Development of Solid SEDDS,V: Compaction and Drug Release Properties of Tablets Prepared by Adsorbing Lipid-Based Formulations onto Neusilin® US2

Purpose

To develop tablet formulations by adsorbing liquid self-emulsifying drug delivery systems (SEDDS) onto Neusilin®US2, a porous silicate.

Methods

Nine SEDDS were prepared by combining a medium chain monoglyceride, Capmul MCM EP, a medium chain triglyceride, Captex 355 EP/NF, or their mixtures with a surfactant Cremophor EL, and a model drug, probucol, was then dissolved. The solutions were directly adsorbed onto Neusilin®US2 at 1:1 w/w ratio. Content uniformity, bulk and tap density, compressibility index, Hausner ratio and angle of repose of the powders formed were determined. The powders were then compressed into tablets. The dispersion of SEDDS from tablets was studied in 250 mL of 0.01NHCl (USP dissolution apparatus; 50 RPM; 37°C) and compared with that of liquid SEDDS.

Results

After adsorption of liquid SEDDS onto Neusilin®US2, all powders demonstrated acceptable flow properties and content uniformity for development into tablet. Tablets with good tensile strength (>1 MPa) at the compression pressure of 45 to 135 MPa were obtained. Complete drug release from tablets was observed if the SEDDS did not form gels in contact with water; the gel formation clogged pores of the silicate and trapped the liquid inside pores.

Conclusion

Liquid SEDDS were successfully developed into tablets by adsorbing them onto Neusilin®US2. Complete drug release from tablets could be obtained.

     

Enhanced oral bioavailability of curcumin via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique

In this study, a novel liquid self-emulsifying drug delivery system (SEDDS) containing curcumin was formulated and further developed into a solid form by a spray drying method using Aerosil 200 as the solid carrier. The optimum liquid SEDDS consisted of Lauroglycol Fcc, Labrasol and Transcutol HP as the oil phase, the surfactant and the co-surfactant at a weight ratio of 15.0 : 70.8 : 14.2 (w/w/w), respectively. There was no difference in droplet size between the emulsions obtained from the liquid and solid forms of SEDDS. Solid state characterization of the solid SEDDS was performed by scanning electron micrograph (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The drug formulated in the solid SEDDS was quickly and completely dissolved within 5 min, both in 0.1 N HCl and phosphate buffer pH 6.8 dissolution media, whereas crude curcumin powder was significantly less dissoluble. The solid SEDDS formulation was stable for at least 3 months at 40°C with 75% relative humidity. After oral administration to rats, curcumin in the solid SEDDS resulted in significant improvement in in vivo absorption compared with that of curcumin powder. As the dose of curcumin formulated in solid SEDDS increased from 25 to 100 mg/kg, the C(max) and area under the drug concentration time curve (AUC) of curcumin were increased by 4.6 and 7.6 times, respectively. However, the over-proportional increase in the AUC in the higher dose group might be due to underestimation of AUC in the lower dose group. In conclusion, this solid SEDDS is a promising solid dosage form for poorly water-soluble curcumin.     

Formulation development and evaluation of pioglitazone hydrochloride self-emulsifying drug delivery systems

As a widely prescribed anti diabetic drug, pioglitazone belongs to class IΙ under BCS and exhibits low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited, and its solubility and dissolutionrate need to be enhanced in order to increase its oral bioavailability. In the present study, we aimed to screen various oils, surfactantsand cosolvents. The highest solubility was observed in Labrafac, Tween-80 and propylene glycol. Then the feasibility of formulatingpioglitazone SEDDS was evaluated, and the effect of dilution on the dissolution rate and dissolution efficiency of pioglitazone was also analyzed. A comparative evaluation of pioglitazone from SEDDS was made in SGF and 1% SLS. Dissolution of pioglitazone from SEDDS was rapid and higher compared with pure drug. The rate and extent of release of pioglitazone hydrochloride from stable SEDDS (F1) were higher in 1% SLS compared with SGF. The FTIR spectra proved that there was on chemical interaction between excipients and drug. SEM studies confirmed that the size was small and spherical.     

Systematic Development of Self-Emulsifying Drug Delivery Systems of Atorvastatin with Improved Bioavailability Potential

The aim of this study was to prepare and characterize a self-emulsifying drug delivery system (SEDDS) with a high drug load of poorly water-soluble atorvastatin for the enhancement of dissolution and oral bioavailability. Solubility of atorvastatin in oil, surfactant, and cosurfactant was determined. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations. A high drug load (10% w/w) was achieved with a combination of oleic acid, Tween 80, and polyethylene glycol 400, ensuring the maximum dissolution property (in the case of SES6). Effects of lipids and surfactants on physical properties of SEDDS such as in vitro emulsification efficiency in terms of self-emulsification time, emulsion droplet size, and percent transmittance were measured. Multiple regression analysis revealed that a higher amount of surfactants significantly increased dissolution of ATV while decreasing emulsion droplet size and emulsification time. About a four-fold increase in dissolution was achieved by SEDDS compared to pure ATV powder. Overall, this study suggests that dissolution and oral bioavailability of ATV could be improved by SEDDS technology.     

Investigation of drug-porous adsorbent interactions in drug mixtures with selected porous adsorbents

The adsorption of drugs onto porous substrates may prove to be a convenient method by which to enhance the dissolution rate of certain poorly water-soluble drugs in body fluids. The purpose of this research is to provide a better understanding of the type of interactions occurring between drugs and certain pharmaceutically acceptable porous adsorbents that leads to enhanced drug dissolution rates. The interactions between ibuprofen (acidic drug), acetaminophen (acidic drug), dipyridamole (basic drug), and the porous adsorbents used (calcium silicate and silica gel) were investigated using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier Transform infrared spectroscopy (FTIR). DSC and PXRD results indicated a significant loss of crystallinity of both ibuprofen and acetaminophen but not dipyridamole. In the case of ibuprofen, FTIR results indicated the ionization of the carboxylic group based on the shift in the FTIR carboxylic band. Dissolution of ibuprofen from its mixtures with porous adsorbents was found to be significantly higher compared to the neat drug, whereas dipyridamole dissolution from its mixtures with porous adsorbents was not significantly different from that of the neat drug.     

茴拉西坦自乳化给药系统与片剂的药代动力学及体内外相关性的研究

目的：研究茴拉西坦自乳化制剂和普通片剂的体内外相关关系;评价其大鼠口服给药的体内药代动力学。方法：通过测定自乳化制剂和普通片剂的体外溶出度考察其释药特性,采用RP-HPLC法测定活性代谢产物对氨基甲氧基丁酸的浓度血浆中,通过Wagner-Nelson法计算体内吸收分数（f）,研究两制剂的吸收分数（f）与体外累积溶出度（Q%）的相关性。结果：自乳化微乳体外15min的溶出度为（80±4）%,比片剂的溶出度（50%）明显提高;体内代谢产物的回收率为90%,日内日间精密度分别小于4%和6%,该方法灵敏度高、准确可靠。自乳化微乳的AUC0-∞为（11168±2395）ng·mL^-1·h,是普通片剂的3倍。自乳化微乳和片剂的MRT0-∞分别为（2.7±0.6）h和（1.7±0.5）h,具有统计学差异（P〈0.05）。体内外相关性结果表明,片剂的体内吸收与体外溶出度呈线性相关,线性方程的斜率为0.7765,截距为-2.9527;自乳化微乳的体内外相关性符合二次模型,其拟合系数为0.972。结论：茴拉西坦自乳化给药系统可显著提高药物体内的生物利用度。自乳化制剂处方中含有促吸收的复合表面活性剂和油相,其体外药物呈快速释放的特性,而体内自发与胃肠液形成o/w型微乳后可通过淋巴转运的吸收途径。     

Effect of Ingested Lipids on Drug Dissolution and Release with Concurrent Digestion: A Modeling Approach

Purpose

To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen.

Methods

Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model.

Results

Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion was observed and predicted by the developed model. Ninety minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion.

Conclusion

A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.

     

Development and characterization of liquid and solid self-emulsifying drug delivery system of fexofenadine

Fexofenadine, the active metabolite of terfenadine, a well known and effective H1 receptor antagonist, is administered by the oral route. The objective of present investigation was to develop and characterize a liquid self-emulsifying drug delivery system (SEDDS) and a solid SEDDS by using bioenhancer excipients like Tween 80 and Labrasol which are known for their inhibiting action on CYP450 and P-glycoprotein pump. Solubility of fexofenadine was determined in various vehicles, including oils, surfactants and co-solvents. Various evaluation parameters (emulsification study, particle size, poly-dispersibility index, % drug release, etc.) were carried out to find out optimized liquid SEDDS formulation. Optimized liquid formulations were converted in solid SEDDS by simple and convenient physical adsorption technique. Solid SEDDS was characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transport infra-red spectroscopy. The optimized liquid SEDDS formulation contained 29 % Captex 200P/Capmul MCM C8 EP as oil, 47 % Labrasol/Tween 80 as a surfactant and 24 % Ethanol as a co-solvent. The optimized liquid and solid SEDDS showed higher drug release than pure API powder. DSC and XRD results of solid SEDDS confirmed that the drug presented in the formulation was in an amorphous state. The prepared liquid SEDDS and solid SEDDS containing bio-enhancer excipients increased the in vitro dissolution rate of fexofenadine compared to pure drug and has potential to increase bioavailability by blocking Pgp efflux pump and CYP450 hepatic metabolism.     

Comparison between lipolysis and compendial dissolution as alternative techniques for the in vitro characterization of alpha-tocopherol self-emulsified drug delivery systems (SEDDS)

In vitro characterization of alpha-tocopherol SEDDS formulations was performed by (1) lipolysis in bio-relevant media, and (2) physical assessment by dissolution, particle size, and turbidity analyses. Both methods were statistically correlated using a 25-run, five-factor multiple-level d-optimal mixture design. Independent variables were SEDDS composition [vitamin E (12.5-25%), Tween 80 (10-40%), labrasol (0-10%), alcohol (0-10%), and captex 355 (20-50%)]. Measured responses were percent lipolysis, percent vitamin E retained in the aqueous layer of the digestion medium, and percent vitamin E dissolved in the dissolution medium. Percent lipolysis ranged from 0% to 66.3%. Percent vitamin E retrieved in the aqueous layer of the digestion and dissolution media ranged from 3% to 29.3% and from 25.9% to 101.7%, respectively. Turbidity ranged from 28 to 403JTU and the average droplet size was >1.0 microm. All formulation ingredients had significant (p<0.05) effect on percent lipolysis. Only two factors, Tween and vitamin E had significant effect on vitamin retention in the aqueous layer post-lipolysis. Tween, labrasol, and captex 355 had significant effect on vitamin E dissolution. Poor correlation was observed between the responses. Formulation ingredients influenced each response differently; and therefore, each method can only reveal distinctive characteristics of the SEDDS formulation and may not be used interchangeably.     

Self‐emulsifying system for improving drug dissolution and bioavailability: in vitro/in vivo evaluation

The present study focuses on enhancement of the dissolution and oral absorption of poorly water‐soluble etodolac. A self‐emulsifying drug delivery system (SEDDS) composed of oil, surfactant, and co‐surfactant for oral administration was formulated. The SEDDS formulations were optimized by evaluating their ability to self‐emulsifying when introduced to an aqueous medium under gentle agitation, and by determination of particle size of the resulting emulsion. Optimized formulation of SEDDS was selected for bioavailability assessment in rabbits. Also, the anti‐inflammatory effect of SEDDS formulation was determined in rats, compared with powder drug and etodolac suspension in water (50 mg kg^?1). The peak plasma concentration of 16.4±1.07 µg ml^?1 appeared after 1.3±0.2 h, whereas with powder drug and etodolac suspension the values were 7.5±0.5 and 10.6±0.7 µg ml^?1 appearing at 4.2±0.4 and 2.4±0.2 h, respectively. The AUC_0‐8 of the etodolac SEDDS formulation was approximately 2.3 times as that of the pure drug and 1.5 times as much as that of the suspension form. There was no significant change in the elimination rate constant and the elimination half‐life. Thus, oral absorption is improved significantly using the SEDDS formulation. The anti‐inflammatory activity of SEDDS formulation was compared with etodolac suspended in water at a dose of 20 mg kg^?1, using a carrageenan‐induced rat paw edema model. At 4 h, the SEDDS formulation reduced edema by 69% as compared a similar dose of etodolac suspension, which reduced edema by 45%. The results support the utility of SEDDS formulation for the oral delivery of etodolac, and potentially other lipophilic drugs. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

生脉散超微粉的显微特征和溶出度研究

目的 研究生脉散超微粉的显微特征和溶出度差异,为生脉超微粉应用提供实验依据.方法 采用光学显微镜观察颗粒显微结构;电镜扫描观察微观形貌;以五味子甲素和五味子乙素为指标,采用HPLC法测定生脉散细粉和超微粉在不同时间溶出的量,计算累积溶出度.结果 生脉散经超微粉碎后,基本无完整细胞存在,粒度均匀;生脉散超微粉中五味子甲素和五味子乙素溶出速率高于细粉,但是180 min后累积溶出量没有明显差异.结论 超微粉碎可使生脉散显微特征变化明显,化学成分五味子甲素和五味子乙素溶出速率加快.     

Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability

The objective of this study was to prepare a solid supersaturatable self-emulsifying drug delivery system (S-sSEDDS) using docetaxel (DTX). Different from conventional self-emulsifying drug delivery systems (SEDDSs), a solid supersaturatable self-emulsifying drug delivery system of docetaxel (DTX-S-sSEDDS) was prepared by spray drying, using lactose as the solid carrier and hydroxypropyl methylcellulose (HPMC) as the supersaturation promoter. Physicochemical properties and in vitro dissolution was observed while taking into account factors such as formulations, supersaturated promoters, solid carriers, and preparation methods. The bioavailability of the DTX-S-sSEDDS(1) compared with other formulations of DTX was evaluated in rats. The results showed that the presence of HPMC effectively sustained the supersaturated state by retarding the precipitation kinetics. Although the total amount of emulsifying excipients in the DTX-S-sSEDDS(1) was only 3/5 as much as that of the conventional SEDDS (DTX-SEDDS(2)), the percent of the accumulated dissolved DTX-S-sSEDDS(1) at 2 h reached 90.96%, which was higher than that of the DTX-SEDDS(2) (76.26%) and approximately 29.8 times as much as that of the DTX crude powder. The in vivo studies indicated that the area under the concentration-time curve (AUC(0-∞)) of the DTX-S-sSEDDS(1) increased by nearly 8.77-fold, 1.45-fold more than those of the DTX powder and the conventional SEDDS without the presence of HPMC (DTX-SEDDS(1)) at a dose of 10 mg/kg. In conclusion, the S-sSEDDS provides an effective approach for improving the dissolution and bioavailability of docetaxel with a low level of emulsifying excipients and provides a reference for good stabilization and the safety of SEDDSs.     

Characterization and evaluation of solid self-microemulsifying drug delivery systems with porous carriers as systems for improved carbamazepine release

The purpose of this study was to investigate solid self-microemulsifying drug delivery system (SSMEDDS), as potential delivery system for poorly water soluble drug carbamazepine (CBZ). Self-microemulsifying drug delivery system (SMEDDS) was formulated using the surfactant polyoxyethylene 20 sorbitan monooleate [Polysorbate 80] (S), the cosurfactant PEG-40 hydrogenated castor oil [Cremophor(?) RH40] (C) and the oil caprylic/capric triglycerides [Mygliol(?) 812] (O). Four different adsorbents with high specific surface area were used: Neusilin(?) UFL2, Neusilin(?) FL2 (magnesium aluminometasilicate), Sylysia(?) 320 and Sylysia(?) 350 (porous silica). Microemulsion area at the surfactant to cosurfactant ratio (K(m)) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio 8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33.771±0.041mg/ml. Rheological measurements of unloaded and CBZ-loaded SMEDDS at water content varied from 10 to 60% (w/w) were conducted. It has been found that CBZ has great influence on rheological behaviour of investigated system upon water dilution. Photon correlation spectroscopy has shown the ability of CBZ-loaded SMEDDS to produce microemulsion droplet size. SSMEDDS improved release rate of CBZ, but the type of adsorbent significantly affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate adsorbents, release rate of CBZ decreased with increasing specific surface area due to entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium. With porous silica adsorbents no difference in release rate was found in comparison to physical mixtures. In physical mixtures at 12.5% (w/w) CBZ content, presence of amorphous CBZ led to high dissolution rate.     

Experimental determination of the diffusion boundary layer width of micron and submicron particles

Powder dissolution kinetics have shown that for particles in the so called "large" size regime (more than about 50 microm), the dissolution rate scales as the specific surface area, i.e. rate proportional to d(-1) where d is the particle diameter. This is consistent with an effective diffusion boundary layer width h(EFF) that is constant with respect to particle size. However, for particles in the so called "small" size regime (d less than about 50 microm), the dissolution rate has a stronger dependence than proportional to d(-1) [Bisrat, M., Anderberg, E.K., Barnett, M.I., Nystroem, C., 1992. Physicochemical aspects of drug release. XV. Investigation of diffusional transport in dissolution of suspended, sparingly soluble drugs. Int. J. Pharm., 80, 191-201; Mosharraf, M., Nystroem, C., 1995. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int. J. Pharm., 122, 35-47]. In this regime, Prandtl boundary layer theory predicts an h(EFF) approximately equal to the particle radius or diameter. This paper presents the first experimental determination of h(EFF) for particles less than about 2 microm. The powder dissolution kinetics of six suspensions over the particle diameter range of 5.9 +/- 0.1 to 0.53 +/- 0.05 microm are analyzed to yield h(EFF) values of 8.5 +/- 1.9 to 0.34 +/- 0.14 microm. The theoretical expectation for mass transport, dissolution time proportional to d(2.0), is in good agreement with the experimental results of dissolution time proportional to d(2.3). An understanding of these mass transfer mechanisms allows pharmaceutical scientists to achieve targeted release rates with minimum ensemble instability.     

Formulation and in vivo evaluation of chlorpropham (CIPC) oral formulations

The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract.     

Enhanced oral bioavailability of dexibuprofen by a novel solid Self-emulsifying drug delivery system (SEDDS)

The main objective of this study was to prepare a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 to improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS was a system that consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10 mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (P < 0.05). The solid SEDDS gave significantly higher AUC and Cmax than did dexibuprofen powder (P < 0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. Our results suggested that this solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen.     

Development and characterization of self emulsifying drug delivery system of a poorly water soluble drug using natural oil

Objective of present study involves preparation and evaluation of self emulsifying drug delivery system (SEDDS) of ibuprofen using peanut oil. SEDDS were composed of varying concentrations of peanut oil (solvent), tween 80 (surfactant) and span 20 (co-surfactant). Influence of concentration of surfactant/co-surfactant and globule size on dissolution rate was investigated. Dissolution rate was studied in phosphate buffer pH 6.8 using dissolution apparatus II. The dissolution rate of self emulsifying capsule was found to be significantly faster than that from conventional tablet. The optimized SEDDS released approximately above 85% of ibuprofen within 30 min, while conventional ibuprofen tablet could released only 36% in 30 min. Therefore, these SEDDS could be a better alternative to conventional drug delivery system of ibuprofen.     

Availability of norethisterone acetate from combined oral contraceptive tablets.

The availability of norethisterone acetate in HCl (0.1 mol/l) from combined oral contraceptive tablets in the presence of certain proprietary preparations and adsorbent drugs which are used as antacids, intestinal adsorbents and for peptic ulcer was investigated. The percent dissolution of the hormone in the presence of these drugs was greatly reduced depending mainly on the nature of the adsorbent drugs.     

Taste-masked orodispersible tablets of cyclosporine self-nanoemulsion lyophilized with dry silica

Abstract

The aim of the current study was to investigate the effects of formulation parameters on the disintegration, water absorption and dissolution characteristics of cyclosporine A (CyA) loaded self-emulsifying drug delivery system (SEDDS) in an orodispersible compacts. Its taste masking efficiency was also attempted using an electronic tongue. ODTs were prepared by freeze-drying liquid SEDDS and synthetic amorphous silica suspension followed by direct compression. The influences of the compression forces and super-disintegrant were evaluated to optimize tablet characteristics. The liquid SEDDS was characterized by vesicular size of 48.5?nm, polydispersity index of 0.95, turbidity of 40.7?NTU and rapid CyA dissolution and emulsification rate. The results of micrometric studies demonstrated an acceptable flow, hardness and friability to indicate good mechanical strength of ODTs. The interaction and Pareto charts demonstrated a greater effect of low compression force to increase the porosity and facilitate the disintegration rather than the deformation action of the super-disintegrant. Super-disintegrant level was the most important factor affecting the dissolution parameter followed by the compression force then their interaction effect. Moreover, as indicated by Euclidean distance values and discrimination indices, the unpalatable taste and aversion taste of CyA to stimuli were masked in its optimized SEDDS incorporated ODTs.     

Application of a mixture experimental design in the optimization of a self-emulsifying formulation with a high drug load

Response surface methodology (RSM) was applied to optimize the self-emulsifying drug delivery system (SEDDS) containing 25% (w/w) Drug A, a model drug with a high lipophilicity and low water solubility. The key objective of this study was to identify an optimal SEDDS formulation that: 1) possesses a minimum concentration of the surfactant and a maximum concentration of lipid and 2) generates a fine emulsion and eliminates large size droplets (> or = 1 microm) upon dilution with an aqueous medium. Three ingredient variables [PEG 400, Cremophor EL, and a mixture of glycerol dioleate (GDO), and glycerol monooleate (GMO)] were included in the experimental design, while keeping the other ingredients at a fixed level (25% Drug A, 6% ethanol, 3% propylene glycol, 4% water, and 2% tromethamine) in the SEDDS formulation. Dispersion performance of these formulations upon dilution with a simulated gastrointestinal fluid was measured, and the population of the large droplets was used as the primary response for statistical modeling. The results of this mixture study revealed significant interactions among the three ingredients, and their individual levels in the formulation collectively dictated the dispersion performance. The fitted response surface model predicted an optimal region of the SEDDS formulation compositions that generate fine emulsions and essentially eliminates large droplets upon dilution. The predicted optimal 25% Drug A-SEDDS formulations with the levels of Cremophor EL ranging from 40-44%, GDO/GMO ranging from 10-13%, and PEG 400 ranging from 2.7-9.0% were selected and prepared. The dispersion experiment results confirmed the prediction of this model and identified potential optimal formulations for further development. This work demonstrates that RSM is an efficient approach for optimization of the SEDDS formulation.