Optimization of self-microemulsifying drug delivery system for telmisartan using Box-Behnken design and desirability function

( Hyuk Jun Cho ),( Dong Won Lee ),( Nirmal Marasini ),( Bijay Kumar Poudel ),( Jeong Hwan Kim ),( Thiruganesh Ramasamy ),( Bong Kyu Yoo ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0

Objectives: To develop and optimize the novel self-microemulsifying drug delivery system (SMEDDS) formulation for enhanced water solubility and bioavailability of telmisartan (TMS) using the Box-Behnken design (BBD) and desirability function. Method: TMS-SMEDDS formulation consisted of the mixture of oil (Peceol), surfactant (Labrasol), co-surfactant (Transcutol), TMS and triethanolamine. A three-level BBD was applied to explore the main effect, interaction effect and quadratic effect of three independent variables, including the amount of Peceol (X1), Labrasol (X2) and Transcutol (X3). Determined conditions were 20<X1 <40, 50<X2 <80 and 5<X3 <30. The response variables were droplet size (Y1), polydispersity index (Y2) and dissolution percentage of TMS after 15min (Y3). KEY FINDINGS: The optimized conditions were 28.93, 80 and 28.08 (mg) for X1 , X2 and X3 , respectively, and the response variables were predicted to be 159.8nm, 0.241 and 85.8% for Y1 , Y2 and Y3 , respectively. The actual values from the optimized formulation showed good agreement with predicted values. The optimized TMS-SMEDDS formulation showed faster drug dissolution rate and higher bioavailability than TMS powder. Conclusions: Our results suggest that response surface methodology using BBD and desirability function is a promising approach to understand the effect of SMEDDS variables and to optimize the formulation.

Biowaiver Extension Potential and IVIVC for BCS Class II Drugs by Formulation Design: Case Study for Cyclosporine Self-microemulsifying Formulation

양수근 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.11

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC0→24h, Cmax and Tmax, respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

Formulation, Characterization and Optimization of Valsartan Self-Microemulsifying Drug Delivery System Using Statistical Design of Experiment

( Bijay Kumar Poudel ),( Nirmal Marasini ),( Tuan Hiep Tran ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0

The aim of the present research was to systematically investigate the main, interaction and the quadratic effects of formulation variables on the performance of self-microemulsifying drug delivery system (SMEDDS) of valsartan using design of experiment. A 17-run Box-Behnken design (BBD) with 3-factors and 3-levels, including 5 replicates at the centre point, was used for fitting a 2nd-order response surface. After the preliminary screening, Labrafil M 2125 CS as oil, Tween 20 as surfactant and Capryol 90 as co-surfactant were taken as independent variables. The dependent factors (responses) were particle size, polydispersity index (PDI), dissolution after 15 min and equilibrium solubility. Coefficients were estimated by regression analysis and the model adequacy was checked by an F-test and the determination coefficient (R(2)). All the responses were optimized simultaneously by using desirability function. Our results demonstrated marked main and interaction effects of independent factors on responses. The optimized formulation consisted of 26.8% (w/w) oil, 60.1% (w/w) surfactant and 13.1% (w/w) co-surfactant, and showed average micelle size of 90.7 nm and 0.246 PDI, 91.2% dissolution after 15 min and 226.7 mg/g equilibrium solubility. For the optimized formulation, predicted value and experimental value were in close agreement. After oral administration, the optimized formulation gave more than 2-fold higher area under curve (AUC) and about 6-fold higher C(max) in rats than valsartan powder (p<0.05). The BBD facilitated in the better understanding of inherent relationship of formulation variables with the responses and in the optimization of valsartan SMEDDS in relatively time and labor effective manner.

Self microemulsifying particles of loratadine for improved oral bioavailability: preparation, characterization and in vivo evaluation

Katla Venu Madhav,Veerabrahma Kishan 한국약제학회 2018 Journal of Pharmaceutical Investigation Vol.48 No.4

The objective was to study the phase behavior of different formulations, to identify the micro emulsion area and to prepare solid SMEDDS particles (SSMED) of loratadine (LOR) for improving oral bioavailability (BA). Formulations were prepared with either Lauroglycol 90 or Peceol as oils, Solutol HS15 as surfactant and Transcutol P as co-surfactant. Then water titrations were done to know the phase behavior to identify microemulsion zone. The SSMEDs were prepared by physical adsorption on novel silicon based porous particulate carriers. The flow properties of SSMEDs were studied. SSMED with syloid XDP (SSMED-XS) was optimized based on the free flowing nature. The optimized formulation was evaluated for self microemulsifying efficiency, size, PDI, Zeta potential (ZP), robustness in different pH conditions, surface morphology and in vitro release studies. Further, the pharmacokinetic (PK) behavior of SSMEDs was evaluated in wistar rats. The optimized L-SMEDDS formulation possessed a mean globule size of 140.90 ± 2.01 nm. Stearyl amine at 1% level was added as positive charge inducer. The PXRD and SEM studies indicated loss of crystallinity of the drug. In vitro % drug release for LOR powder was 65% and for L and SSMED was ranging in between 95–99% in 2 h. The BA of SSMED with stearyl amine (SSMED-XS) was 2.28 fold (p < 0.05); S-SMEDDS without stearyl amine (SSMED-X) was 1.78 fold (p < 0.001) more, when compared with plain LOR suspension. Cationic SSMEDs showed significant difference over negatively charged SSMED during in vivo studies. The SSMED-XS was found to be stable upto 3 months at room temperature (RT).

자가미세유화시스템을 이용한 매스틱의 헬리코박터파일로리 대한 In vitro 및 In vivo 활성 연구

김수지(Su Ji Kim),정상영(Sang-Young Jeong),길영식(Young Sig Gil),신병철(Byung-Cheol Shin),황성주(Sung-Joo Hwang),조선행(Sun Hang Cho) 대한약학회 2011 약학회지 Vol.55 No.1

Mastic is a bleed resin formed in pistacia lentiscus tree extract form the anacatdiaceae family. Mastic is used as a food ingredient in the Mediteraanean resin, and has been used by local inhabitants as a traditional medicine for relief of upper abdominal discomfort, dyspepsiaand peptic ulcer. Clinically, mastic has been effective in the treatment of benign gastric and duodenal, ulcers, giving symptomatic relief and endoscopically proven healing. In this study, to enhance activiteies of poorly water soluble Mastic with oils, surfactants and cosurfactants and then the mixure was microemulsified in aqueous media under condition of gentle agitation and digestive motility that would be encountered in the gastrointestinal tract. Formulation development and screening were based on phase diagrams and characteristics of resultant microemulsion. For optimum mastic formulation, microemulsions with various ratio (w/w%) of mastics, oils, surfactants and cosurfactants were prepared and their solubility was evaluated by monitoring particles size in their buffer through visual asessment and electrophoretic light scattering spectrophotomerter (ELS). In vitro activity of self microemulsified mastic (SME mastic) was determined by minimum ingibition concentration (MIC) test against a panel of Helicobacter pylori (H.pylori) clinical strains. Additionally, in vivo activity of SME masitc was investigated us mouse infected by CH275 of H. pylori. The mean diameter of SME mastic was less then 100 nm in water and SME mastic was showed similar antiboisis effect compared to tometronidazole, clarithromycin and omeproazole. Consequently, SME mastic would be effective system to exterminate H. pylori. If mastic were dose with combined treatment, mastic might augur well for effect of H. pylori eradication as good remedy.

Self-microemulsifying Drug Delivery System for Improved Oral Bioavailability of Dipyridamole: Preparation and Evaluation

Feng Guo,Haijun Zhong,Jing He, Baogang Xie,Fen Liu, Helin Xu,Minmin Liu,Chunlian Xu 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.7

Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.

SMEDDS를 이용한 난용성 약물의 용출율 향상

김계현,이윤석,배준호,지상철,박은석 성균관대학교 약학연구소 1999 成均藥硏論文集 Vol.11 No.-

ABSTRACT-A self-microemulsifying drug delivery system (SMEDDS) was developed to enhance the solubility and dissolution rate of poorly water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The system was optimized by evaluating the solubility of DDB and the microemulsion existence range after the preparation of microemulsions with varying compositions of triacetin and surfactant-cosurfactant mixtures (Labrasol as surfactant (S) and the combination of Transcutol, Cremophor RH 40 and Plurol oleique as cosurfactant (CoS)). SMEDDS in this study markedly improved the solubility of DDB in water up to 10 mg/ml and the size of the o/w microemulsion droplets measured by dynamic light scattering showed a narrow monodisperse size distribution with an average diameter less than 50nm. The microemulsion existing range is increased proportional to the ration of S/CoS, however, it decreased remarkably as the oil content was more than 20%. In vitro dissolution study of SMEDDS showed a significantly increased dissolution rate of DDB in water (>12 fold over DDB powder), and SMEDDS also had significantly greater permeability of DDB in Caco-2 cell compared to powders.

Development of novel flurbiprofen-loaded solid self-microemulsifying drug delivery system using gelatin as solid carrier

Kim, Dong Wuk,Kang, Jun Hyeok,Oh, Dong Hoon,Yong, Chul Soon,Choi, Han-Gon Informa UK, Ltd. 2012 Journal of microencapsulation Vol.29 No.4

<P>To develop a novel flurbiprofen-loaded solid self-microemulsifying drug delivery system (solid SMEDDS) with improved oral bioavailability using gelatin as a solid carrier, the solid SMEDDS formulation was prepared by spray-drying the solutions containing liquid SMEDDS and gelatin. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Transcutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a <I>z</I>-average diameter of about 100 nm. The flurbiprofen-loaded solid SMEDDS formulation gave a larger emulsion droplet size compared to liquid SMEDDS. Unlike conventional solid SMEDDS, it produced a kind of microcapsule in which liquid SMEDDS was not absorbed onto the surfaces of carrier but formed together with carrier in it. However, the drug was in an amorphous state in it like conventional solid SMEDDS. It greatly improved the oral bioavailability of flurbiprofen in rats. Thus, gelatin could be used as a carrier in the development of solid SMEDDS with improved oral bioavailability of poorly water-soluble drug.</P>

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

조영대,박영준 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.2

Fenofibrate is indicated in hypercholesterolemiaand hypertriglyceridemia alone or combined (typesIIa, IIb, III, IV, and V dyslipidemias). However, due to itslow solubility in water, it has low bioavailability after oraladministration. In order to improve the dissolution rate,fenofibrate was formulated into a self-microemulsifyingdrug delivery system (SMEDDS). We used pseudoternaryphase diagrams to evaluate the area of microemulsification,and an in vitro dissolution test was used to investigate thedissolution rate of fenofibrate. The optimized formulationfor in vitro dissolution and bioavailability assessmentconsisted of propylene glycol laurate (Lauroglycol FCC)(60 %), macrogol-15-hydroxystearate (Solutol HS 15)(27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in themicroemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS wassignificantly higher than that of the reference tablet. In vivopharmacokinetics study of fenofibrate in beagles administeredSMEDDS-A form resulted in a 3.7-fold increase inbioavailability as compared with the reference drug. Ourstudies suggested that the fenofibrate containing SMEDDScomposition can effectively increase the solubility and oralbioavailability of poorly water-soluble drugs.

Optimization of self-microemulsifying drug delivery system for telmisartan using Box-Behnken design and desirability function.

Cho, Hyuk Jun,Lee, Dong Won,Marasini, Nirmal,Poudel, Bijay Kumar,Kim, Jeong Hwan,Ramasamy, Thiruganesh,Yoo, Bong Kyu,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Pharmaceutical Society of Great Britain 2013 Journal of pharmacy and pharmacology Vol.65 No.10

<P>To develop and optimize the novel self-microemulsifying drug delivery system (SMEDDS) formulation for enhanced water solubility and bioavailability of telmisartan (TMS) using the Box-Behnken design (BBD) and desirability function.</P>