용매증발법에 의한 부피바카인 microsphere의 제조 및 평가

곽손혁(Son Hyok Kwak),황성주(Sung Joo Hwang),이병철(Byung Chul Lee) 대한약학회 2000 약학회지 Vol.44 No.6

Various bupivacaine-loaded microspheres were prepared from poly (d,l-lactide) (PLA) or poly (d,l-lactic-co-glycolide) (PLGA) by a solvent evaporation method for the sustained release of drug. PLA and PLGA microspheres were prepared by w/o/w and w/o/o multiple emulsion solvent evaporation, respectively. The effects of process conditions such as emulsification speed, emulsifier type, emulsifier concentration and internal/external phase ratio on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their drug loading, size distribution, surface morphology and release kinetics. Drug loading efficiency was higher in the microspheres prepared by w/o/o multiple emulsion than that by w/o/w multiple emulsion mehtod, because the solubility of bupivacaine HCl was decreased in oil phase compared with water phase. The prepared microspheres had an average diameter between 1 and 2mcm in all conditions of two methods. In morphology studies the PLA microspheres showed an irregular shape and smooth surface, but PLGA microspheres had a spherical shape and smooth surface. The release pattern of the drug from microspheres was evaluated on the basis of the burst effect and the extent of the release after 24h. The in vitro release of bupivacaine HCl from microspheres showed a large initial burst release and 60-80% release within one day in all conditions of two methods. The extents of the burst release against PLA and PLGA microspheres were 30-50% and 50-80% within 20min, respectively. This burst release seems to be due to the smaller size of microspheres and the solubility of drug in water.

용매증발법에 의한 부피바카인 마이크로스피어의 제오 및 평가 (II)

곽손현(Son Hyok Kwak),이시범(Sibeum Lee),우종수(Jong Soo Woo),이병철(Byung Chul Lee),황성주(Sung Joo Hwang) 大韓藥學會 2001 약학회지 Vol.45 No.6

Various bupivacaine-loaded microspheres were prepared using poly(d,1-lactide) (PLA) and poly(d ,1-lactic-co-glycolide) (PLGA) by a solvent evaporation method for the sustained release of drug. The effects of process conditions such as drug loading, polymer type and solvent type on the characteristics of microspheres were investigated. The prepared microspheres were characterized for their drug loading, size distribution, surface morphology and release kinetics. Drug loading efficiency and yield of PLGA microspheres were higher than those of PLA microspheres. The prepared microspheres had an average particle size below 5mcm. The particle size range of microspheres was 1.65∼2.24mcm. As a result of SEM, the particle size of PLA microspheres was smaller than that of PLGA microspheres. In morphology studies, micro- spheres showed a spherical shape and smooth surface in all process conditions. In thermal analysis, bupivacaine-loaded microspheres showed no peaks originating from bupivacaine. This suggested that bupivacaine base was molecular-dispersed in the polymer matrix of microspheres. The release pattern of the drug from microspheres was evaluated for 96 hours. The initial burst release of bupivacaine base decreased with increasing the molecular weight of PLGA, and the drug from microspheres released slowly, In conclusion, bupivacaine-loaded microspheres were successfully prepared from poly(d,1-lactide) and poly (d,1-lactic-co-glycolide) polymers with different molecular weights allowing control of the release rate.

Biodegradable uniform microspheres based on solid-in-oil-in-water emulsion for drug delivery: A comparison of homogenization and fluidic device

Ryu, Tae-Kyung,Kim, Sung Eun,Kim, Joo-Hwan,Moon, Seung-Kwan,Choi, Sung-Wook Technomic Pub. Co 2014 Journal of bioactive and compatible polymers Vol.29 No.5

<P>Based on solid-in-oil-in-water emulsification, we fabricated biodegradable poly(ϵ-caprolactone) microspheres containing gentamicin using conventional homogenization and a fluidic device. The feasibility of the poly(ϵ-caprolactone) microspheres as drug carriers was evaluated in terms of encapsulation efficiency, release behavior of gentamicin, and antimicrobial activity. The poly(ϵ-caprolactone) microspheres prepared using a fluidic device (fluidic device microspheres) had a uniform diameter and a smooth surface, whereas the poly(ϵ-caprolactone) microspheres prepared using conventional homogenization (conventional homogenization microspheres) exhibited polydisperse and a porous structure. At 0.3 wt% of gentamicin concentration, the encapsulation efficiencies of the conventional homogenization and fluidic device microspheres were 39.5% and 72.0%, respectively. In addition, a significant amount of gentamicin was only released initially from the conventional homogenization microspheres, whereas the fluidic device microspheres released gentamicin in a sustained manner for 28 days. These results confirmed the superior performances of the uniform fluidic device microspheres for drug delivery system. We further proposed a model for microsphere formation to explain the difference in performance of the conventional homogenization and fluidic device microspheres.</P>

용매추출법을 이용한 부피바카인 마이크로스피어의 제조 및 평가

김민수,황성주 충남대학교 약학대학 의약품개발연구소 2003 藥學論文集 Vol.18 No.-

Various bupivacaine-loaded microspheres were prepared with poly (d,l-lactide) (PLA) by solvent extraction method. The internal solution of polymer(PLA R104) and drug in glacial acetic acid was introduced into the external phase of polyvinylpyrrolidone (PVP K-30) in polyethyleneglycol (PEG), and emulsified to be an oil-in-oil (o/o) emulsion. The o/o emulsion was poured to the buffer solution. During this process, microspheres were precipitated because the buffer solution is miscible with PEG and glacial acetic acid. The microspheres were acquired by filtration, redispersion, washing and lyophihzation. The effects of process conditions such as drug loading, emulsification speed. emulsifier concentration. external phase, internal/external phase ratio and temperature on the characteristics of microspheres were investigated. And bupivacaine-loaded microspheres were also prepared when citric acid or meglumine was added into the internal polymer solution, and/or when meglumine or bupivacaine was added into the external PEG phase. Itraconazole was used as a water insoluble model drug. Itraconazole-loaded microspheres were prepared by the same method as the above to compare the characteristics of microspheres between the bupivacaine microspheres. The prepared microspheres were characterized for their drug loading efficiency, particle size distribution and surface morphology. Drug loading efficiency was higher in the itraconazole-loaded microspheres than the bupivacaine-loaded microspheres, because itraconazole has a very low solubility. The average number mean diameters of bupivacaine-loaded microspheres were 27.64~47.92μm, while those of itraconazole-loaded microspheres were 16.18~25.74pm. In morphology studies, bupivacaine-loaded microspheres showed an irregular shape and had a rough surface.

PEGylated TNF-related apoptosis-inducing ligand (TRAIL)-loaded sustained release PLGA microspheres for enhanced stability and antitumor activity

Kim, T.H.,Jiang, H.H.,Park, C.W.,Youn, Y.S.,Lee, S.,Chen, X.,Lee, K.C. Elsevier Science Publishers 2011 Journal of controlled release Vol.150 No.1

The purpose of this work was to develop an effective PEGylated TNF-related apoptosis-inducing ligand (PEG-TRAIL) delivery system for antitumor therapy based on local injection to tumor sites that has a sustained effect without protein aggregation or an initial release burst. The authors designed poly (lactic-co-glycolic) acid (PLGA) microspheres that deliver PEG-TRAIL locally and continuously at tumor sites with sustained biological activity and compared its performance with that of TRAIL microspheres. TRAIL or PEG-TRAIL was microencapsulated into PLGA microspheres using a double-emulsion solvent extraction method. Prepared TRAIL and PEG-TRAIL microspheres showed entirely spherical, smooth surfaces. However, PEG-TRAIL microspheres exhibited a 2.07-fold higher encapsulation efficiency than TRAIL microspheres, and exhibited a tri-phasic in vitro release profile with a lower initial burst (15.8%) than TRAIL microspheres (42.7%). Furthermore, released PEG-TRAIL showed a continued ability to induce apoptosis over 14days. In vivo pharmacokinetic studies also demonstrated that PEG-TRAIL microspheres had a sustained release profile (18days), and that the steady-state concentration of PEG-TRAIL in rat plasma was reached at day 3 and maintained until day 15; its steady-state concentration in rat plasma changed from 1444.3+/-338.4 to 2697.7+/-419.7pg/ml. However, TRAIL microspheres were released out within 2days after administration. Finally, in vivo antitumor tests revealed that tumor growths were significantly more inhibited by a single dose of PEG-TRAIL microspheres than TRAIL microspheres when delivered at 300μg of TRAIL/mouse. Tumors taken from mouse treated with PEG-TRAIL microspheres showed 78.3% tumor suppression at 24days, and this was 3.02-fold higher than that observed for TRAIL microspheres (25.9% tumor inhibition). Furthermore, these improved pharmaceutical characteristics of PEG-TRAIL microspheres resulted in superior therapeutic effects without detectable side effects. These findings strongly suggest that PEG-TRAIL microspheres offer a new therapeutic strategy for the treatment of cancers.

Micromeritics and Release Behaviours of Cellulose Acetate Butyrate Microspheres Containing Theophylline Prepared by Emulsion Solvent Evaporation and Emulsion Non-solvent Addition Method

Mitra Jelvehgari,Fatemeh Atapour,Ali Nokhodchi 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.7

The present research work compares the effect of microsphere preparation technique on micromeritics and release behaviors of theophylline microspheres. Microspheres were prepared by oil-in oil (O1/O2) emulsion solvent evaporation method (ESE) using different ratios of anhydrous theophylline to cellulose acetate butyrate (CAB). Cyclohexane was used as non-solvent to modify the ESE technique (MESE method) and the effect of non-solvent volume on properties of microspheres was investigated. The obtained microspheres were analyzed in terms of drug content, particle size and encapsulation efficiency. The morphology of microsphere was studied using scanning electron microscope. The solid state of microspheres, heophylline and CAB were investigated using X-ray, FT-IR and DSC. The drug content of microspheres prepared by MESE method was significantly lower (15.54% ± 0.46) than microspheres prepared by ESE method (41.08 ± 0.40%). The results showed that as the amount of cyclohexane was increased from 2 mL to 6 mL the drug content of microspheres was increased from 15.54% to 28.71%. Higher encapsulation efficiencies were obtained for microspheres prepared by ESE method (95.87%) in comparison with MESE method (64.71%). Mean particle size of microsphere prepared by ESE method was not remarkably affected by drug to polymer ratio, whereas in MSES method when the volume of cyclohexane was increased the mean particle size of microsphere was significantly decreased. The ratio of drug to polymer significantly changed the rate of drug release from microspheres and the highest drug release was obtained for the microsphere with high drug to polymer ratio. The amount of cyclohexane did not significantly change the drug release. Although, x-ray showed a small change in crystallinity of theophylline in microspheres, DSC results proved that theophylline in microspheres is in amorphous state. No major chemical interaction between the drug and polymer was reported during the encapsulation process.

음전하를 띤 Microsphere 에 의한 정전기적 반발력이 정밀여과에서 투과 플럭스에 미치는 영향 고찰

박정민,최성욱,방시원,함승주,김중현,김우식 한국화학공학회 2001 Korean Chemical Engineering Research(HWAHAK KONGHA Vol.39 No.6

본 연구에서는 일정 압력하에서 음전하를 띤 microspheres의 정전기적 반발력에 따른 투과 플럭스의 변화에 관하여 고찰하였다. Microsphere의 정전기적 반발력에 관한 영향을 관찰하기 위해 표면전하 밀도(N_c: 0.45, 5.94, 10.25)가 각각 다른 poly(Styrene/Methacrylic acid) microspheres를 제조하였다. 교반속도는 300, 400, 600 rpm, 이온강도는 0.1, 0.01, 0.001로 변화시켜 실험하였다. 투과 플럭스는 표면전하밀도, 교반속도, 이온강도에 큰 영향을 받음을 알 수 있었으며, 투과 플럭스는 표면전하밀도가 클수록, 교반속도가 증가할수록, 이온강도가 작을수록 증가함을 알 수 있었다. 교반속도가 크면 막표면의 농도분극층의 두께가 얇아지기 때문에 투과 플럭스는 증가한다. 이온강도가 작을수록, 표면전하밀도(surface charge density)가 클수록 투과 플럭스가 커지는 원인은 microspheres의 정전기적 이중 층의 두께가 두꺼워짐에 따라 입자 사이의 거리가 멀어져 공극률(porosity)이 커지기 때문이다. 정상상태 플럭스 자료로부터 비 저항 정의식을 이용하여 케이크층의 공극률을 구할 수 있었다. 전하를 나타내지 않는 polystyrene microspheres의 입자크기가 480㎚일 때 농도분극 층의 이론적인 공극률은 0.211이었고, microspheres의 표면이 methacrylic acid로 완전히 개질된 것은 비 저항정의식에 의해 3.04로 계산되었다. 또한 microspheres들간의 정전기적 상호작용력이 작아지면 농도분극층의 공극률도 줄어드는 것을 알 수 있었다. The effect of the surface charge density(N_c: 0.45, 5.94, 9.14 and 10.25) and the stirrer speed(300, 400 and 600 rpm) on the variation of permeate flux was investigated in a stirred cell filled with negatively charged microspheres under constant pressure. It was found that the permeate flux depended on the surface charge density, the ionic strength and the stirrer speed. High permeate flux was obtained in the condition of high surface charge density, low ionic strength and high stirrer speed due to the force of electrostatic interaction between microspheres. The porosity of a cake layer was calculated from the steady-state flux data. It was found that the reduction of porosity was due to a decrease in repulsive interaction between microspheres.

Mechanism of Albumin Release from Alginate and Chitosan Beads Fabricated in Dual Layers

남윤식,배민수,김성원,노인섭,서준교,이강봉,권일근 한국고분자학회 2011 Macromolecular Research Vol.19 No.5

Biocompatible polysaccharides, such as alginate and chitosan are widely used as drug carriers. Microspheres based on the electrostatic interaction between these two polymers have been attractive as a means to deliver protein drugs because the use of organic solvents can be avoided during their preparation. On the other hand, the mechanisms for drug release, such as disintegration of microspheres, are not completely understood. This paper examined the phenomena of disintegration of the core-shell type microspheres consisting of alginate and chitosan. The microspheres formed by either chitosan-coated alginate or alginate-coated chitosan were generated using a labmade instrument consisting of a syringe pump connected to a glass nozzle. Using fluorophore-labeled polysaccharides,the disintegration of each polymer layer from the microspheres was monitored as a function of time. The alginate-coated chitosan microspheres demonstrated enhanced stability with increasing concentration of the chitosan core. The presence of an alginate shell itself also increased the stability of the microsphere compared to the microspheres without an alginate coating. The chitosan concentration, however, did not have any effect on the stability of the chitosan-coated alginate microspheres. The microspheres synthesized with alginate in the core demonstrated concentration-dependent stability. In these microsphere experiments, the microsphere stability was found to be related directly to the protein release kinetics. In the alginate/chitosan-based microspheres, the disintegration property is the primary factor modulating the encapsulated drug release, which suggests the easiest simple method for time-dependent protein drug delivery.

Dextran/PLGA Double-Layered Microspheres for Sustained Release of Doxorubicin

( Jong Hak Park ),( Shin Eom ),( Sik Il Ahn ),( Hyun Hye Hong ),( Cho Min Kim ),( Soon Hong Yuk ),( Dong Won Lee ),( John M Rhee ),( Kye Hwan Lee ),( Gil Son Khang ) 한국조직공학·재생의학회 2009 조직공학과 재생의학 Vol.6 No.4

Biodegradable polymer microspheres have been extensively developed as drug carriers that alleviate burst release and control drug release profiles. In this study, we report a simple method to develop double-layered microspheres for controlled and sustained drug release. Double layered microspheres were prepared using PLGA and natural hydrophilic polymer dextran by a simple method based on an emulsion-solvent evaporation method. Microspheres had a double layered structure with dextran layer in the core and PLGA on the surface due to phase separation and encapsulated doxorubicin as a model drug in their core. The molecular weight and concentration of PLGA dominated the structure, in vitro degradation and drug release profiles of microspheres. Dextran/PLGA double- layered microspheres had a diameter about 200 m and alleviated initial burst release. Drug release profiles from dextran/PLGA double-layered microspheres can becontrolled by manipulating the thickness of shell of the microspheres. We anticipate great potential of dextran/PLGA double-layered microspheres for controlled and sustained drug delivery, given their simple formulation and the control of drug release profiles.

Preparation and characterization of ibuprofen-loaded alginate microspheres using ethylenediamine as a crosslinker

Maiti, Sabyasachi,Sa, Biswanath Kyung Hee Oriental Medicine Research Center 2008 Oriental pharmacy and experimental medicine Vol.8 No.2

In this study, ionotropic gelation method was used for the preparation of ibuprofen-loaded calcium alginate (CALG) and ethylenediamine (EDA) treated calcium alginate (EDA-CALG) microspheres. The effect of EDA-treatment on drug entrapment efficiency, particle size, morphology, swelling behavior and in vitro release characteristics of the microspheres was investigated by varying its concentration from 0.5 to 2% (v/v). The reduction in drug entrapment efficiency by a maximum of 44.60% was noted for EDA-CALG microspheres compared to untreated CALG microspheres. The particle size and swelling index of EDA-CALG microspheres were reduced with increasing EDA concentration. All the microspheres were observed to retain their spherical shapes with rough surfaces. EDA-CALG microspheres prepared using 1% and 2% v/v EDA, released almost all of its content within 7 h in pH 6.8 phosphate buffer, however, CALG microspheres were found to release the same within 3 h. The intensity of melting endothermic peak of ibuprofen reduced significantly at lower drug load as experienced from DSC thermograms. The FT-IR spectrum of pure ibuprofen, ibuprofen-loaded CALG and EDA-CALG microspheres showed the characteristic band of C = O stretching vibration of ibuprofen. Hence, this study revealed that EDA can be employed for the preparation of ibuprofen-loaded CALG microspheres to retard the drug release to some extent.