Biphasic Release Characteristics of Dual Drug-loaded Alginate Beads

Lee, Beom-Jin,Cui, Jing-Hao,Kim, Tae-Wan,Heo, Min-Young,Kim, Chong-Kook The Pharmaceutical Society of Korea 1998 Archives of Pharmacal Research Vol.21 No.6

The dual drug-loaded alginate beads simultaneously containing drug in inner and outer layers were prepared by dropping plain (single-layered) alginate beads into $CaCl_2$ solution. The release characteristics were evaluated in simulated gastric fluid for 2 h followed by intestinal fluids thereafter for 12 h. The surface morphology and cross section of dual drug-loaded alginate beads was also investigated using scanning electron microscope (SEM). The poorlv water-soluble ibuprofen was chosen as a model drug. The surface of single-layered and dual drug-loaded alginate beads showed very crude and roughness, showing aggregated particles, surface cracks and rough crystals. The thickness of dual drug-loaded alginate beads surrounded by outer layer was ranged from about 57 to 329mcm. The distinct chasm between inner and outer layers was also observed. In case of single-layered alginate bead, the drug was not released in gastric fluid but was largely released in intestinal fluid. However, the release rate decreased as the reinforcing $Eudragit^{\circledR}$ polymer contents increased. When the plasticizers were added into polymer, the release rate largely decreased. The release rate of dual drug-loaded alginate beads was stable in gastric fluid for 2 h but largely increased when switched in intestinal fluid. The drug linearly released for 4 h followed by another linear release thereafter, showing a distinct biphasic release characteristics. There was a difference in the release profiles between single-layered and dual drug-loaded alginate beads due to their structural shape. However, this biphasic release profiles were modified by varying formulation compositions of inner and outer layer of alginate beads. The release rate of dual drug-loaded alginate beads slightly decreased when the outer layer was reinforced with $Eudragit^{\circledR}$ RS1OO polymers. In case of dual drug-loaded alginate beads with polymer-reinforced outer layer only, the initial amount of druc released was low but the initial release rate (slope) was higher due to more swellable inner cores when compared to polymer-reinforced inner cores. The current dual drug-loaded alginate beads may be used to deliver the drugs in a time dependent manner.

서방정으로부터의 약물 용출에 대한 고분자-약물 상호작용의 영향

김행자,이승진 梨花女子大學校 藥學硏究所 1997 藥學硏究論文集 Vol.- No.6

To develop oral controlled release dosage forms, ionic interactions between polymers and drugs were evaluated. Hydroxypropylmethyl cellulose and carboxymethylene were used as model nonionic and ionic polymers, respectively. 5-fluorouracil, propranolol-HCL and sodium salicylate were selected as model nonionic, cationic and anionic, respectively. Polymer-drug mixtures were compressed into tablets and drug release kinetics from these tablets were determined. Drug release from the tablets made of the nonionic polymer was not affected by the charge of drugs, rather, was regulated by the solubility of drugs in different pH releasing media. However, drug release kinetics were significantly affected when drug-polymer ionic interactions exist. Enhanced drug release was observed from anionic drug-anionic polymer tablets due to ionic repulsion. Whereas drug release was retarded in cationic drug-anionic polymer tablets owing to ionic attractive force. Therefore, the results suggested that the polymer-drug interactions are important factors in designing controlled release dosage forms.

Modified Release of Coated Sugar Spheres Using Drug-Containing Polymeric Dispersions

Kim, Tae-Wan,Ji, Chang-Won,Shim, Sang-Young,Lee, Beom-Jin 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.1

A drug-containing polymeric dispersion was applied onto nonpareil sugar spheres (18/20 mesh) using a fluid-bed spray coater. $Eudragit^{(R)}$ RS30D was selected as the polymeric coating material. Melatonin secreted by the pineal gland in a circadian rhythm was used as a model drug. The release behaviors of the coated sugar spheres were investigated in gastric fluid (pH 1.4) for 2 h, and then continuously in intestinal fluid (pH 7.4) for 14 h. The release rate of the coated sugar spheres decreased with increasing coating levels. The solvent (ethanol) in the coating dispersions significantly decreased the release of the drug due to the good dispersion of the low solubility melatonin in the polymeric films. The polymer (polyvinylpyrrolidone, PVP) and drug contents in the coating dispersions did not affect the release rate. Most of all, the release profiles were drastically changed according to the type and concentration of plasticizers used. The current coating methods that use drug-containing polymeric dispersions could be useful for simultaneous drug loadings and their modified release. The solubilization and controlled release of poorly water-soluble drugs can be achieved as both the solubilizers and drugs are present in the drug-containing polymeric dispersions.

Electrospun tri-layered zein/PVP-GO/zein nanofiber mats for providing biphasic drug release profiles

Lee, Hoik,Xu, Gang,Kharaghani, Davood,Nishino, Masayoshi,Song, Kyung Hun,Lee, Jung Soon,Kim, Ick Soo Elsevier/North Holland 2017 International journal of pharmaceutics Vol.531 No.1

<P><B>Abstract</B></P> <P>Simple sequential electrospinning was utilized to create a functional tri-layered nanofiber mesh that achieves time-regulated biphasic drug release behavior. A tri-layered nanofiber mesh −composed of zein and poly(vinylpyrrolidone) (PVP) as the top/bottom and middle layers, respectively − was constructed through sequential electrospinning with ketoprofen (KET) as the model drug. PVP was blended with graphene oxide (GO) to improve the drug release functionality of PVP nanofiber as well as its mechanical properties. Scanning electron microscopy confirmed that the resultant nanofibers had a linear morphology, smooth surface, and tri-layered structure. In addition, X-ray diffraction patterns, differential scanning calorimetric analyses, and Fourier transform infrared spectra verified that the drugs were uniformly dispersed throughout the nanofiber due to good compatibility between the polymer and KET induced by hydrogen interaction. <I>In vitro</I> release test of the tri-layered structure, each component of which had distinct release features, successfully demonstrated time-regulated biphasic drug release. Also, it was confirmed that the drug release rate and duration can be controlled by designing a morphological feature – namely, mesh thickness – which was achieved by simply regulating the spinning time of the first and third layer. This multilayered electrospun nanofiber mesh fabricated by sequential electrospinning could provide a useful method of controlling drug release behavior over time, which will open new routes for practical applications and stimulate further research in the development of effective drug release carriers.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Dual-Layer Coated Drug-Eluting Stents with Improved Degradation Morphology and Controlled Drug Release

Bedair, Tarek M.,Park, Wooram,Park, Bang-Ju,Moon, Myoung-Woon,Lee, Kwang-Ryeol,Joung, Yoon Ki,Han, Dong Keun The Polymer Society of Korea 2018 Macromolecular Research Vol.26 No.7

Drug-eluting stents (DESs) are used to treat cardiovascular diseases such as atherosclerosis. The anti-proliferative drug released from the DES suppress the proliferation of smooth muscle cells and reduced in-stent restenosis. However, a burst release of the drug in the early stages and degradation morphology of the polymer coating represent major disadvantages, which might increase the incidence of in-stent restenosis and/or thrombosis under in vivo clinical studies. To solve these problems, in this study, a double-layer coating system composed of poly(lactide) (PLLA) bottom layer and poly(lactide-co-glycolide) (PLGA) top layer are used for the fabrication of DES. PLLA bottom layer was firstly coated on the metal surface followed by oxygen ion beam treatment. It was found that increasing the ion beam exposure time, increased the roughness of PLLA surface with a nanoscale pocket (or hole)-like structure. The top layer coating represented a mixture of PLGA and paclitaxel (PTX) with 5, 10, and 20% PTX contents. The coating was performed through ultrasonic spray technique, and the morphology showed not only a smooth and uniform surface but also no irregularities were observed at zero day. The drug release and degradation morphology for single-layer (PLGA/PTX) and double-layer (PLLA/PLGA/PTX) coatings were compared. The drug release from the double-layer stainless steel (SS) group showed a slower and controlled drug release for all PTX content samples as compared to single-layer SS group. Moreover, the degradation morphology of double-layer SS group presented a smoother and uniform surface after 12 weeks of degradation under physiological conditions. Therefore, an oxygen ion beam technique with double-layer coating system could effectively control the drug release, i.e., prevent initial burst drug release, and improve the degradation morphology of biodegradable polymer-based DESs.

Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles

손기호,이범진,조정원 한국약제학회 2017 Journal of Pharmaceutical Investigation Vol.47 No.4

Drug release from a polymeric nanocarrier is affected by several factors including the sort of composition (drug, polymer, and excipient), the ratio of composition, physical or chemical interaction between components, and manufacturing methods. Depending on the mechanism of drug release from the vehicles, it can be divided into four categories (diffusion, solvent, chemical interaction, and stimulated release). Recently, lipids have attracted great interest as carriers for water-insoluble drug delivery. Lipidbased drug-delivery systems have received a lot of interest because of their ability to improve solubility and bioavailability of drugs that are poorly soluble in water. The lipid carrier, formulation strategy, and rational drug-delivery system should be selected appropriately for a lipid-based drug-delivery system to be successful. In this review, the general release characteristics and mechanisms of drug from nanocarriers will be discussed.

Construction of Programmable Drug Delivery System with Additive Manufacturing

명노현(Noehyun Myung),강현욱(Hyun-Wook Kang) Korean Society for Precision Engineering 2018 한국정밀공학회지 Vol.35 No.9

A programmable drug delivery system can control the release rate of a drug. It can minimize side effects while maximizing therapeutic effects. In this research, we investigated the feasibility of producing a programmable drug delivery system using 3D printing technology. A capsule with a micro-orifice and a drug-laden hydrogel was designed. The designed system was then fabricated by the printing process using polycaprolactone and hydrogel. The printed drug delivery system was immersed in PBS at 37°C and the number of molecules released was measured thorough colorimetric analysis. The effect of diameter and length of the micro-orifice and concentration of the hydrogel on drug release characteristics was then determined. The initial burst release rate was found to be increased with increasing orifice size. Increasing the length of the orifice linearly delayed the start time of drug release. At length of 600 μm and 1,200 μm, drug release was initiated after 36 h and 72 h for, respectively. When the concentration of hydrogel was increased, drug release rate tended to decrease. These results successfully confirmed that a drug delivery system with controlled release rate and initiation time could be manufactured using 3D printing technology.

Cellulose Acetate Butyrate의 작용기 비율에 따른 스텐트의 약물방출거동 및 물리화학적 특성과 그에 따른 세포 독성의 변화 관찰

장부남 ( Bunam Jang ),강성남 ( Sung Nam Kang ),금창헌 ( Chang Hun Kum ) 한국키틴키토산학회 2018 한국키틴키토산학회지 Vol.23 No.1

CAB 작용기 비율에 따라 스텐트의 약물 방출 거동 및 세포 독성 등의 차이를 관찰해 본 결과 표면적, 기계적 특성에서는 유사한 결과를 나타내었지만, 약물 방출 거동, 세포 독성 등과 같은 결과에서는 유의한 의미를 갖는 결과 값이 도출될 수 있었다. 특히 약물 방출 거동에서 CAB_B를 사용한 스텐트에 비해 CAB_A 사용 스텐트가 전반적으로 방출률이 저하되었고, 그에 따른 세포 독성이 저하되어 세포의 생존율이 증가됨을 관찰할 수 있었다. 본 연구를 통해 약물 방출 스텐트 필수 조건인 약물 방출 조절을 위한 CAB 고분자의 기능성을 살펴보았고, 그에 따른 세포 독성 실험을 통해 생체 적합성을 갖춘 고분자로서의 활용성과 스텐트 내 재협착 등의 부작용을 효과적으로 치료할 수 있는 잠재성 등을 평가할 수 있었다. Although drug eluting stent effectively reduce restenosis compared to bare metal stent, it still has the side effect of the drug, which are continuously caused after the interventional procedure of the coronary artery stent, such as delayed re-endothelialization and thrombosis induced by hypersensitivity of drug and inflammation. In order to solve this problem, a controlled drug release profile was able to induce re-endothelialization of vessel sufficiently by minimizing the side effect of drug. In this study, we investigated drug release behavior, physico-chemical characteristics and cytotoxicity of the stent prepared according to the ratio of butyrate functional group of cellulose acetate butyrate (CAB) in order to demonstrate the possibility of minimizing side effect of drug. CAB exhibits hydrophobic properties as the ratio of butyrate functional groups increases. The drug release rate of high butyrate group decreased about 1.5-3.8 times compared with low butyrate group in case of hydrophobic drug such as paclitaxel. The cytotoxicity was confirmed by the MTT assay. The cell viability in high butyrate group increased about 29% compared to low butyrate group. These results indicate drug release profile was able to controlled by the ratio of the butyrate functional group in CAB. In addition, it suggests that it can be used as a factor to minimize secondary adverse effects such as delayed reendothelialization and thrombosis through inhibition of hypersensitivity and toxicity induced by drug continuously.

약물 방출 스텐트의 약물 방출 및 기계적 특성에 Ethylene Vinyl Alcohol와 Cellulose Acetate Butyrate가 미치는 영향

장부남 ( Bunam Jang ),강성남 ( Sung Nam Kang ),금창헌 ( Chang Hun Kum ) 한국키틴키토산학회 2017 한국키틴키토산학회지 Vol.22 No.1

Although drug-eluting stents have reduced the problem of restenosis, such stents exhibit side effects such as inhibition of re-endothelialization and inflammatory reactions due to persistent drug reactions and sensitivity of polymers. To solve this problem, suppressing the continuous drug reaction by controlling drug release behavior induce rapid vascular re-endothelization. In this study, we attempted to control drug release from a paclitaxel- and cilostazol-containing stent using ethylene vinyl alcohol (EVOH). We then used a scanning electron microscope and atomic force microscope to observe changes on the surface of the drug-releasing stent following the inclusion of EVOH in comparison with stent without EVOH. There were almost no differences on the surface of the drug-eluting stent due to EVOH. The drug release was initially higher in the EVOH-containing stent compared to the stent without EVOH, and the degradation behavior of the polymer not affected by addition of EVOH. Cytotoxicity of the stent containing EVOH was evaluated. EVOH did not exhibit any cytotoxicity due to the degree of controlled release of the drug. Additionally, mechanical property of stent was confirmed by using EVOH and cellulose acetate butyrate (CAB). Radial force increased in stent with EVOH compared to without EVOH although flexibility was not changed. These results suggest that the application of EVOH to drug-eluting stents does not affect the degradation behavior of the stent surface and polymer, but it could be expected to suppress the sustained and excessive response of the drug by rapid release of the drug.

Polymeric Tube-Shaped Devices with Controlled Geometry for Programmed Drug Delivery

박민,최영빈,박천권,이승호,이지은,조은빛,Mark R. Prausnitz 한국고분자학회 2012 Macromolecular Research Vol.20 No.9

We developed a modular tube-shaped device as a proof of principle to enable the programmed release of encapsulated molecules for controlled drug delivery. Each drug-delivery tube module was prepared by assembling two separate silicone tubes in a series, one filled with a model compound (sodium fluorescein) and the other with a diffusional barrier material (polyethylene oxide, PEO). We varied the length of the PEO-filled tubes to control the release from the drug-delivery tube devices. The onset times and periods of drug release increased with the length of the PEO tube. To program the drug release, therefore, we prepared devices with combinations of drug-delivery tube modules with different lengths of PEO-filled tubes. Using PEO-filled tubes with very different lengths achieved a pulsatile drug release while a continuous drug release was realized by using PEO-filled tubes with small differences in length. We concluded that the modular combination of drug-delivery tubes, each composed of a diffusionbarrier tube of different length, demonstrates good potential for applications in programmed drug delivery.