Integrated in silico formulation design of self-emulsifying drug delivery systems

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.     

Formulation and evaluation of mefenamic acid emulgel for topical delivery

Emulgels have emerged as a promising drug delivery system for the delivery of hydrophobic drugs. The objective of the study was to prepare emulgel of mefenamic acid, a NSAID, using Carbapol 940 as a gelling agent. Mentha oil and clove oil were used as penetration enhancers. The emulsion was prepared and it was incorporated in gel base. The formulations were evaluated for rheological studies, spreading coefficient studies, bioadhesion strength, skin irritation studies, in vitro release, ex vivo release studies, anti-inflammatory activity and analgesic activity. Formulation F2 and F4 showed comparable analgesic and anti-inflammatory activity when they compared with marketed diclofenac sodium gel. So, it can be concluded that topical emulgel of mefenamic acid posses an effective anti-inflammatory and analgesic activity.     

穿心莲内酯自乳化软胶囊的制备和溶出度评价

目的研制穿心莲内酯自乳化软胶囊,并对其溶出度进行评价。方法制备穿心莲内酯自乳化软胶囊,通过穿心莲内酯溶出条件的筛选,考察自乳化软胶囊与市售片剂的溶出曲线。结果穿心莲内酯自乳化释药系统处方为油酸乙酯（10%）、吐温80（54%）、正丁醇（36%）。采用药典2005年版二部溶出度测定第一法,以0.2%SDS为溶出介质,穿心莲内酯自乳化软胶囊与穿心莲内酯片溶出度有显著性差异。结论自乳化软胶囊能显著提高穿心莲内酯的体外溶出度。     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Investigations on mefenamic acid sustained release tablets with water-insoluble gel

Mefenamic acid (MA) has analgesic, anti-inflammatory and antipyretic properties. Available conventional dosage forms are capsules and film-coated tablets. No commercial sustained release preparation of MA exists in the market. The usual oral dose is 250 or 500 mg and reported half-life is 2 h. Sodium alginate (NaAL) is the sodium salt of alginic acid, a natural polysaccharide extracted from marine brown algae. It has the ability to form a water-insoluble gel with a bivalent metal ions as calcium. Therefore, NaAL has been studied for preparing sustained release formulations in pharmaceutical technology. In this study, tablet formulations containing different ratios of NaAL and calcium gluconate (CaGL) were prepared by direct compression method. In vitro release studies were carried out using USP 23 basket method and release data were kinetically evaluated. According to release studies, it can be emphasized that NaAL and CaGL can be used for design of sustained release preparation of MA.     

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.     

Quality assessment and dissolution profile comparison studies on 250-mg mefenamic acid tablets available in local market of Karachi

In the present study, we aimed todetermine the quality of different brands (Test₁–Test₆) of mefenamic acid, which are commercially available in local market of Karachi, Pakistan. Various quality evaluation tests, including weight variation, hardness, thickness, friability, disintegration, assay and drug release, were carried out. Results were found to be in acceptable limits. Moreover, release profiles were compared using different dissolution media, such as phosphate buffer pH 6.8, 7.4 and biorelevant media (FaSSGF, FaSSIF, FeSSIF and SCoF). Release profiles at pH 6.8 and 7.4 were evaluated by one-way ANOVA, model-independent and model-dependent methods. Results of ANOVA showed that no significant difference was found among tester and reference brands (Test₁–Test₆). Similarly, all the brands were found to be best fitted with Weibull model.     

头孢泊肟酯自乳化制剂的研究

目的 优化制备头孢泊肟酯自乳化最佳处方条件使其达到目标浓度50mg·g-1.方法 通过溶解度实验、相图绘制、以及形成乳剂的乳化程度、乳滴粒径大小,对头孢泊肟酯自乳化体系中的油相、表面活性荆、助表面活性剂进行筛选,寻找最佳处方条件.结果 优选的头孢泊肟酯自乳化制剂处方中油相为Lauroglycol FCC,表面活性剂为Labrasol,助表面活性荆为Labrafil M1944 CS.结论 初步成功地制备了头孢泊肟酯自乳化传递体系.     

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.     

A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets

The aim of the current study was the development of a new pellet based self-emulsifying (SE) drug delivery system for the oral delivery of poorly soluble drugs. Furthermore, we wanted to investigate the influence of physiological dilution media and enzymatic digestion on the solubilization capacity of the formulation for the model drug Progesterone.Lipid mixtures composed of Solutol^® HS 15 and medium chain glycerides were optimized with respect to their self-emulsifying properties. The liquid SE lipid was mixed with microcrystalline cellulose and transformed into pellets by extrusion/spheronization. The pellets were characterized for size, shape, surface characteristics and friability. In vitro dissolution and digestion experiments were carried out using physiological dissolution media.The droplet diameter of the dispersed SE mixtures was largely affected by changing the oil to Solutol^® HS 15 ratio. Moreover, digestion of SE mixtures changed the solubilization capacity for Progesterone. Pellets with good properties (size, shape and friability) have been produced through the incorporation of a selected SE mixture into MCC.In conclusion, extrusion/spheronization is a suitable process to produce solid self-emulsifying pellets with up to 40% load of a liquid SE mixture. Digestion induces a change in lipid composition which affects the solubilization capacity of the lipid phase.     

A double-blind,crossover trial of mefenamic acid,sulindac and flurbiprofen in rheumatoid arthritis

Summary

A double-blind crossover trial was carried out in 24 patients to compare the effects of mefenamic acid, flurbiprofen, sulindac and placebo. Each drug was given for 2 weeks, the treatment sequence being randomized. Daily doses were 1500?mg mefenamic acid, 150?mg flurbiprofen or 150?mg sulindac. All of the active drugs were significantly superior to placebo in terms of pain score, patients' assessment, articular index of joint tenderness, and duration and severity of morning stiffness. There was improvement in grip strength compared with placebo, but the diferences were not statistically significant with sulindac. There was slight reduction in joint circumference but this was only statistically significant in the right hand with flurbiprofen and sulindac. No significant differences were found in technetium uptake in knee joints. The three drugs appeared to be equally effective and tolerated, and no significant differences were noted.     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

氟比洛芬自乳化给药系统的制备及体外溶出度考察

目的：制备氟比洛芬自乳化给药系统（SEDDS）以提高药物的溶出度。方法：通过绘制假三元相图和体外自乳化效率的评价确定最优处方；以氟比洛芬片为参比制剂测定SEDDS的溶出度。结果：最优SEDDS处方中的油相为油酸乙酯，乳化剂为聚山梨醇酯80，助乳化剂为PEG400，其比例N50．0：35．0：15．0，药物为辅料总量的5．0％。结论：氟比洛芬SEDDS与片剂相比，药物的溶出度有显著提高。     

Dissolution testing of acetylsalicylic acid by a channel flow method—correlation to USP basket and intrinsic dissolution methods

A new modification of the channel flow dissolution method is introduced together with the theoretical basis to extract the solubility and mass transfer parameters from the dissolution experiments. Correlation of drug dissolution profiles in the channel flow apparatus was evaluated with respect to USP basket and intrinsic dissolution methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compositions with microcrystalline cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissolution tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compositions containing lactose, while the slowest dissolution rate was observed with the composition containing MCC as the only excipient. As presumed, the dissolution rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissolution methods. MCC forms matrix tablets and in the USP basket method the dissolution profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissolution. Also the channel flow results indicated that the dissolution of ASA was controlled by mass transfer. The swelling behaviour of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissolution medium in the channel flow system. The contact between the tablet surface and the dissolution medium is more similar between the channel flow and intrinsic dissolution methods.     

Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system

This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22–55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69–85%) was slightly affected. Zafirlukast absorption (33–36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein

The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C_max and AUC for S-SNEDDS. The enhancement of C_max for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.     

新型降脂药物bempedoic acid

血脂异常是心血管疾病的一个高危因素,目前临床上仍以药物治疗为主要手段。bempedoic acid是一种人工合成的、以口服为给药途径的二羧酸衍生物,其对肝脏三磷酸腺苷-柠檬酸裂解酶(ACL)和腺苷单磷酸-活化蛋白激酶(AMPK)有双重调节作用,很有潜力成为另一个非他汀类的降脂药。多项临床试验研究表明bempedoic acid具有良好的安全性和有效性。主要从bempedoic acid的药物概况、相关背景、合成路线、作用机制和药理作用、临床研究等方面进行介绍。     

阿立哌唑自乳化释药系统的制备与质量评价

目的 制备阿立哌唑自乳化释药系统（ARP-SEDDSs）以提高药物的口服生物利用度。方法 HPLC法检测ARP在不同的油、表面活性剂和助表面活性剂中的溶解度,根据溶解度确定处方组成;采用伪三元相图筛选SEDDSs的处方比例;通过动态光散射、透射电镜、稀释稳定性和体外溶出对ARP-SEDDSs进行表征;大鼠分别ig给予自制ARP-SEDDSs和ARP混悬液（20 mg·kg^-1）后,HPLC法进行药动学研究,考察大鼠ig ARP-SEDDSs的生物利用度。结果 以油酸作为油相,以聚乙二醇15-羟基硬脂酸酯和异丙醇作为表面活性剂和助表面活性剂,优化得到ARP-SEDDSs处方为油酸-聚乙二醇15-羟基硬脂酸酯-异丙醇为2.0∶5.6∶2.4,载药量为10 mg·g^-1;ARP-SEDDSs经水稀释后可快速形成微乳,在透射电镜下可观察到微乳呈类球形,经动态光散射仪检测其平均粒径为（54.6±2.3）nm,聚合物分散性指数（PDI）为0.201±0.011,Zeta电位（-13.5±0.4）mV;ARP-SEDDSs在pH 6.8磷酸盐缓冲液中10 min的药物溶出度接近100%,远高于阿立哌唑口崩片（约10%）。大鼠体内药动学研究表明,与ARP混悬液相比,ARP-SEDDSs相对生物利用度为248.8%。结论 将ARP制备成自乳化释药系统,有助于药物快速溶出,显著提高了ARP的口服生物利用度。     

Influence of sulfobutyl ether beta-cyclodextrin (Captisol) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion

The aim of this study was to investigate the influence of sulfobutyl ether β-cyclodextrin (SBE₇-β-CD; Captisol^®) on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also produced for comparative evaluation to assess the benefits of SBE₇-β-CD. Hot-melt extrudates were produced at 100 °C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE₇-β-CD and β-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE₇-β-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE₇-β-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.     

Application of ascorbic acid 2-glucoside as a solubilizing agent for clarithromycin: solubilization and nanoparticle formation

Clarithromycin (CAM) was co-ground with l-ascorbic acid 2-glucoside (AA-2G), a newly developed food additive, to improve the solubility characteristics. The complete solubilizing effect of AA-2G was observed for the ground mixture with 1:1 molar ratio. When ground mixtures of CAM and AA-2G (2:1) were dispersed into water, not only the solubilization of CAM was observed but also nanoparticle formation with a mean particle diameter of 280 nm. The CAM particles obtained in this manner were stable in suspension for at least 7 days. Zeta potential analysis showed that positive charges on the particle surface may be contributing to the stability of the suspension. 1H NMR spectrum of CAM dissolved in a phosphate buffer (pH 5.5) showed a signal derived from the N,N-dimethylamino group at 2.73 ppm, while that of an equimolar ground mixture of CAM with AA-2G in D2O (pH 5.5) showed clearly two signals at 2.65 and 2.77 ppm derived from the splitting of the two methyl groups. The 13C NMR spectrum of the equimolar ground mixture dissolved in D2O exhibited two signals derived from N,N-dimethyl carbons of desosamine group at 37.2 and 42.3 ppm, whereas unprocessed CAM showed no resonance signal arising from those carbons. Moreover, the carbon resonance at 163 and 173 ppm arising from the ketone group in the CAM lactone ring shifted downfield to 177 and 180 ppm after the co-grinding with AA-2G. The formation of nanoparticles was only observed when CAM was co-ground with AA-2G in the molar ratio of 2:1, which might be attributable to a grinding-induced interaction in the solid-state via the ketone group in lactone ring of CAM.