Chin-Yang Kang

New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method.

The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The aim of this study was to prepare uniformly and homogeneously distributed dosage forms of very low-dose drugs using twin screw hot-melt extrusion (HME) and to investigate the distribution of drugs using instrumental analyses. For the feasibility of HME method, a very low amount of coumarin-6, a fluorescent dye, was used to visualize distribution images using confocal laser scanning microscope (CLSM). Limaprost, tamsulosin and glimepiride were then used as low-dose model drugs to study the applicability of HME for content uniformity and distribution behaviors. Hydrophilic thermosensitive polymers with low melting point, such as Poloxamer188 and polyethylene glycol (PEG) 6000, were chosen as carriers. The melt extrusion was carried out around 50°C, at which both carriers were easily dissolved but model drugs remained in solid form. The physicochemical properties of the hot-melt extrudates, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were measured. Content uniformity of the drugs was also checked by HPLC. CLSM imaging showed that model drugs were well distributed throughout the hot-melt extrudate, giving better content uniformity with low batch-to-batch variations compared with simple physical mixtures. DSC, PXRD and FT-IR data showed that there was no interaction or interference between model drugs and thermosensitive polymers. The current HME methods could be used to prepare uniformly distributed and reproducible solid dosage forms containing very low dose drugs for further pharmaceutical applications.

Advances in hot-melt extrusion technology toward pharmaceutical objectives

Hot Melt Extrusion (HME) technology is a widely used for manufacturing process in the plastic and pharmaceutical industries and is an efficient and simple for the production of a solid dispersion. This technique is an environmental friendly, continuous process that does not use solvents. It is time and cost efficient and can be easily scaled up. In addition, HME may be used in conjunction with other technologies to effectively increase the solubility and dissolution rate of poorly water-soluble drugs. Numerous research papers on the progress of HME technology in the pharmaceutical industry have been written, and products manufactured using HME have been approved by the FDA. However, there are some drawbacks to the products manufactured using through HME. These are related to the high energy input coming from the applied shear forces and high temperature, which could lead to drug or polymer degradation and thus significantly impact the product quality. Despite these disadvantages, HME has been employed in various advanced applications, such as taste masking and targeted drug delivery. This review article focuses on advances in HME technology, which include improvement in the weaknesses of HME, patient-centric formulations, and the outlook for uses such as formulation development.

Drug Release-Modulating Mechanism of Hydrophilic Hydroxypropylmethylcellulose Matrix Tablets: Distribution of Atoms and Carrier and Texture Analysis

Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets.

Process analytical quality control of tailored drug release formulation prepared via hot-melt extrusion technology

The objective of the present study was to compare the influence of Eudragit® RS PO and RL PO blends on the release of water-soluble and insoluble drugs from hot-melt extruded formulations. In addition, we aimed to evaluate drug content uniformity and distribution by Fourier transform-infrared (FT-IR) chemical imaging. Theophylline (TP) and carbamazepine (CBZ) were selected as the water-soluble and insoluble model drugs, respectively. Eudragit® RS PO and RL PO were selected as the polymeric matrices. FT-IR chemical imaging clearly demonstrated the content uniformity and distribution for both drugs in the extrudates, which was confirmed by HPLC. Increasing the ratio of Eudragit® RL PO led to an increase in the in vitro drug release, whereas an increase in the ratio of Eudragit® RS PO sustained the drug release for up to 12 h. The hot-melt extrusion of TP and CBZ with varying ratios of Eudragit® RS PO and RL PO can be employed to tailor the drug release profiles. In this study, we demonstrated, for the first time, the use of FT-IR chemical imaging as a process analytical technique to determine the drug content uniformity and distribution. Our data correlated well with the results of HPLC analysis in the study of tailored drug release from the prepared hot-melt extruded formulation.

Effects of absorbent materials on a self-emulsifying drug delivery system for a poorly water soluble drug

In order to compare the effects of a solid carrier on the formulation of a solid self-microemulsifying drug delivery system (s-SMEDDS), a liquid SMEDDS was prepared with simvastatin. The SMEDDS was optimized using polyoxyl 35 castor oil [Kolliphor® EL] as a surfactant (S), diethylene glycol monoethylether [Transcutol® P] as a co-surfactant (C), and prophyleneglycol monocaprylate [Capryol 90] as the oil phase (O). The microemulsion area at the surfactant to co-surfactant ratio (1:1) was evaluated, and the SMEDDS at an S and C/O ratio of 7:3 was selected. Four types of adsorbents with high specific areas were used: Aerosil® 200, Sylysia® 350, Neusilin® US2, Neusilin® UFL2. SEM, DSC, and PXRD results revealed rough-surfaced particles that represent the amorphous state of s-SMEDDS. The optimized formulation with Neusilin® UFL2 markedly improved drug release. The present study concluded that s-SMEDDS was effectively formulated via adsorption with solid carriers.

In Vitro-In Vivo Correlation Using In Silico Modeling of Physiological Properties, Metabolites, and Intestinal Metabolism

BACKGROUND Recently, pharmaceutical research has focused on in vitro-in vivo correlation as a novel challenge, and in silico modeling has been an important component. As in silico models are highly representative of practical use, regulatory agencies such as the US Food and Drug Administration and European Medicines Agency have recognized and utilized in silico modeling as a useful tool; this allows pharmaceutical organizations to use Physiologically Based Pharmacokinetic (PBPK) models for decision-making, which may aid the financial efficiency of a clinical trial. However, some studies have shown differences of up to approximately 40% in pharmacokinetic parameters such as area under the curve or maximum serum concentration between observed and simulated data. METHODS Gastroplus™ was used to demonstrate current PBPK simulation. 46 research papers were compared with each others applications of PBPK simulation. RESULTS To improve the accuracy of simulation, additional factors may need to be considered, such as precise volume of gastrointestinal sections, specific metabolism of the target drug, and physicochemical data of drug metabolites. Furthermore, the results of these simulations would be extremely valuable to the relevant applications. Simulation programs using Advanced Compartmental Absorption and Transit (ACAT)/PBPK modeling could be a powerful tool for companies performing pre-clinical experiments, and could provide a solution for the ethical issues and economic constraints of clinical trials. CONCLUSION If in silico modeling produced more precise results that could closely match clinical data, it could be more readily used to screen drug pharmacodynamics in bodily systems, and the efficiency of clinical trials would be improved. However, simulation programs are currently limited in their accuracy of pharmacodynamic predictions. In developing new drugs, pharmaceutical companies should address this issue in order to improve in silico/PBPK modeling in the future.

Zero-order Delivery of Alfuzosin Hydrochloride with Hydrophilic Polymers

ABSTRACT − Manufacturing a multi-layered tablet such as Xatral XL ® is more complex and expensive than monolayeredtablets, but mono-layered tablets may have less favorable release properties depending on the pharmacodynamics and phar-macokinetics of the active ingredient. We therefore sought to develop a monolayer tablet with a similar dissolution profileto the commercial alfuzosin sustained-release triple layered tablet (Xatral XL ® ). We prepared four different mono-layeredalfuzosin tablets with different concentrations of hydroxypropyl methycellulose and PVP K-90. Fomulation III with alfu-zosion/ mg-stearate/ HPMC/ PVP K-90 (10/5/110/95 mg/tab) has a similar dissolution rate to Xatral XL ® , with a similarityfactor score of 81.4. However, the swelling and erosion rates of the two formulations were different, and NIR analysisshowed differences in the mechanisms of drug release. Thus, although formulation III and Xatral XL ® show similar dis-solution rates, the mechanisms of drug release are different.Key words

Development of Pharmaceutical Dosage Forms with Biphasic Drug Release using Double-Melt Extrusion Technology

The aim of this study was to develop pharmaceutical dosage forms with a bi-phasic drug using a double extrusion approach. Hot melt extrusion was performed using a co-rotating twin-screw extruder. The. 1st melt extrusion was performed using polymer with a relatively higher Tg, such as HPMC and the 2nd melt extrudate was obtained using the 1st extrudate and polymers with a lower Tg, such as HPMC-AS and PEO. In addition, the formulation with all the content in the same proportion as the double extudate was produced using single extrusion for comparison. Physical characterization was performed on the formulations employing differential scanning calorimetry (DSC). In vitro release tests were studied using a USP Type-I apparatus at 37 ± 0.5°C and 100 rpm. The similarity factor (f2) was also used to check the difference statistically. The DSC results indicated that the crystallinity of ibuprofen was changed to an amorphous state after extrusion in both double and single melt extrusion. Double melt extrudate with ibuprofen showed the desired release in acidic media (pH 1.2) in the first two hours and basic (pH 6.8) during six hours. Double melt extrudate with glimepiride showed faster release in 60 min of over 80%, whereas the single extrudate with glimepiride showed retarded release due to the interaction with HPMC. The similarity factor(f2) value was 28.5, which demonstrates that there were different drug release behavior between the double and single extrusion. Consequently, the double melt extrudated formulation was robust and gave the desired drug release pattern. Keyword : Biphasic drug release, Double melt extrusion, Hot melt extrusion, Bi-layer 본 논문은 삼육대학교 교내 연구과제(RI정책2015006)에 의해 수행되었음. Corresponding Author : Jun-Bom Park(Sahmyook Univ.) Tel: +82-2-3399-1624 email: junji4@gmail.com Received August 9, 2016 Accepted September 9, 2016 Revised (1st August 17, 2016, 2nd August 19, 2016) Published September 30, 2016 이중 고온용융 압출 성형된 이중 방출능을 가지는 제형의 개발

Physical Properties of Gelucire-based Solid Dispersions Containing Lacidipine and Release Profiles

Lacidipine used for the treatment of hypertension has low water solubility and is classified as BCS Class II category. Gelucire-based solid dispersions (SD) containing lacidipine were prepared by solvent evaporation method to enhance drug dissolution. The powdered forms of SD showed irregularly spherical shape. Thermal behaviors of SD from differential scanning calorimetry indicated that distinct endothermic peak of lacidipine () was shifted to lower region (). Drug was present in a crystalline form. NMR spectra also showed some molecular interaction between drug and Gelucire. There was no significant difference in DSC and NMR behaviors between Gelucire 44/14 and Gelucire 50/13. The initial dissolution rate of SD-loaded tablet linearly increased both in water and in water containing 1% tween 20, and much higher than the commercial tablet, . When the amount of SD was increased, the release rate was greater. The Gelucire 50/13 showed higher dissolution than the Gelucire 44/14. The produced solid dispersion with various kinds of excipients and making tablets, it was found that solid dispersions can increase the solubility in artificial gastric juice and finally increases dissolution rate.