Enhancement of solubility and therapeutic potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly compressed spray dried magnesium aluminometasilicate liquid loadable tablets: A study in diet induced hyperlipidemic rabbits

The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems (SMEDDS) containing lovastatin and to further explore the ability of porous Neusilin^® US2 tablet as a solid carrier for SMEDDS. SMEDDS formulations of varying proportions of peceol, cremophor RH 40 and transcutol-P were selected and subjected to in-vitro evaluation, including dispersibility studies, droplet size, zeta potential measurement and release studies. The results indicated that the drug release profile of lovastatin from SMEDDS formulations was statistically significantly higher (p-value < 0.05) than the plain lovastatin powder. Thermodynamic stability studies also confirmed the stability of the prepared SMEDDS formulations. The optimized formulation, which consists of 12% of peceol, 44% of cremophor RH 40, and 44% of transcutol-P was loaded into directly compressed liquid loadable tablet of Neusilin^® US2 by simple adsorption method. In order to determine the ability of Neusilin^® US2 as a suitable carrier pharmacodynamics study were also carried out in healthy diet induced hyperlipidemic rabbits. Animals were administered with both liquid SMEDDS and solid SMEDDS as well. From the results obtained, Neusilin^® was found to be a suitable carrier for SMEDDS and was equally effective in reducing the elevated lipid profile. In conclusion, liquid loadable tablet (LLT) is predicted to be a promising technique to deliver a liquid formulation in solid state.     

Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine

The aim of present investigation is to improve dissolution rate of poor soluble drug Zotepine by a self-microemulsifying drug delivery system (SMEDDS). Ternary phase diagram with oil (Oleic acid), surfactant (Tween 80) and co-surfactant (PEG 400) at apex were used to identify the efficient self-microemulsifying region. Box–Behnken design was implemented to study the influence of independent variables. Principal Component Analysis was used for scrutinising critical variables. The liquid SMEDDS were characterised for macroscopic evaluation, % Transmission, emulsification time and in vitro drug release studies. Optimised formulation OL1 was converted in to S-SMEDDS by using Aerosil^® 200 as an adsorbent in the ratio of 3:1. The S-SMEDDS was characterised by SEM, DSC, globule size (152.1?nm), zeta-potential (?28.1?mV), % transmission study (98.75%), in vitro release (86.57%) at 30?min. The optimised solid SMEDDS formulation showed faster drug release properties as compared to conventional tablet of Zotepine.     

Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin,and absorption studies in rats

This study describes the development and characterization of self-microemulsifying drug delivery systems (SMEDDS) in liquid and pellet forms that result in improved solubility, dissolution, and in vivo oral absorption of the poorly water-soluble compound curcumin. Solubility of curcumin was determined in various vehicles, including oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were constructed to identify the most efficient self-emulsification region. The optimized SMEDDS used for curcumin formulations in liquid and pellet forms contained 70% mixtures of two surfactants: Cremophor EL and Labrasol (1:1), and 30% mixtures of oil: Labrafac PG and Capryol 90 (1:1). The curcumin-SMEDDS in liquid and pellet formulations rapidly formed fine oil-in-water microemulsions, with particle size ranges of 25.8–28.8 nm and 29.6–32.8 nm, respectively. The in vitro rate and extent of release of curcumin from liquid SMEDDS and SMEDDS pellets was about 16-fold higher than that of unformulated curcumin. Plasma concentration–time profiles from pharmacokinetic studies in rats dosed with liquid and pelleted SMEDDS showed 14- and 10-fold increased absorption of curcumin, respectively, compared to the aqueous suspensions of curcumin. Curcumin-SMEDDS liquid and curcumin-SMEDDS pellets were found to be stable up to 6 months under intermediate and accelerated conditions. These studies demonstrate that the new self-microemulsifying systems in liquid and pellet forms are promising strategies for the formulation of poorly soluble lipophilic compounds with low oral bioavailability.     

Comparison of solid self-microemulsifying drug delivery system (solid SMEDDS) prepared with hydrophilic and hydrophobic solid carrier

In order to compare the effects of hydrophilic and hydrophobic solid carrier on the formation of solid self-microemulsifying drug delivery system (SMEDDS), two solid SMEDDS formulations were prepared by spray-drying the solutions containing liquid SMEDDS and solid carriers. Colloidal silica and dextran were used as a hydrophobic and a hydrophilic carrier, respectively. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100 nm. Colloidal silica produced an excellent conventional solid SMEDDS in which the liquid SMEDDS was absorbed onto its surfaces. It gave a microemulsion droplet size similar to that of the liquid SMEDDS (about 100 nm) which was smaller than the other solid SMEDDS formulation. In the solid SMEDDS prepared with dextran, liquid SMEDDS was not absorbed onto the surfaces of carrier but formed a kind of nano-sized microcapsule with carrier. However, the drug was in an amorphous state in two solid SMEDDS formulations. Similarly, they greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats due to the fast spontaneous emulsion formation and the decreased droplet size. Thus, except appearance, hydrophilic carrier (dextran) and hydrophobic carrier (colloidal silica) hardly affected the formation of solid SMEDDS such as crystalline properties, dissolution and oral bioavailability.     

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

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 z-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.     

Development of SMEDDS using natural lipophile: application to beta-Artemether delivery

The objective of the present investigation was to formulate self-microemulsifying drug delivery systems (SMEDDS) using a novel, indigenous natural lipophile (N-LCT) as an oily phase. SMEDDS based on N-LCT and commercially available modified oil (Capryol 90) were formulated and their application in improving the delivery of a lipophilic anti-malarial drug, beta-Artemether (BAM) was also evaluated. BAM-loaded SMEDDS were characterized with respect to mean globule size and in vitro drug release profile in comparison to the marketed formulation (Larither((R))). Comparative in vivo anti-malarial performance of the developed SMEDDS was evaluated against the (Larither((R))) in Swiss male mice infected with lethal ANKA strain of Plasmodium berghei. The parameters studied were percent parasitemia, activity against time and animal survival period. Both the BAM-SMEDDS showed excellent self-microemulsification efficiency and released >98% of the drug in just 15min whereas (Larither((R))) showed only 46% drug release at the end of 1h. The mean globule size for optimized BAM-SMEDDS was <100nm. The anti-malarial studies revealed that BAM-SMEDDS resulted in significant improvement in the anti-malarial activity (P<0.05) as compared to that of (Larither((R))) and BAM solubilized in the oily phases and surfactant. The developed SMEDDS highlight safety for use and potential applications of indigenous natural lipophile in the development of novel colloidal drug carriers.     

Preparation and evaluation of self-microemulsifying drug delivery system of oridonin

The objective of this study was to develop self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of the poorly water-soluble drug, oridonin. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SMEDDS were investigated in detail. The SMEDDS were characterized by morphological observation, droplet size and zeta-potential determination, cloud point measurement and in vitro release study. The optimum formulation consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 46.7% Cremopher EL, and 23.3% Transcutol P. Invitro release test showed a complete release of oridonin from SMEDDS in an approximately 12h. The absorption of oridonin from SMEDDS showed a 2.2-fold increase in relative bioavailability compared with that of the suspension. Our studies demonstrated the promising use of SMEDDS for the delivery of oridonin by the oral route.     

口服固体自微乳化给药系统的研究进展

目的对新近发展的固体自微乳化给药系统（S-SMEDDS）文献进行综述。方法查阅近年国内外相关文献并进行归纳和总结。结果对固体自微乳的载体、固化技术以及缓控释制剂进行了探讨,为研究水难溶性药物的生物利用度及适合药物释放特性的S-SMEDDS技术提供相关参考。结论固体自微乳化系统可以显著提高难溶性药物的口服生物利用度,且兼顾了液态自微乳和固体制剂二者的优势,是一个极具潜力的新型制剂。     

Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of alpha-Asarone in beagle dogs

A self-microemulsifying drug delivery system (SMEDDS) for enhancement of oral absorption of a poor water-soluble drug, alpha-Asarone (ARE), is reported. Solubility of ARE was determined in various vehicles. SMEDDS consisted of a mixture of oils, surfactants, and cosurfactants that were emulsified in an aqueous medium under the gentle agitation and digestive motility. Pseudo-ternary phase diagrams were used to identify the efficient self-emulsification regions. The particle size distribution of the resulting microemulsions was determined using a laser scatter particle size analyzer (LSPSA). The optimized SMEDDS formulations containing Ethyl oleate (20%), Tween 80 (60%), and PEG 400 (20%) were tested for in vitro dissolution. The percentage of ARE released from the SMEDDS was significantly higher than that from the conventional tablets. Oral bioavailability of ARE in the SMEDDS via the hard capsules and the conventional tablets was evaluated in fasted beagle dogs. The bioavailability of ARE formulated in SMEDDS showed approximately 4.8-fold higher bioavailability than that in the conventional tablets. The results indicated that SMEDDS is potentially a good drug delivery system for oral delivery of the hydrophobic compound ARE.     

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.     

银杏酮酯口服自微乳化给药系统的药物代谢动力学分析

目的：探讨自微乳化给药系统（SMEDDS）促进银杏酮酯（GBE50）口服吸收的效果。方法采用高效液相色谱法,以其市售颗粒剂做对照,桑色素为内标,柚皮素、黄芩素、槲皮素为对照品,进行大鼠体内生物利用度研究,并利用DAS药动学软件处理血药浓度数据。结果血药浓度数据表明,市售的对照品颗粒剂与银杏酮酯口服自微乳化给药系统（GBE50-SMEDDS）对比,发现对照品颗粒剂消除半衰期（t1/2β）、药峰浓度（Cmax）和0-25 h药时曲线下面积（AUC0-25）分别为（4.327±0.768）h,（199.49±24.59） ng/ml,（240.29±24.22）mg/（h·ml） GBE50-SMEDDS则分别为（10.975±1.887）h,（221.53±46.88）ng/ml,（378.83±20.65）mg/（h·ml）,两组t1/2β、Cmax和AUC0-25比较,差异有统计学意义（P〈0.05）。结论与市售颗粒剂相比, GBE50-SMEDDS明显提高了生物利用度,在临床上值得推广应用。     

胸腺五肽缓释微球的制备及其质量评价

目的确立胸腺五肽（TP-5）微球的制备及质量评价方法。方法以聚乳酸一羟基乙酸（PLGA）为载体材料,采用复乳法（w／o／w）制备TP-5长效缓释注射微球,考察其粒径大小、外观、包封率等理化性质;采用HPLC测定微球中TP-5的含量。结果TP-5微球球形圆整,包封率在80％以上,平均粒径为67．8μm,27d体外累积释放百分率在80％以上．结论TP-5微球的制备工艺合理,评价方法简便、快速、准确。     

替尼泊苷自微乳的处方筛选及体外评价

目的筛选替尼泊苷自微乳的最优处方,并对其进行体外评价。方法通过溶解度实验、伪三元相图的绘制、粒径考察筛选出最优处方;以替尼泊苷混悬液为对比,测定替尼泊苷自微乳在不同溶出介质中的溶出度;考察替尼泊苷自微乳的稳定性。结果实验筛选得到的最优处方为油酸乙酯∶Cremopher ELP∶异丙醇=20∶60∶20,载药量1.5%。在不同溶出介质中,替尼泊苷释药2h后的累积释药量均可达90%以上,且3h后的累积释药量接近100%。稳定性实验结果表明替尼泊苷自微乳在40℃、25℃和冷热循环条件下是稳定的。结论实验制得替尼泊苷自微乳具有较好的溶解度,在不同溶出介质中有较高溶出度,稳定性良好。     

Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.     

Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate

The present work was aimed at formulating a SMEDDS (self-microemulsifying drug delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The solubility of fenofibrate was determined in various vehicles. Pseudoternary phase diagrams were used to evaluate the microemulsification existence area, and the release rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS formulations were tested for microemulsifying properties, and the resultant microemulsions were evaluated for clarity, precipitation, and particle size distribution. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate. The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months. Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.     

汉防己甲素自微乳的研制

目的研究汉防己甲素白微乳的制备。方法通过考察汉防己甲素在不同介质中的溶解度,采用伪三元相图法制备汉防己甲素自微乳,利用自微乳化效率和载药量考察,筛选最佳处方。结果汉防己甲素自微乳化制剂的处方为：乳化剂OP-10：异丙醇：油酸：油酸乙酯=4：8：1．5：1．5。结论汉防己甲素自微乳载药量为33．31g·L^-1,处方切实可行,性质稳定。     

坎地沙坦酯自微乳的制备及其体外评价

目的:建立坎地沙坦酯自微乳制剂,并评价其质量。方法:通过溶解度试验、三元相图的研究筛选了坎地沙坦酯自微乳处方,在此基础上制备坎地沙坦酯自微乳制剂;建立HPLC法测定坎地沙坦酯自微乳中药物的含量;对自微乳的外观性状、形态、粒径及粒径分布、含量和稳定性进行研究,并对制剂进行了溶出度的考察。结果:坎地沙坦酯自微乳为无色澄明液体且稳定性良好,遇水形成O/W型微乳,稀释100倍后电镜下观察成圆球形,平均粒径为37.6 nm。经计算后坎地沙坦酯自微乳化液载药量为10.5 mg.mL-1。体外释放试验表明自微乳制剂受溶出介质的影响小。结论:坎地沙坦酯自微乳制备工艺简单,性质稳定,质量易控。     

Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment

A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of vinpocetine (VIP), a poor water-soluble drug. The formulations of VIP-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. The optimal ratio in the formulation of SMEDDS was found to be Labrafac : oleic acid : Cremophor EL : Transcutol P=40 : 10 : 40 : 10 (w/w). The average particle diameter of VIP was less than 50 nm. In vitro dissolution study indicated that the dialysis method in reverse was better than the ultrafiltration method and the dialysis method in simulating the drug in vivo environment. Comparing with VIP crude drug power and commercial tablets, (-)VIP-SMEDDS caused a 3.4- and 2.9-fold increase in the percent of accumulated dissolution at 3 h. Further study on the absorption property of VIP-SMEDDS employing in situ intestine of rats demonstrated that VIP in SMEDDS could be well-absorbed in general intestinal tract without specific absorption sites. In addition, the developed SMEDDS formulations significantly improved the oral bioavailability of VIP in rats. Relative bioavailability of (-)VIP-SMEDDS and (+)VIP-SMEDDS increased by 1.85- and 1.91-fold, respectively, in relative of VIP crude powder suspension. The mechanisms of enhanced bioavailability of VIP might contribute to the improved release, enhanced lymphatic transport, and increased intestinal permeability of the drug.     

Design and evaluation of prostaglandin E1 (PGE1) intraurethral liquid formulation employing self-microemulsifying drug delivery system (SMEDDS) for erectile dysfunction treatment

Liquid intraurethral prostaglandin E1 (PGE1) delivery system was developed using self-microemulsifying drug delivery system (SMEDDS). For this, pseudo-ternary phase diagrams were constructed and characterized. The viscosity of optimized formulation was increased gradually upon the addition of water and it was decreased from the water contents over 40%. With excessive mass of water, the present system transformed to a free flowing microemulsion. These results demonstrate that the present liquid PGE1 SMEDDS formulation might stay in the urethra as a viscous sol or gel state with contacting the moisture of urethra and easily eliminated by urination. Draize test and long-term stability study revealed that the present system would be safe and PGE1 would be stable for more than one year at 4 degrees C, respectively. In the feline animal model, SMEDDS formulation was as effective as PGE1 intracavernosal injections in terms of ICP (intracavernosal pressure), penile length increment, and erection sustaining time was more elongated than PGE1 injections. Therefore, SMEDDS was considered as a promising PGE1 intraurethral liquid formulation for erectile dysfunction treatment.     

N-trimethyl chitosan chloride as absorption enhancer in oral peptide drug delivery. Development and characterization of minitablet and granule formulations.

In this study, minitablet and granule formulations were developed as solid oral dosage forms for the delivery of peptide drugs with the absorption enhancer N-trimethyl chitosan chloride (TMC). Minitablets were deemed suitable as a dosage form due to their ability, as components of multiple unit dosage forms (MUDFs), to disperse from each other, before disintegration, effectively increasing the area in which the polymer can assert its absorption-enhancing effect. The polymer should be released from the dosage forms prior to the release of the peptide, which was, together with achieving maximum release of both ingredients, the main focus of this study. Desmopressin (1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (DDAVP) was used as model peptide drug. The optimized minitablet formulation consisted of two types of granules, namely DDAVP and TMC granules. DDAVP granules, containing tetraglycerol pentastearate (TGPS), were specifically aimed at delaying the release of the peptide from the dosage form. Burst release of TMC was attempted with TMC granules. Both these granule types were included in the granule formulation. Release profiles for both the optimized minitablet formulation as well as the granule formulation showed that the release of DDAVP was effectively delayed from the formulation compared to the formulation where no attempt at delaying the release was made. In comparison, more TMC was released, and at a faster rate, from the granule formulation than the optimized minitablet formulations. Both the optimized minitablet formulation and the granule formulation show suitable release profiles for the delivery of peptide drugs with TMC as absorption enhancer in solid oral dosage forms.