Solubilized formulation of olmesartan medoxomil for enhancing oral bioavailability

Olmesartan medoxomil (OLM) is an antihypertensive angiotensin II receptor blocker. OLM has a low bioavailability (BA), approximately 26% in humans, due to its low water solubility and efflux by drug resistance pumps in the gastrointestinal tract. Self-microemulsifying drug delivery system (SMEDDS), which is easily emulsified in aqueous media under gentle agitation and digestive motility, was formulated to increase the oral BA of OLM. Among the surfactants and oils studied, Capryol 90, Tween 20, and Tetraglycol were chosen and combined at a volume ratio of 1:6:3 on the basis of equilibrium solubility and phase diagram experiments. The mean droplet size of SMEDDS was 15 nm. In an oral absorption study in rats, SMEDDS formulation brought faster absorption compared to suspension, showing a T _max value of 0.2 hr. The C _max and AUC values of SMEDDS formulation were significantly higher than those of suspension, revealing a relative BA of about 170%. Our study demonstrated the potential usefulness of SMEDDS for the oral delivery of poorly absorbable compounds, including OLM.     

Formulation and biopharmaceutical evaluation of silymarin using SMEDDS

Silymarin has been used to treat hepatobiliary diseases. However, it has a low bioavailability after being administered orally on account of its low solubility in water. In order to improve the dissolution rate, silymarin was formulated in the form of a self-microemulsifying drug delivery system (SMEDDS). The optimum formulation of SMEDDS containing silymarin was obtained based on the study of pseudo-ternary phase diagram. The SMEDDS consisted of 15% silymarin, 10% glyceryl monooleate as the oil phase, a mixture of polysorbate 20 and HCO-50 (1:1) as the surfactant, Transcutol as the cosurfactant with a surfactant/cosurfactant ratio of 1. The mean droplet size of the oil phase in the microemulsion formed from the SMEDDS was 67 nm. The % release of silybin from the SMEDDS after 6 hours was 2.5 times higher than that from the reference capsule. After its oral administration to rats, the bioavailability of the drug from the SMEDDS was 3.6 times higher than the reference capsule.     

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.     

Optimized self-microemulsifying drug delivery systems (SMEDDS) for enhanced oral bioavailability of astilbin

The main purpose of this research work was to design an optimized self micro-emulsifying drug delivery system (SMEDDS) to enhance the bioavailability of the poor water soluble drug, astilbin. The solubility of astilbin was evaluated in various vehicles. Pseudoternary phase diagrams were used to select the components and their ranges by evaluating the micro-emulsification area. Central composite design was applied to optimize the properties of the formulation, including particle size, polydispersity index, drug loading capacity and effective intestinal permeability. The optimized SMEDDS characteristics were investigated including the study of factors influencing particle size and showed the stability of microemulsion when varying the pH and volume of diluents. In vitro drug release profile study was performed using the reverse dialysis method where 95% of the drug was released after 4 h. The developed astilbin SMEDDS was subjected to bioavailability studies in beagle dogs by LC-MS and showed a significant enhancement of bioavailability, indicating the possibility of using SMEDDS as possible drug carrier for astilbin.     

Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: Preparation and evaluation

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.     

吡罗昔康自微乳化药物传递系统的处方筛选与体外评价

筛选吡罗昔康自微乳化药物传递系统(SMEDDS)的处方并进行体外评价。考察了吡罗昔康在不同油相和表面活性剂中的溶解度；对不同油相和表面活性剂进行初步配伍研究；通过绘制三元相图研究处方中不同油相、表面活性剂和辅助表面活性剂形成微乳的能力和区域；对制剂粒径及溶出度进行考察。处方选用肉桂醇作为吡罗昔康的溶剂，以Labrafil M 1944CS为油相，Cremophor EL为表面活性剂，Transcotol P为辅助表面活性剂。所得3个处方乳化后的粒径及分布分别为(32.2±5.0)、(40.1±6.4)、(81.9±12.2)nm。制剂溶出速度快。通过处方研究确定了最优处方，研制了吡罗昔康SMEDDS。     

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

PURPOSE: The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors. METHODS: Paclitaxel SMEDDS formulation was optimized, in terms of droplet size and lack of drug precipitation following aqueous dilution, using a ternary phase diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting microemulsions were evaluated. The plasma concentrations of paclitaxel were determined using a HPLC method following paclitaxel microemulsion administrations at various doses in rats. RESULTS: Following 1:10 aqueous dilution of optimal paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4 nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various doses. There was a significant improvement in area under the curve (AUC) and time above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of Taxol following coadministration of both formulations with 40 mg cyclosporin A (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following coadministration of tacrolimus and etoposide, but plasma drug concentrations did not reach the therapeutic level. The nonlinear pharmacokinetic trend was not modified after paclitaxel was formulated in SMEDDS. CONCLUSIONS: The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.     

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.     

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

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted 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 the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

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.     

新型抗血吸虫药物QH917自微乳化释药系统的优化和评价

筛选新型抗血吸虫药物QH917自微乳化释药系统的处方。以油相的用量(%)和表面活性剂与助表面活性剂的质量比(K_m)作为自变量，自乳化时间(t)、平均粒径(PS)和多分散系数(PI)作为因变量，采用星点设计——效应面法进行处方优化，模拟体内环境，考察了离子强度、食物、pH值、转速和介质体积对优化处方释放的影响，并采用大鼠在体小肠吸收试验评价了优化处方的吸收情况。结果表明，优化处方为：油相中链甘油三酸酯(MCT)的质量分数为30%～34%，表面活性剂聚氧乙烯40氢化蓖麻油(Cremophor RH40)与助表面活性剂乙醇的质量比为4.8～5.2。优化处方的释放行为基本不受介质环境的影响。大鼠在体小肠吸收试验表明胆管结扎与未结扎对吸收率无显著影响，个体间吸收行为差异性较小。以星点设计——效应面法对自微乳化释药系统的处方进行优化，预测性良好，优化处方体外释放和大鼠小肠吸收行为均比较稳定。     

萘哌地尔自微乳化释药系统的制备

通过萘哌地尔在不同辅料中的平衡溶解度和伪三元相图筛选了空白自微乳化释药系统(SMEDDS)的组分,并继续用正交设计和单因素试验优化载萘哌地尔SMEDDS的处方。所得优化处方中萘哌地尔的溶解度显著高于水中溶解度,稀释后能形成平均粒径约23 nm的微小乳滴。体外释放试验表明,萘哌地尔SMEDDS及其混悬液在pH 6.8磷酸盐缓冲液中8 h累积释放率均低于20%;但在0.1 mol/L盐酸中,前者释放较快且完全。     

Development and oral bioavailability assessment of a supersaturated self‐microemulsifying drug delivery system (SMEDDS) of albendazole

Objectives Albendazole's (ABZ) poor aqueous solubility is a major determinant of its variable therapeutic response (20–50%). The purpose of this study was to develop and optimize the composition of a self‐microemulsifying drug delivery system (SMEDDS) of ABZ and assess its oral pharmacokinetics in rabbits. Methods A D‐optimal mixture design of experiments was used to select the levels of constraints of the formulation variables. The predicted composition was optimized using four responses: dispersion performance, droplet sizes, dissolution efficiency (DE) and time for 85% drug release (t_85%). Key findings The optimal composition of the ABZ‐SMEDDS formulation, with approximately 5 mg/g drug loading of ABZ, was predicted to be Cremophor EL (30% w/w), Tween 80 (15% w/w), Capmul PG‐8 (10% w/w) and acidified PEG 400 (45% w/w). An increase of 63% in the relative bioavailability compared with the commercial suspension was obtained with ABZ‐SMEDDS as measured by albendazole sulfoxide (ABZSO) plasma levels. The area under the curve (AUC_0→24h) and the peak plasma concentration (C_max) of ABZ‐SMEDDS was higher than those obtained with the commercial suspension by 56% and 52%, respectively. Conclusions This study demonstrates a strategy for the development of a supersaturated SMEDDS formulation of a drug with low aqueous solubility.     

葛根素自微乳制剂的制备工艺研究

目的:研究制备葛根素自微乳制剂。方法:根据葛根素的饱和溶解度选取油相、乳化剂和助乳化剂,通过伪三元相图,以自乳化效率及成乳后粒径为指标,确定最佳处方。结果:最佳处方为油酸乙酯∶吐温80/蓖麻油聚氧乙烯醚40(1∶2)∶聚乙二醇400∶葛根素∶三七总皂苷=15∶35∶35∶6∶9;微乳的平均粒径为32.9nm。结论:加入三七总皂苷的葛根素自微乳粒径小,稳定性好,这为自微乳制剂的增效减毒提供了新的思路和途径。     

Disposition of lipid-based formulation in the intestinal tract affects the absorption of poorly water-soluble drugs

Solvent Green 3 (SG), a model poorly water-soluble compound, was orally administered to rats with soybean oil emulsion or the Self-microemulsifying drug delivery system (SMEDDS) composed of Gelucire44/14. The bioavailability of SG after oral administration with SMEDDS was 1.7-fold higher than that with soybean oil emulsion. The intestinal absorption of lipid-based formulations themselves was evaluated by the in situ closed loop method. The effect of lipase and bile salt on their absorption was also evaluated. SMEDDS itself was rapidly absorbed in the intestine even in the absence of lipase and bile salt, and the absorption was increased by the addition of lipase and bile salt. On the other hand, no soybean oil emulsion was absorbed in the absence of lipase and bile salt. However, mixed micelle prepared from emulsion by incubating soybean oil emulsion with lipase and bile salt was rapidly absorbed through the intestine. Without lipase and bile salt, SG was not absorbed after administration with soybean oil emulsion. Therefore, we concluded that the degradation of soybean oil emulsion was needed for SG to be absorbed through the intestine. Furthermore, we investigated the intestinal absorption of SG after oral administration to rats whose chylomicron synthesis were inhibited by pretreatment with colchicine. Colchicine completely inhibited the intestinal absorption of SG after administration with each lipid-based formulation, suggesting that SG was absorbed from the intestine via a lymphatic route. Absorption of the dosage formulation should be paid attention when poorly water-soluble drugs are orally administered with lipid-based formulation.     

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。     

Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction

Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

葛根素自微乳化释药系统的处方筛选与体外评价

目的筛选葛根素自微乳化释药系统（Pur-SMEDDS）的处方并进行体外评价。方法通过溶解度、处方配伍实验和伪三元相图的绘制,以色泽、乳化时间和乳化后粒径大小为指标,筛选油相、表面活性剂、助表面活性剂的处方配比。测定葛根素自微乳化释药系统的溶出度。结果处方选用油酸为油相,聚山梨酯80为表面活性剂,Transcutol P为助表面活性剂。自微乳化后的粒径为（49.8±4.7）nm,ξ电位为（4.8±0.8）mV。pH 6.8磷酸盐缓冲液中30 min累积溶出百分率〉85%,而葛根素片60 min的累积溶出百分率〈10%。结论通过处方研究确定了最优处方,研制了葛根素SMEDDS。