The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture

A method of converting self-emulsifying drug delivery systems to a pellet form has been studied. Formulations with varied relative quantities of an oil/surfactant mixture, water, microcrystalline cellulose (MCC), and lactose were chosen in a statistical design after preliminary ranging experiments. Pellets were produced by extrusion/spheronization. The characteristics of the pellets were studied by sieving, disintegration testing, diametral compression, image analysis, non-contact laser profilometry, and scanning electron microscopy. The effects of the formulation variables on pellet properties were evaluated by analysis of variance. It was possible to relate the formulation variables to all the quantified pellet properties except the shape. The relative quantities of oil/surfactant and water had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, extrusion force, median diameter, size spread, disintegration time, tensile strength, and surface roughness. The relative quantities of lactose and MCC had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, tensile strength, and roughness only. Water was an essential element of the formulations. The maximum quantity of the specific oil/surfactant combination studied that can be incorporated was 42% of the dry pellet weight.     

Preparation and characterization of a self-emulsifying pellet formulation.

The purpose of the current study is to investigate the feasibility of producing solid self-emulsifying pellets using the extrusion/spheronization technique. Pellets were made from a mixture of C18 partial glycerides, Solutol HS15 and microcrystalline cellulose. Pellets with good physical properties (size, shape, friability) and self-emulsifying properties were produced. The pellets were, in contrast to pellets lacking Solutol, able to transfer a lipophilic dye and a spin probe into the aqueous media. The release kinetics and the microenvironment of the pellets during the release process were assessed using electron spin resonance (ESR) spectroscopy. The ESR results showed that the hydrophobic spin probe was localized mainly in the lipid environment all over the release time. Furthermore, the formulation was capable of accelerating the release of the drug diazepam and achieving a diazepam concentration above its saturation solubility. In conclusion, spherical pellets with low friability and self-emulsifying properties can be produced by the standard extrusion/spheronization technique. The pellets are capable of transfering lipophilic compounds into the aqueous phase and have a high potential to increase the bioavailability of lipophilic drugs.     

氟比洛芬自乳化给药系统中释放的体内外分析

目的:研究氟比洛芬(furbiprofen,FB)自乳化释药系统的自乳化能力及在家犬体内的药动学。方法:评价系统自乳化速度,激光散射仪测定乳化后形成乳剂粒径的大小及分布情况,采用HPLC法测定家犬血浆药物浓度,与市售片比较,考察FB自乳化制剂体外溶出行为及体内药动学。结果:体系在1min内已基本乳化完全,乳化后乳剂粒子粒径大多数在70nm左右。与市售片剂相比,以水为溶出介质,氟比洛芬自乳化制剂120min可以溶出95%,而市售胶囊溶出约为50%。家犬体内药动学研究结果表明:与市售片剂相比,自乳化制剂达峰时间提前,tmax为0.75h,而市售胶囊tmax为1.5h;AUC0-∞提高了40%。结论:自乳化制剂可以显著提高FB的体外溶出及体内吸收。     

Development of a self-emulsifying formulation that reduces the food effect for torcetrapib

Torcetrapib is a highly lipophilic (Clog P=7.45) and water insoluble cholesteryl ester transfer protein (CETP) inhibitor developed for the treatment of atherosclerosis. Self-emulsifying drug delivery system (SEDDS) formulations have been developed to reduce the food effect observed in early clinical trials using medium chain triglyceride (MCT) softgels and to increase the dose per capsule. MCT/Triacetin/Polysorbate 80/Capmul MCM (20/30/20/30) (MTPC) increased fasted exposure and thus reduced the food effect from 5- to 3-fold in dogs at a dose of 90 mg. Self-emulsifying formulations also accelerated absorption and generally decreased variability. Use of the lipophilic, GRAS cosolvent triacetin allowed a 2-fold increase in the dose per capsule. For the three formulations evaluated in dogs that showed significant differences in absorption, emulsion droplet size did not appear to play a significant role. Absorption did increase with Cremophor RH40 content, and at 50% Cremophor RH40 there was no food effect (at 30 mg). High polar surfactant content also resulted in poor dose proportionality, while there was good dose proportionality for MTPC. Studies of in vitro lipolysis are being conducted to aid in understanding the in vitro/in vivo relationships for torcetrapib SEDDS absorption.     

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.     

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF), composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor^® 742, Tween^® 60, Cremophore^® EL and Transcutol^® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor^® 742, Tween^® 60 and Transcutol^® HP (10:30:60) can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant), 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.     

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.     

Influence of formulation on the physicochemical properties of casein microparticles.

Casein microparticles (CAS/MP) have a potential clinical use for targeting drugs. However, the use of organic solvents in their preparation is undesirable. This study was designed to investigate the influence of preparation procedures in aqueous media on the formulation and physicochemical properties of CAS/MP. The first stage involved the influence of the coacervating agents (lactic acid, succinic anhydride, succinic acid and tartaric acid). The second stage studied was the influence of the ionic strength and the third, the influence of adding a thickener, hydroxypropyl cellulose or hydroxypropyl methycellulose (HPC or HPMC), and a plasticizing agent (gelatin). Some physicochemical properties of CAS/MP were evaluated. While the infrared and the thermal analysis showed that all coacervating agents were appropriate for coacervation, the scanning electron microscopy studies showed that the external morphology of the particles was more homogeneous when lactic acid was used. Utilizing lactic acid as the coacervating agent, there was a trend effect of adding NaCl implying that the increasing of the ionic strength resulted in better stability. Finally, the addition of 0.1% HPC plus either 0.25 or 0.5% gelatin resulted in homogeneous formulations. In conclusion, the use of lactic acid plus 0.1% HPC and 0.25% gelatin results in biodegradable and homogeneous CAS/MP, presenting a potentially useful drug delivery system.     

Influence of binder type on interacting variables acting on mechanical properties of a sulfadimidine tablet formulation

A study of the quantitative effect of type of binder (N), applied pressure (P), and granular size (G) on two mechanical properties-tensile strength (TS) and brittle fracture index (BFI) - of a sulfadimidine tablet formulation has been carried out by using a 2(3) factorial experimental design. The results obtained from this work suggest that P exhibited the largest individual effect on TS and BFI. It is also seen from this work that the nature of binders in combination affects the influence that P and G had on the TS or BFI.     

Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption

The aim of this work was to produce by co-extrusion-spheronization pellets with two cohesive layers, one of them containing a self-emulsifying system for vinpocetine, a poorly water soluble model drug. Two layers were prepared: an inert layer of microcrystalline cellulose, lactose and water and a second one wetted with the self-emulsifying system. Different formulations of both layers were tested, evaluating the effects of formulation variables with an experimental design. The screening amongst formulations was performed preparing rod extrudates and using the extrusion profiles to assess their suitability for extrusion and to anticipate quality of the spheronized extrudates. Tubular extrudates and co-extrudates/spheronized pellets were then produced. Two types of bi-layered pellets were prepared: type I with the self-emulsifying system internally and the inert matrix externally, whereas type II vice versa. The pellets were characterized for sizing and shape, density, hardness, in vitro dissolution and disintegration and released droplets size and in vivo tests. Although both types of pellets demonstrated adequate morphological and technological characteristics, pellets type II revealed an improved drug solubility and in vivo bioavailability. These preliminary technological and pharmacokinetic data demonstrated that co-extrusion/spheronization is a viable technology to produce bi-layered cohesive self-emulsifying pellets of good quality and improved in vivo bioavailability.     

Influence of processing methods on physico-mechanical properties of Ibuprofen/HPC-SSL formulation

Abstract

The objective of the present study was to investigate the influence of processing methods on the physical and mechanical properties of formulations containing Ibuprofen and HPC-SSL. The powder blends, containing Ibuprofen and HPC-SSL in ratio of 9:0.5, were processed using melt granulation (MG) by hot melt extrusion (HME) and wet granulation (WG) by high shear mixer. Formulated granules and powder blends were compressed into round flat faced tablets using Riva Piccola tablet press. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) studies proved that granulation process did not significantly alter the crystallinity of Ibuprofen, however, particle density and flow properties were significantly improved. Scanning electron microscopy (SEM) and particle size analysis corroborate with the findings that the flow characteristics of granules from MG were relatively superior to other formulations. Formulations were investigated for out-of-die compaction behaviour using Heckel, Kawakita, and CTC profile analysis. Detailed examination revealed that all three formulations differed in particle size due to the granulation, thus conferring to different compaction behaviour. In WG and MG, granulation offered an increase in particle size resulting in high compressibility along with deformation at low compression pressure. This results into low yield pressure, low yield strength, and higher densification, as compared with dry blend. The current work provides an insight into factors affecting physical and mechanical properties tablets, which can facilitate the rational selection of suitable change in processing method instead of changing excipients.     

Enhanced dissolution of celecoxib by supersaturating self-emulsifying drug delivery system (S-SEDDS) formulation

A supersaturating self-emulsifying drug delivery system (S-SEDDS) was prepared and evaluated for enhanced dissolution of celecoxib (CXB), a poorly water-soluble drug. The selected CXB-dissolved SEDDS formulation consisting 10 % Capryol 90 (oil), 45 % Tween 20 (surfactant), and 45 % Tetraglycol (cosurfactant) had the characteristics of small droplet size and great solubility as 208 nm and 556.7 mg/mL in average, respectively. CXB dissolution from SEDDS in simulated gastric fluid was increased to about 20 % for the initial period of 5 min, but decreased to a half level as time elapsed. Thus, precipitation inhibitors were screened to stabilize the supersaturation. The stabilizing effect of Soluplus, an amphiphilic copolymer, was concentration-dependent, revealing the greatest dissolution of approximately 90 % level with delayed drug crystallization by the addition of the copolymer. CXB dissolution from S-SEDDS was pH-independent. We concluded that S-SEDDS formulation would be very useful in the future for developing oral delivery product of poorly water-soluble drugs.     

Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations

A single dose comparative bioavailability study was conducted to evaluate the bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion that readily lipolysed under in vitro condition (SES-A), while the other produced a finer dispersion with negligible lipolysis (SES-B) in comparison with that of a non-self-emulsifying formulation in soya oil. The study was conducted according to a three-way crossover design using six healthy human volunteers. Statistically significant differences were observed between the logarithmic transformed peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC(0-infinity)) values of both SES-A and -B compared to NSES-C indicating that SES-A and -B achieved a higher extent of absorption compared to NSES-C. Moreover, the 90% confidence interval of the AUC(0-infinity) values of both SES-A and -B over those of NSES-C were between 2-3 suggesting an increase in bioavailability of about two-three times compared to NSES-C. Both SES-A and -B also achieved a faster onset of absorption. However, both SES-A and -B had comparable bioavailability, despite the fact that SES-B was able to form emulsions with smaller droplet size. Thus, it appeared that both droplet sizes as well as the rate and extent of lipolysis of the emulsion products formed were important for enhancing the bioavailability of the tocotrienols from the self-emulsifying systems.     

Controlled release of a self-emulsifying formulation from a tablet dosage form: stability assessment and optimization of some processing parameters

The objective of this study was to evaluate the effect of some processing parameters on the release of lipid formulation from a tablet dosage form. A 17-run, face-centered cubic design was employed to evaluate the effect of colloidal silicates (X(1)), magnesium stearate mixing time (X(2)), and compression force (X(3)) on flow, hardness, and dissolution of Coenzyme Q(10) (CoQ(10)) lipid formulation from a tablet dosage form. The optimized formulation was subsequently subjected to a short-term accelerated stability study. All preparations had a flowability index values ranging from 77 to 90. The cumulative percent of CoQ(10) released within 8h (Y(5)) ranged from 40.6% to 90% and was expressed by the following polynomial equation: Y(5)=49.78-16.36X(1)+2.90X(2)-3.11X(3)-0.37X(1)X(2)+1.06X(1)X(3)-1.02X(2)X(3)+11.98X(1)(2)+10.63X(2)(2)-7.10X(3)(2). When stored at 4 degrees C, dissolution rates were retained for up to 3 months. Storage at higher temperatures, however, accelerated lipid release and caused leakage, and loss of hardness. Processing parameters have a profound effect on the release of lipid formulations from their solid carriers. While optimized controlled release formulations could be attained, further considerations should be made to prepare "liquisolids" that are physically stable at higher storage temperatures.     

Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization

Four commercial grades of microcrystalline cellulose, Avicel PH 101, Avicel PH 102, Avicel PH 112 and Avicel PH 302 were compared for extrusion spheronization. Model mixes containing Avicel PH 101 with different proportions of fillers like lactose and dicalcium phosphate dihydrate (DCPD) were also compared to observe the influence of these fillers on the pellet properties. The amount of water used for granulation of Avicel/ Avicel mixes was kept constant so as to evaluate and quantitate the influence of these excipients/fillers on the pellet properties. The various pellet properties evaluated included, drug release, size and size distribution, shape, density, friability and flow. Mean pellet diameter did not vary among the Avicel grades. Pellets prepared with different proportions of Avicel PH 101 and lactose were more or less similar in mean diameter. The same phenomena were observed in case of DCPD as well. Plain lactose pellets were the largest in size. Therefore, it can be inferred that the presence of Avicel suppressed the change in pellet size. Circularity was found to be significantly linear function of log of bulk density of Avicel powders. As revealed by the SEM photographs, pellets of Avicel PH 101 were fairly round where as those containing Avicel PH 302 were dumbbell shaped. Formulations containing DCPD showed the highest circularity. Drug release rate varied in all the formulations. Among the Avicel grades, Avicel PH 302 showed the highest drug release rate where as Avicel PH 101 showed the least. Drug release also varied as a function of the type of filler and their proportion in the pellets. For both the fillers, the drug release increased with an increase in their proportion. Less water was required for formulations containing higher amounts of lactose and DCPD. Plain DCPD failed to spheronize, although pellets of plain lactose could be formed at the investigated level of water.     

The emulsification and solubilisation properties of polyglycolysed oils in self-emulsifying formulations

Self-emulsifying drug delivery systems (SEDDS), whereby drugs are dispersed in an oil-surfactant mix that emulsifies on contact with water, represent a highly promising approach for enhancing oral bioavailability. However, the choice of formulation is, at present, largely empirical both in terms of the composition dependence of the emulsification process and the solubilisation of the drug in the initial oil-surfactant mixture. In this investigation, a range of chemically related self-emulsifying systems have been studied, based on the Labrafil family of polyglycolysed oils, using Tween 80 and Tween 20 as surfactants. The ease of emulsification, the particle size distribution and the appearance of the emulsion droplets were studied as a function of composition, while the solubility of danazol and mefenamic acid in the various oil-surfactant mixes was measured. It was noted that dilution of the emulsions led to apparent change in particle size distribution. The more hydrophilic oil-surfactant mixes showed a greater ease of emulsification and a lower particle size. It was also noted that multiple emulsions could be formed using systems of lower polarity. A linear relationship was observed between the hydrophile-lipophile balance (HLB) of the mix and the solubility of both danazol and mefenamic acid, with more hydrophilic mixes showing greater drug solubility values. The study has indicated that, within the range studied, more hydrophilic mixes tend to result in superior emulsification properties and greater drug solubility.     

自乳化释药系统与液固压缩技术联合开发难溶性药物新剂型的进展

提高难溶性药物溶解度,改善难溶性口服药物的生物利用度,一直是药剂学的热点和难点。本文旨在通过对自乳化释药系统和液固压缩技术的介绍,并阐述2种技术联合开发难溶性药物新剂型的优势,说明固体自乳化释药系统可以作为液体自乳化释药系统的提高或者替代,其具有降低生产成本,简化工业生产,提高稳定性与患者耐受性等方面的优势。