared with each others. On the other hand, most previous studies of lymphatic transport have not addressed the question of whether an increase in mesenteric or thoracic lymph transport by the manipulation of a suspected variable was due to a selective delivery to the intestinal lymphatics or an overall increase availability. Therefore, based on a physiologically based pharmacokinetic model which represents the characteristics of lymphatic systems, we are also going to determine the contributions of mesenteric lymph transport versus thoracic lymph transport of tegafur reported in reference(13). In comparison with tegafur solution, AUC and mean residence time of plasma tegafur were significantly increased in W/O emulsion but significantly decreased in O/W emulsion. Lymph flow rates were similar in both solution and W/O emulsion but half in O/W emulsion. AUC of tegafur in mesenteric lymph and in plasma for W/O emulsion were 3.7 times and 2.9 times more than those for O/W emulsion, respectively. And AUC of 5-FU in thoracic lymph for W/O emulsion was 3.7 times more than that for O/W emulsion. These results suggested that lymphatic delivery or tegafur by W/O emulsion was more effective than that by on emulsion due to its differences or formation ability of chylomicrons.

• Journal of Pharmaceutical Investigation
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• 제23권3호spc1호
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• pp.19-30
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• 1993

The influence of emulsion type of tegafur, an oral anticancer agent, on lymphatic transport was studied in rats. The water-in-oil-type of emulsion and the oil-in-water-type emulsion of tegafur each in 50 mg, calculated in terms of tegafur, were prepared by adding tegafur aqueous solution to sesame oil containing hydrogenated castor oil following ultrasonic treatment, and then the prepared emulsions and aqueous solution as a comparative formulation were administered orally to rats (50 mg/5 ml/kg). The concentration levels of tegafur in plasma of femoral artery and lymph from thoracic duct cannula were measured simultaneously along a time course after administration and the pharmacokinetic parameters were investigated. At the same time, we examined the above described factors of 5-FU which is known as an active metabolite of tegafur. In comparison with tegafur solution, AUC and mean residence time of plasma tegafur were significantly increased in w/o-emulsion but significantly decreased in o/w-emulsion. Lymph flow rates were similar in both solution and w/o-emulsion but half in o/w-emulsion. Ratios between area under the lymph and plasma concentration time curves were always less than 1 reflecting the passive lymphatic delivery after oral administration of the prepared tegafur emulsions, but those to the 5-FU in the case of w/o-emulsion were more than 1. These results suggested that lymphatic delivery of tegafur by w/o-emulsion was more effective than that by o/w-emulsion due to its differences of formation ability of chylomicrons.

• Biotechnology and Bioprocess Engineering:BBE
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• 제10권6호
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• pp.516-521
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• 2005

Drug delivery to the lymphatic system may be important in terms of the treatment with lymphatic involvement, such as tumor metastases and immunization. Especially, drug transport via the intestinal lymphatics after oral administration has been attracted lots of interests. The purpose of this study was to prepare cyclosporin A (CSA)-loaded liposomes, with different characteristics, and evaluate their mucoadhesivity. Three liposome preparations were formulated: cationic stearylamine liposomes (SA-Lip), anionic phosphatidylserine liposomes (PS-Lip), Polymer (chitosan)-coated liposomes (CS-Lip), and characterized. The liposome preparations were found to be spherical in shape, with PS-Lip being the smallest. The liposome preparations exhibited entrapment efficiencies in the order: PS-Lip $(52.5{\pm}2.9%)$ > SA-Lip $(48.8{\pm}3.3%)$ > CS-Lip $(41.7{\pm}4.2%)$. Finally, mucoadhesive tests were carried out using rat intestine, with SA-Lip (67%) showing the best adhesive rate of the three preparations (PS-Lip: 56%, CS-Lip: 61%). These results suggest that a positive charge on the surface of drug carriers may be an important factor for the intestinal drug delivery.

• Journal of Microbiology and Biotechnology
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• 제18권9호
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• pp.1599-1605
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• 2008

Biodistribution and lymphoscintigraphy of cyclosporine A (CyA) and technetium-99m ($^{99m}Tc$) were studied using ${^99m}Tc$-labeled dextran acetate (DxA) including CyA. DxA particles were prepared from dextran with acetic anhydride, and CyA was loaded into them. Lymphatic delivery of ${^99m}Tc$-labeled DxA particles containing CyA was evaluated after subcutaneous injection into the foot pad of rats and compared with those of ${^99m}Tc$-labeled human serum albumin (HSA). The labeling efficiency of CyA-loaded ${^99m}Tc$-DxA particles was about 95% at 30 min. The labeling efficiency maintained stably above 80% for 12 h. The percent injected dose (%ID) of CyA-loaded ${^99m}Tc$-DxA was similar to that of ${^99m}Tc$-HSA at the inguinal lymph node after 40 min. The CyA-loaded ${^99m}Tc$-DxA could be as well distributed as ${^99m}Tc$-HSA through the lymph node. The DxA particles could steadily distribute the CyA as well as the ${^99m}Tc$ radiolabeling through the lymph node.

• Journal of Pharmaceutical Investigation
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• 제38권3호
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• pp.191-197
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• 2008

The purpose of the present study was to examine the pharmacokinetics and lymphatic delivery of the oligopeptide, a model peptide of X antigen epitope peptides, after the intramuscular administration of the peptide-bearing liposomes in rats. $^{14}C$-labelled peptide was used as a tracer to analyze the peptide levels in plasma, bile, urine, tissue homogenates, and lymph nodes (superior cervical nodes, brachial nodes and superior mesenteric nodes). Model peptide rapidly disappeared from the plasma by 30 min (${\alpha}$ phase) after i.v. administration, which was followed by the late disappearance. The apparent plasma half-lives ($t_{1/2({\alpha}),app}$) of the peptide at the ${\alpha}$ phase when administered at a dose of 0.2-1.0 mg/kg were about 5 min. The maximum plasma concentration ($C_{max}$) was $1.52\;{\mu}g/mL$, after the i.m. administration of the peptide at a dose of 1.0 mg/kg. The bioavailability, which was calculated from the time zero to last quantitative time, of the i.m. administered peptide was over 60%. Of the various tissues tested, the peptide was mainly distributed in the kidney after the i.m. administration. The peptide levels in the kidney 3 hr after the i.m. administration were higher than those of maximum plasma concentration ($C_{max}$). The cumulative amounts of the peptide found in the urine 72 hr after the administration of 1.0 mg/kg were 2-folder higher than those in the bile, suggesting that the peptide is mostly excreted in the urine. Moreover, the concentrations of the peptide in the lymph nodes were as high as that of the plasma and the tissues. In conclusion, the peptide concentration in the lymph nodes was maintained by 24 hr after the i.m. administration of the peptide-bearing liposomes.

• 대한화장품학회지
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• 제40권2호
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• pp.195-201
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• 2014

생체수는 링거액, 인공관절액, 세포 배양 등 다양한 분야에서 연구되어 왔다. 이는 생체수가 체온을 조절하는데 결정적인 역할을 하고, 생체 내 다양한 대사 과정에서 용매로 사용되며, 삼투압이나 능동적 섭취를 통한 혈액 또는 림프액을 통해 세포에서 세포로 전달되는 미네랄, 에너지원, 호르몬, 시그널과 약물의 전달 물질로 이용되기 때문이다. 세포외 지질과 자연보습성분(natural moisturizing factor, NMF)을 함유하는 각질층은 외부의 수분을 끌어들여 내부 수화에 이용하며, 이러한 과정들은 피부 장벽 기능과의 연관성이 높다. 본 연구에서는 피부 장벽 기능을 강화하는 아미노산, 펩타이드, 단당류를 포함한 생체모사수(Cell Bio Fluid SyncTM)를 인체 피부에 처리하여 세포활성을 관찰하고, 생체 모사수를 함유한 제품을 피부에 도포하여 인체피부 개선 효과를 연구 하였다. 피부 세포 활성을 보기 위해 각질세포인 HaCaT 세포를 이용하였고, 에너지 고갈상태로 만들기 위해 3시간 동안 PBS에 전 처리한 후 이후 세포 배양액인 DMEM 및 등장액인 PBS, 생체 모사수(Cell Bio Fluid $Sync^{TM}$)에 각각 3시간 처리하였다. 이후 MTT assay와 이미지 분석을 수행하였다. 인체의 피부 개선 효능을 위한 임상 연구에 21명의 여성이 참여하였다. 생체 모사수를 함유한 제품을 1주일간 안면에 도포하였고, 수분량, 피부결, 밝기 그리고 피부 균일도를 측정하였다. 모든 측정은 피험자가 세안 후 항온항습조건($22{\pm}2^{\circ}C$, $50{\pm}5%$)에서 20분 간 대기하고 수행하였다. 모든 데이터는 SPSS ver. 21을 이용하여 분석하였다. 그 결과, 생체 모사수(Cell Bio Fluid $Sync^{TM}$)가 세포 활성을 높이고 인체의 피부에서 수분, 거칠기, 밝기, 균일도, 투명도 등의 개선 효과가 있음을 확인할 수 있었다.

• Journal of Chest Surgery
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• 제37권8호
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• pp.691-701
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• 2004

배경: 악성종양에서 신생혈관 생성 및 당분해의 증가는 저산소 상태의 미세환경을 나타내며, 이는 종양의 침습성, 전이 등으로 환자의 예후와 관련이 있는 것으로 알려져 있다. Hypoxia-inducible factor 1(HIF-1)는 당원 수송체, 당분해 효소, 혈관내피세포 성장인자 등의 유전자의 전사를 활성화한다고 알려져 있다. 그리고 HIF-1의 전사 활성도는 HIF-1 a subunit의 표현이 조절되는 정도에 의존한다. 그러나 식도암에서 HIF-1의 발현과 혈관 생성능 및 종양세포 증식능과의 관계 및 예후에 관한 연구는 전무하다. 대상 및 방법: 고신대학교 의과대학 흉부외과학교실에서 1995년부터 2000년까지 수술치험한 77예의 식도 편평세포암 환자의 조직에서 채취한 정상 편평상피와 암조직에서 면역조직화학검사를 이용하여 HIF-1 a의 발현을 조사하고 혈관생성인자, 증식지수, p53 단백과의 상관관계, 임상-병리학적인 인자 및 생존율과의 상관관계를 분석하였다. 결과: HIF-1 a의 고발현율은 42.9% (33예/77예)였다. HIF-1 a의 고발현은 조직학적 등급(p=0.032), 병리학적 병기(p=0.002), 종양 침윤의 깊이(p=0.022), 주위 림프절 전이(p=0.002), 원격전이(p=0.049), 림프관 침윤(p=0.004)과 관련이 있었다. HIF-1 a의 고발현은 혈관내피세포 성장인자의 발현, Ki-67 증식지수와 관련이 있었으나, 미세혈관수와는 관련이 없었고, p53의 발현과는 관련이 있는 경향을 보였다. 단변량분석과 다변량분석에서 HIF-1 a의 고발현은 불량한 예후를 나타내는 인자로 보였다. 결론: 식도 편평세포암 조직에서 HIF-1 a의 발현은 종양조직내 신생혈관의 생성과 관련이 있는 것으로 나타났고, 고발현 된 경우는 림프절 전이와 수술 후 불량한 예후를 나타내었으므로 보다 강화된 치료전략이 필요할 것으로 사료된다.