리포좀에 봉입된 아클라루비신의 약물동태, 세포독성, 항암효과 및 비장/혈구 세포독성

박목순,박진규,이계원,명평근,석대은,황성주,지웅길 충남대학교 약학대학 의약품개발연구소 1998 藥學論文集 Vol.14 No.-

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 the 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_0-8hr values were 122±42, 382±140, 419±171, 835±206 and 443±309 ㎍·min/㎖ for free ACL, ACL-liposome formulation Ⅰ, Ⅱ, Ⅲ and Ⅳ, respectively. Cytotoxicity 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 moce. The loss of body weight was much smaller with ACL-entrapped liposomes than free ACL after i.p. injection at a dose of 2 ㎎/㎏/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.

마이크로플루다이저를 이용한 아클라루비신 리포좀의 제조 및 평가

박목순,박진규,이계원,백명기,지웅길 충남대학교 약학대학 의약품개발연구소 1998 藥學論文集 Vol.14 No.-

In order to attain a sustained release at targeted argans in a prolonged time which can reduce the side effects and maximize the therapeutic effect, aclarubicin (ACL) was entrapped into liposomes of different lipid compositions using Microfluidizer, and dry liposomes were prepared by lyophilization. The dry aclarubicin-entrapped liposomes weer evaluated in terms of mean particle size and size distribution, entrapment efficiency and in vitro drug release profile. The Entrapment efficiency of liposome, when the concentration of aclarubicin and lipid were 0.5 to 1.0 ㎎/㎖, respectively, was over 80% using Microfluidizer, in contrast to 70% of entrapment efficiency using hand-shaking method. Mean particle size and size distribution of aclarubicin-entrapped liposomes of various lipid compositions did not change considerably by the freeze drying. The range of particle size was between 80 and 20 ㎚. Among aclarubicin-entrapped liposomes. ACL-liposome of PC/DPPC/CHOL/TA displayed the most significant sustained release. The addition of DPPC appeared to be favorable for the control of release. In general, aclarubicin entrapped in liposomes was less stable than free aclarubicin either in pH 7.4 phosphate buffer or in human plasma. formulation Ⅰ(t_½, 20.3 hr) devoid of lipid additive was the most unstable in the phosphate buffer solution while formulation Ⅱ(t_½, 40.7 hr) with cardiolipin was the most stable. Half lives of aclarubicin-entrapped liposomes in human plasma were 43.2, 50.7, 35.9 and 35.3 hr for formulation Ⅰ, Ⅱ, Ⅲ and Ⅳ, respectively, in contrast to 57.8 hr for free aclarubicin.

마이크로플루다이저를 이용한 아클라루비신 리포좀의 제조 및 평가

박목순(Mork Soon Park),박진규(Jin Kyu Park),이계원(Gye Won Lee),백명기(Myoung Ki Baek),지웅길(Ung Kil Lee) 대한약학회 1998 약학회지 Vol.42 No.3

In order to attain a sustained release at targeted organs in a prolonged time which can reduce the side effects and maximize the therapeutic effect, aclarubicin (ACL) was entrapped into liposomes of different lipid compositions using Microfluidizer, and dry liposomes were prepared by lyophilization. The dry aclarubicin-entrapped liposomes were evaluated in terms of mean particle size and size distribution, entrapment efficiency and in vitro drug release profile. The Entrapment efficiency of liposome, when the concentration of aclarubicin and lipid were 0.5 to 1.0mg/ml and 200mcmol/ml,respectively, was over 80% using Microfluidizer, in contrast to 70% of entrapment efficiency using hand-shaking method. Mean particle size and size distribution of aclarubicin-entrapped liposomes of various lipid compositions did not change considerably by the freeze drying. The range of particle size was between 80 and 200nm. Among aclarubicin-entrapped liposomes, ACL-liposome of PC/DPPC/CH0L/TA displayed the most significant sustained release. The addition of DPPC appeared to be favorable for the control of release. In general, aclarubicin entrapped in liposomes was less stable than free aclarubicin either in pH 7.4 phosphate buffer or in human plasma. Formulation I(t1/2, 20.3 hr) devoid of lipid additive was the most unstable in the phosphate-buffer solution while formulation II(t1/2, 40.7 hr) with cardiolipin was the most stable. Half lives of aclarubicin-entrapped liposomes in human plasma were 43.2, 50.7, 35.9 and 35.3 hr for formulation I. II, III and IV, respectively, in contrast to 57.8 hr for free aclarubicin.

리포좀에 봉입된 아클라루비신의 약물동태, 세포독성, 항암효과 및 비장/혈구 세포독성

박목순(Mork Soon Park),박진규(Jin Kyu Park),이계원(Gye Won Lee),명평근(Pyung Keun Myung),석대은(Dai Eun Sok),황성주(Sung Joo Hwang),지웅길(Ung Kil Lee) 大韓藥學會 1998 약학회지 Vol.42 No.3

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 the 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.

병풀(Centella asiatica)엑스 - 베타시클로덱스트린 고체 분산체를 함유한 폴록사머 407 히드로겔 제조 및 피부투과

지웅길,박목순,이계원,박진규,김경국,곽은선 한국약제학회 1998 Journal of Pharmaceutical Investigation Vol.28 No.1

Extract of Centella asiatica(ECA), which is poorly water-soluble extract from the Centella asiatica is known to express excellent wound healing properties. ECA-β-cyclodextrin (asiaticoside-β-cyclodextrin and genin-β-cyclodextrin) solid dispersion system, which was prepared by freeze-drying method, was formulated as gels containing poloxamer 407 and propylene glycol, and evaluated with respect to their viscosity, stability, skin permeation and drug amount in the skin of hairless mouse. The average molar ratio asiaticoside-β-CD and genin-β-CD was 1:1.7 and 1:22. respectively. When the molar ratio of genin and β-CD was 1:5, madecassic acid made 100% solid dispersion system and asiatic acid about 65%. In dissolution study. >99% of asiaticoside from asiaticoside-β-CD was dissolved in 5 minutes, and >99% madecassic acid and >64% asiatic acid from genin-β-CD. The apparent viscosity of poloxamer 407 gels with ECA-β-CD solid dispersion system increased in proportion to poloxamer 407 and propylene glycol concentration. In the accelerated stability test, all ECA-β-CD poloxamer 407 gels showed that asiaticoside was most stable and madecassic acid stable and asiatic acid similar to stability of gel with free ECA. The permeation amount of asiaticoside in poloxamer gels through hairless mouse skin decreased as the concentration of poloxamer 407 increased. When propylene glycol was added at the level of 10%, the permeation amount of asiaticoside at poloxamer gels through hairless mouse skin increased but from 15% it decreased. The permeation of asiaticoside into the skin of hairless mouse was estimated to be about 0.10㎍/㎠.

Norfloxacin과 β-Cyclodextrin간의 Inclusion Complex에 관한 약제학적 연구

智雄吉,朴木淳,權重武 충남대학교 약학대학 의약품개발연구소 1987 藥學論文集 Vol.3 No.-

To increase the bioavailability of norfloxacin, inclusion complex of antimicrobial agent norfloxacin with β-cyclodextrin was prepared and studied by the solubility method, spectrophotometric methods(UV, IR,^1H-NMR), differential thermal analysis, powder X-ray diffractometry, the physical properties, the antimicrobial activity, DNA binding and in situ recirculation technique. The conclusions are summerized as following; 1) The inclusion complexation was identified by means of solubility, spectrophotometry(UV, IR, NMR), DTA and X-ray diffraction. 2) The molar ratio of norfloxacin-β-cyclodextrin complex was 1:1. 3) The stability constant of norfloxacin-β-cyclodextrin complex was 21.5M^-1, and both true and apparent partition coefficients of the inclusion complex were larger than those of norfloxacin. 4) The time required to dissolve 60%(T_60%) of the inclusion complex was 120 min, in distilled water and in the artificial intestinal juice, while norfloxacin did not reach to 60% dissolution within 120 min. 5) The antimicrobial activity of the inclusion complex against Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus showed no significant difference compared to that of norfloxacin alone. 6) Studies on binding properties between the inclusion complex and norfloxacin alone to DNA according to equilibrium dialysis showed no significant differency. 7) In situ absorption rates(Ka) of inclusion complex and norfloxacin alone were 0.229 and 0.102hr^-1, respectively.

5-Fluorouracil과 그 유도체를 봉입한 Multilamellar Vesicle(MLV)과 Microemulsified Liposome(MEL)의 특성 및 약물방출 거동

지웅길,박목순,이계원,류연근 충남대학교 약학대학 의약품개발연구소 1995 藥學論文集 Vol.11 No.-

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(50~200nm), 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-l-acetate: HFA) were made with soybean phosphatidylcholine, cholesterol, stearylamine(SA) and dicetyl phosphate(DCP) employing hydration method or microemulsification method using Microfluidizer^TM. Both of liposome types were MLV and MEL. After preparation, freeze dying 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 bellows. 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 materials. After preparation of liposome, free drug was removed effectively 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).

Norfloxacin과 ${\beta}-Cyclodextrin$간의 Inclusion Complex에 관한 약제학적 연구

지웅길,박목순,권중무,Jee, Ung-Kil,Park, Mork-Soon,Kwon, Joong-Moo 한국약제학회 1987 Journal of Pharmaceutical Investigation Vol.17 No.1

To increase the bioavailability of norfloxacin, inclusion complex of antimicrobial agent norfloxacin with ${\beta}-Cyclodextrin$ was prepared and studied by the solubility method, spectrophotometric methods(UV, IR, $^1H-NMR$), differential thermal analysis, powder X-ray diffractometry, the physical properties, the antimicrobial activity, DNA binding and in situ recirculation technique. The conclusions are summerized as following; 1) The inclusion complexation was identified by means of solubility, spectrophotometry(UV, IR, NMR), DTA and X-ray diffraction. 2) The molar ratio of $norfloxacin-{\beta}-cyclodextrin$ complex was 1 : 1. 3) The stability constant of $norfloxacin-{\beta}-cyclodextrin$ complex was $21.5\;M^{-1}$, and both true and apparent partition coefficients of the inclusion complex were larger than those of norfloxacin. 4) The time required to dissolve 60% $(T_{60}%)$ of the inclusion complex was 120 min. in distilled water and in the artificial intestinal juice, while norfloxacin did not reach to 60% dissolution within 120 min. 5) The antimicrobial activity of the inclusion complex against Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus showed no significant difference compared to that of norfloxacin alone. 6) Studies on binding properties between the inclusion complex and norfloxacin alone to DNA according to equilibrium dialysis showed no significant differency. 7) In situ absorption rates (Ka) of inclusion complex and norfloxacin alone were 0.229 and $0.102hr^{-1}$, respectively.

Norfloxacin 과 β - Cyclodextrin 간의 Inclusion Complex 에 관한 약제학적 연구

지웅길,박목순,권중무 한국약제학회 1987 Journal of Pharmaceutical Investigation Vol.17 No.1

To increase the bioavailability of norfloxacin, inclusion complex of antimicrobial agent norfloxacin with β-cyclodextrin was prepared and studied by the solubility method, spectrophotometric methods (UV, IR, ¹H-NMR), differential thermal analysis, powder X-ray diffractometry, the physical properties, the antimicrobial activity, DNA binding and in situ recirculation technique. The conclusions are summerized as following: 1) The inclusion complexation was identified by means of solubility, spectrophotometry (UV, IR, NMR), DTA and X-ray diffraction. 2) The molar ratio of norfloxacin-β-cyclodextrin complex was 1 : 1.3) The stability constant of norfloxacin-β-cyclodextrin complex was 21.5M^(-1), and both true and apparent partition coefficients of the inclusion complex were larger than those of norfloxacin. 4) The time required to dissolve 60% (T_(60)%) of the inclusion complex was 120 min in distilled water and in the artificial intestinal juice, while norfloxacin did not reach to 60% dissolution within 120 min. 5) The antimicrobial activity of the inclusion complex against Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus showed no significant difference compared to that of norfloxacin alone. 6) Studies on binding properties between the inclusion complex and norfloxacin alone to DNA according to equilibrium dialysis showed no significant differency. 7) In situ absorption rates (Ka) of inclusion complex and norfloxacin alone were 0.229 and 0.102 hr^(-1), respectively.

Hydrochlorothiazide의 microcapsule 제조와 평가

남상철,박목순,나성범,이계원,지웅길 충남대학교 약학대학 의약품개발연구소 1990 藥學論文集 Vol.6 No.-

The microcapsules of hydrochlorothiazide using Eudragit RL were prepared by the solvent evaporation process in liquid paraffin phase, and the microcapsules of hydrochlorothiazide using Ethylcellulose were prepared by the solvent evaporation process in water phases. The size distribution, drug content, interaction between the drug and the polymer, dissolution test, observation of SEM were investigated. The results are summarized as belows. The Eudragit RL microcapsules and Ethylcellulose microcapsules obtained were spherical, uniform and free flowing particles. As the dispersing agents (Eudragit RL-magnesium stearate, Ethylcellulose-sod, lauryl sulfate) were fixed, the preparation of microcapsules showed constant in particle size distribution. The actual drug contents of the Eudragit RL microcpasules were lower than theoretical drug contents, but the actural drug contents of the Ethylcellulose were higher than those. No interaction between the polymer and the drug was observed from the results of TLC, UV, IR, DSC. The release of hydrochlorothiazide from the Eudragit RL microcapsules except for the release in pH 8.0 phosphate buffer solution was not increased when the drug: polymer ratio was increased. The dissolution rate of hydrochlorothiazide from Ethylcellulose microcapsules increased with increasing drug: polymer ratio. Scanning electron micrograph study revealed that microcapsules prepared by this method showed comparatively rough surface when drug: polymer ratio was decreased.