• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.283-283
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• 1996

The hydrolyzed-lactose milk for the lactase-deficient subject is sweeter than whole milk, and some subjects dislike its taste. To overcome this shortcoming the dried liposomes containing ${\beta}$-galactosidase to digest lactose in milk after drinking were prepared and examined the possible application of this dried liposomes to the lactase-deficient subjects. To improve the stability of conventional liposome suspension, the dried liposomes in the presence of trehalose were prepared by the dehydration-rehydration vesicles method. Small unilamellar vesicles, prepared with egg phosphatidyl cholesterol, and cholesterol, were mixed with ${\beta}$-galactosidase solution and then ;up[jo;ozed. The freeze-dried liposome was rehydrated and centrifuged. The resultant multilamellar vesicles were mixed with trehalose(4g/g lipid) and then lyophilized to produce final dried liposome. Trehalose increased the entrapping efficiency of liposomes by 3 fo1d compared to the liposomes without trehalose (13% vs. 46%).

• Bulletin of the Korean Chemical Society
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• 제28권1호
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• pp.99-102
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• 2007

To prepare freeze-dried ascorbyl palmitate (AsP)-containing liposome which can protect the drug from moisture attack and be used instantly by mixing with water for anti-aging and skin whitening therapy, AsP was encapsulated into liposomes and freeze-dried with trehalose. The freeze-dried liposome formulations were characterized by measuring water contents, particle size, time required for complete reconstitution. With the freeze-dried liposomes, we performed the stability test under accelerated conditions, skin permeation and localization test. The measurement of the time to perfect reconstitution showed that the freeze-dried liposomes can be changed to their initial state rapidly and short term stability test of AsP in reconstituted liposomes under accelerated conditions confirmed that the stability of AsP was considerably enhanced as compared to freshly prepared liposomes. The skin permeation and localization properties of AsP in reconstituted liposomes were not significantly different, indicating that the liposomal structures were maintained before and after freezedrying. In conclusion, the freeze-drying method provided a possible way to overcome the instability issue of AsP induced by the moisture and reproduced similar skin permeation and localization properties as shown by freshly prepared liposomes.

• Journal of Pharmaceutical Investigation
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• 제25권3호
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• pp.249-264
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• 1995

Although liposome has many advantages as a pharmaceutical dosage form, its application in the industrial field has been limited because of some problems such as preparation method, reproducibility, scale-up, stability and sterilization etc. Liposomes prepared by microemulsification method had defined size, narrow size distribution, reproducibility and high entrapment efficiency. For enhancing the stability, the dry form of liposome was recommended. These types of liposome are proliposome and freeze-dried liposome. The liposome must have some properties for preparing of freeze-dried liposome; small size $(50{\sim}200\;nm)$, narrow size distribution and cryoprotectant. In this experiment, the liposomes containing 5-Fluorouracil(5-FU) and its prodrug(pentyl-5-FU-1-acetate; PFA, hexyl-5-FU-1-acetate; HFA) were made with soybean phosphatidylcholine, cholesterol, stearylamine(SA) and dicetyl phosphate(DCP) employing hydration method or microemulsification method using $Microfluidizer^{TM}$. Both or liposome types were MLV and MEL. After preparation, freeze drying and rehydration were performed. In the process of freezing, trehalose(Tr) was added as a cryoprotectant. Their evaluation methods were as follows; entrapment efficiency, mean particle size and size distribution, dissolution test, retain of entrapment efficiency and turbidity after freeze-drying. The results are summarized as belows. The entrapment efficiency of 5-FU was dependent on total lipid concentration and cholesterol content but that of PFA and HFA was decreased when cholesterol was added. When DCP and SA were added, entrapment efficiency was decreased. As the partition coefficient of drug was increased, entrapment efficiency was increased. Under the same condition, entrapment efficiency of MEL is similar to that of MLV. The mean particle size and size distribution of MEL were smaller than those of MLV. Dissolution rates of drug from both liposome types were comparatively similar. Dissolution rates of drugs with serum and liver homogenate were faster than without these material. After preparation of liposome, free drug was removed efficiency by Dowex 50W-X4. When liposome was freeze-dried and then rehydrated in the presence of Tr, characteristics of liposome were maintained well in MEL than MLV. Tr Was used successfully as a cryoprotectant in the process of freeze drying and the optimal ratio of Tr:Lipid was 4:1(g/g).

• 약학회지
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• 제42권3호
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• pp.274-274
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• 1998

Aclarubicin(ACL)-entrapped freeze dried liposomes were prepared using Microfludizer to attain a sustained release at targeted organs in a prolonged time so that it can reduce th e side effect and maximize the therapeutic effect. The freeze-dried liposomes were evaluated for pharmacokinetics, antitumor activity against Sarcoma 180, cytotoxicity against L1210 and A549 tumor cells, spleen toxicity and myelosuppressive action. The AUC0->8hr values were 122+/-42, 382+/-140, 419+/-171, 835+/-206 and 443+/-309mcg min/ml for free ACL. ACL-liposome formulation I, II, III and IV, respectively. Cytotoidcity of ACL-entrapped liposomes against L1210 and A549 tumor cells was 2-4 times higher than that of free aclarubicin. ACL-liposome formulation I(PC/CHOL/TA) showed the most potent antitumor activity against Sarcoma 180 in mice. The loss of body weight was much smaller with ACL-entrapped liposomes than free ACL after I.p. injection at a dose of 2 mg/kg/day. Compared to free ACL, ACL-entrapped liposomes expressed a lower and delayed spleen toxicity up to 5th day after I.v. administration. Myelosupperssion seemed to be lower with ACL-entrapped liposome of PC/PC-hydrate/CHOL/TA (formulation III) than free aclarubicin.

• 대한화학회지
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• 제48권6호
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• pp.616-622
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• 2004

약물 수송체로 사용되는 리포솜은 동결 건조를 통하여 분말화 시키는 방법이 사용되어지고 있다. 리포솜 안정제로서 말토스는 동결건조된 리포솜 분말의 안정성을 향상시키고 약물 봉입률에 영향을 주는 것으로 알려져 왔다. 동결건조 전과 후의 리포솜 입자의 크기를 측정하므로서 리포솜의 안정성을 평가하였고 또한, 약물 봉입률은 모델 약물인 칼세인을 사용하여 조건에 따른 봉입양을 측정하였다. 리포솜 제조 후에 말토스를 첨가한 리포솜은 수화하는 과정에서 말토스를 첨가하여 제조한 리포솜보다 훨씬 더 안정한 것으로 확인되었다. 말토스를 첨가하지 않은 리포솜은 시간이 지남에 따라 입자의 크기가 커지는 반면, 리포솜 제조 후에 말토스를 첨가한 리포솜은 $4{\sim}37^{\circ}C$에서 30일 동안 안정하다. 또한, 말토스/지질의 물농도 비가 3과 6일 때 상대적으로 가장 높은 안정성을 보였다.

• 약학회지
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• 제42권3호
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• pp.275-283
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• 1998

Aclarubicin(ACL)-entrapped freeze dried liposomes were prepared using Microfludizer to attain a sustained release at targeted organs in a prolonged time so that it can reduce th e side effect and maximize the therapeutic effect. The freeze-dried liposomes were evaluated for pharmacokinetics, antitumor activity against Sarcoma 180, cytotoxicity against L1210 and A549 tumor cells, spleen toxicity and myelosuppressive action. The $AUC_{0{\rightarrow}8hr}$ values were $122{\pm}42,\;382{\pm}140,\;419{\pm}171,\;835{\pm}206\;and\;443{\pm}309{\mu}g{\cdot}min/ml$ for free ACL. ACL-liposome formulation I, II, III and IV, respectively. Cytotoidcity of ACL-entrapped liposomes against L1210 and A549 tumor cells was 2-4 times higher than that of free aclarubicin. ACL-liposome formulation I(PC/CHOL/TA) showed the most potent antitumor activity against Sarcoma 180 in mice. The loss of body weight was much smaller with ACL-entrapped liposomes than free ACL after I.p. injection at a dose of 2 mg/kg/day. Compared to free ACL, ACL-entrapped liposomes expressed a lower and delayed spleen toxicity up to 5th day after I.v. administration. Myelosupperssion seemed to be lower with ACL-entrapped liposome of PC/PC-hydrate/CHOL/TA (formulation III) than free aclarubicin.

• 약학회지
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• 제40권6호
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• pp.646-652
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• 1996

Epidermal Growth Factor (EGF), discovered by Stanley Cohen in 1960, has a potential healing effect for wounds and bums. Considering wound care, in order to avoid physical stress at the wound surface and efficiently apply EGF, the need for viscous spraying solutions was essential. Viscous spraying solutions containing EGF were prepared by utilizing viscosity-building polymer, poloxamer 407, and by introducing liposome systems. On the other hand, EGF is purified on reverse HPLC gradient program with the mobile solvent of acetonitrile. It is necessary to observe liposomal EGF changes as the acetonitrile contents varied in order to introduce liposome systems at the step of EGF solution (at the time of EGF purifying). By evaluating the size distribution and entrapment efficiency of EGF liposome, it was possible to detemine the limit contents of acetonitrile and establish the optimal conditions for solution formulations. It has been revealed that, as the acetonitrile content increases, mean diameter of EGF liposomes increased and the width of size distribution tends to decrease. The limit contents of acetonitrile were 10%, since there was little difference to the acetonitrile free liposomes.

• 대한핵의학회지
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• 제36권6호
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• pp.333-343
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• 2002

목적: BFCA 중 하나인 HYNIC을 제조하고, 염증부위에 선택적으로 국소화 되어 진단할 수 있는 PEG-liposome과 결합시켜 HYNIC-PEG-liposome을 제조하며, 제조된 HYNIC-PEG-liposome에 방사성 동위원소인 $^{99m}Tc$의 표지 방법을 확립하고자 하였다. 대상 및 방법: 6-Chloronicotinic acid를 출발물질로 하여 succinimidyl 6-BOC-hydrazinopyridine-3-carboxylic acid를 순차적으로 합성하였다. Triethylamine을 이용해 합성된 succinimidyl 6-BOC-hydrazinopyridine-3-carboxylic acid와 DSPE를 접합하였다. HYNIC-DSPE를 제조한 후에 EPC:PEG-DSPE: HYNIC-DSPE:cholesterol을 1.85:0.15 :0.07:1의 몰 비로 혼합하여 HYNIC-PEG-liposome을 제조하였다. 제조된 HYNIC-PEG-liposome에 $SnCl_2{\cdot}2H_2O$와 tricine을 이용하여 $^{99m}Tc$를 표지하였다. $^{99m}Tc$-HYNIC-PEG-liposome과 혈청을 섞어서 실온과 $37^{\circ}C$에서 24시간까지 안정성을 확인하였다. $^{99m}Tc$-HYNIC-PEG-liposome에 DTPA, cysteine, glutathione을 각각 과량의 몰 비로 섞고 $37^{\circ}C$에서 1시간 반응 후에 trans- chelation을 통해 안정성을 확인하였다. 결과: 6-Chloronicotinic acid를 출발물질로 하여 6-hydrazinopyridine-3-carboxylic acid, 6-BOC-hydrazinopyridine -3-carb-oxylic acid, succinimidyl-6-BOC-hydra-zino-pyri- dine-3-carboxylic acid를 합성하였으며 각각의 합성수율은 88.5%, 93.7%, 93.2%였고 최종수율은 77.3%였다. 제조된 HYNIC-PEG-liposome의 직경은 106 nm였고, PEG-liposome에 접합된 HYNIC의 농도는 1.08 nM이었다. HYNIC-PEG- liposome의 개수는 1 ml에 $5.2{\times}10^{14}$개가 존재하였고, PEG- liposome 한 개당 HYNIC은 약 1250개가 접합되었다. 제조된 HYNIC-PEG-liposome에 $SnCl_2{\cdot}2H_2O$와 tricine을 이용하여 $^{99m}Tc$를 표지하였으며 그 표지수율은 99%이상이었다. 혈청 내에서 24시간까지 93.5% 이상의 안정성을 나타내었다. DTPA, cysteine, glutathione을 각각 1000배의 몰 비를 첨가한 경우 $^{99m}Tc$-HYNIC- PEG-liposome의 방사화학적순도가 각각 98%, 96%, 99%으로서 안정하였다. 결론: BFCA중 하나인 HYNIC을 이용한 $^{99m}Tc$-HYNIC-PEG-liposome의 제조는 손쉬운 표지방법과 높은 표지수율 그리고 안정성을 나타낼 수 있는 방법으로서, 이를 염증부위에 선택적으로 국소화되어 염증의 진단에 유용하게 사용될 수 있을것으로 기대된다.