Effect of different polysorbates on development of self-microemulsifying drug delivery systems using medium chain lipids

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80–90%) and the lipid content low (10–20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20?相似文献   

Design and development of SMEDDS for colon-specific drug delivery

Abstract

Context: Lipoidal systems have particularly shown potential for specific accumulation in areas with inflamed tissue increasing the selectivity of local drug delivery.

Objective: Formulation and evaluation of self-microemulsifying drug delivery system (SMEDDS) for colon-specific drug delivery for effective treatment of colonic diseases.

Method: Ternary phase diagram was used to optimize level of oil, surfactant and co-surfactant to optimize SMEDDS and were evaluated for percent transmittance, emulsification time, in vitro release, myeloperoxidase (MPO) activity and intestinal accumulation. The spray dried SMEDDS were filled in capsules which were enteric coated with Eudragit S-100 at 10% weight gain to ensure SMEDDS delivery at colon. The spray dried SMEDDS were also evaluated for IR, DSC, XRD, SEM and stability study.

Result: In ternary phase diagram, Capmul MCM C8 and Capmul PG12 NF with surfactant (Tween 20) and co-surfactant (PG) in ratio 2:1 and 3:1, respectively, showed maximum emulsification area. These liquid SMEDDS show maximum transmittance, globule size of 90–30?nm. The spray-dried SMEDDS with diluents show good flow property. The units of MPO activity show lower level as compared to pure drug and control group, histopathology results supports better healing with SMEDDS. This was attributed to accumulation of SMEDDS in inflammatory area as compared to drug which was further proved by accumulation study. Enteric-coated capsule containing SMEDDS are able to deliver drug, specifically at the colonic region.

Conclusion: Higher accumulation of lipoidal drug in inflammatory area and specific release of liposomes by enteric-coated capsules provide better option for the treatment of colonic disease.     

Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation,characterization, cytotoxicity and permeability enhancement study

Single non-ionic surfactant based self-nanoemulsifying drug delivery system (SNEDDS) was formulated and characterised for poor water soluble drug, Atorvastatin calcium. Capmul MCM oil showing highest solubility for Atorvastatin calcium was selected as oil phase. Self-nanoemulsifying capacity of Cremophor RH 40, Cremophor EL, Tween 20, Tween 60, Tween 80 and Labrasol were tested for the selected oil. In vitro dissolution studies were performed and were characterized by t85% and dissolution efficiency (DE). Cytotoxicity of the formulations and permeation enhancement of the drug across caco-2 cell monolayer was assessed. Capmul MCM was found to be better nanoemulsified in decreasing order of Cremophor RH 40 > Cremophor EL > Tween 20 > Tween 60 > Tween 80. Values of droplet size (range 11–83 nm), polydispersity index (range 0.07–0.65); zeta potential (range ?3.97 to ?19.0) and cloud point (60–85°C) before and after drug loading proves the uniformity and stability of the formulations. SNEDDS formulated with Tween 20 surfactant showed enhanced dissolution with t85% and DE values at 10 min and 78.70, respectively. None of the formulation showed cytotoxicity at the concentration tested. Tween 20 based SNEDDS enhanced permeation of the drug as compared with pure drug across cell lines. It can be concluded that SNEDDS can be formulated by using single non-ionic surfactant system for enhance dissolution and absorption of poorly soluble drug, Atorvastatin calcium.     

Self-microemulsifying smaller molecular volume oil (Capmul MCM) using non-ionic surfactants: a delivery system for poorly water-soluble drug

The main purpose of this work is to formulate self-microemulsifying drug delivery system (SMEDDS) using smaller molecular oil with Atorvastatin calcium as a model drug. Solubility of the selected drug was accessed in oils and surfactants. Percent transmittance (%T) test study was performed to identify the efficient self-microemulsifying formulations. Those formulations which showed higher value for %T were evaluated for droplet size, polydispersity index, ζ potential, refractive index and cloud point measurement. Effect of drug loading on droplet size, increasing dilution in different media, thermodynamic stability and in vitro dissolution was performed to observe the performance of the selected formulation. Further cytotoxicity and permeation enhancement studies were carried out on Caco2 cell lines. Of all the oils accessed for drug solubility, Capmul MCM showed higher solubility capacity for Atorvastatin calcium. Capmul MCM was better microemulsified using combination of Tween 20 and Labrasol surfactant. Droplet size was as low as 86.93?nm with polydispersity index and ζ potential at 0.195?±?0.011 and ?7.27?±?3.11 mV respectively. The selected undiluted formulation showed refractive index values ranging from 1.40 to 1.47 indicating the isotropicity of the formulation. The selected formulation was robust to dilution in different media and thermodynamically stable. Dissolution profile was enhanced for the selected drug as compared to marketed formulation with t85% and DE values at 10?min and 80.15 respectively. Also cytotoxicity measurement showed minimum effect with good permeation enhancing capacity. Thus our study demonstrates the use of smaller molecular oil (Capmul MCM) for developing self-microemulsifying drug delivery system for better in vitro and in vivo performance.     

Microemulsion for simultaneous transdermal delivery of benzocaine and indomethacin: in vitro and in vivo evaluation

This study investigated simultaneous transdermal delivery of indomethacin and benzocaine from microemulsion. Eucalyptus oil based microemulsion was used with Tween 80 and ethanol being employed as surfactant and cosurfactant, respectively. A microemulsion formulation comprising eucalyptus oil, polyoxyethylene sorbitan momooleate (Tween 80), ethanol and water (20:30:30:20) was selected. Indomethacin (1% w/w) and benzocaine (20% w/w) were incorporated separately or combined into this formulation before in vitro and in vivo evaluation. Application of indomethacin microemulsion enhanced the transdermal flux and reduced the lag time compared to saturated aqueous control. The same trend was evident for benzocaine microemulsion. Simultaneous application of the two drugs in microemulsion provided similar enhancement pattern. The in vivo evaluation employed the pinprick method and revealed rapid anesthesia after application of benzocaine microemulsion with the onset being 10?min and the action lasting for 50?min. For indomethacin microemulsion, the analgesic effect was recorded after 34.5?min and lasted for 70.5?min. Simultaneous application of benzocaine and indomethacin provided synergistic effect. The onset of action was achieved after 10?min and lasted for 95?min. The study highlighted the potential of microemulsion formulation in simultaneous transdermal delivery of two drugs.     

Mixed lipid phase SMEDDS as an innovative approach to enhance resveratrol solubility

Context: Despite its promising therapeutic activities, clinical use of resveratrol (RSV) is compromised with unfavorable biopharmaceutical properties, namely low water solubility.

Objective: This work deals with improving RSV solubility and release rate through its incorporation in innovative mixed lipid phase self-microemulsifying drug delivery systems (SMEDDS).

Methods: (Pseudo)ternary diagrams were constructed for different oils and surfactant mixtures. Selected systems were further evaluated for RSV solubility, self-emulsification ability, accelerated stability, dynamic viscosity, compatibility with hard gelatin capsules and in vitro dissolution of RSV.

Results: Lipid phase composed of diverse lipid species, castor oil (long-chained triglyceride) and Capmul MCM (mixture of medium chain mono and diglycerides) allowed formulation of mixed lipid SMEDDS with lower surfactants content (60% Cremophor EL/RH 40/RH?60). Mixed lipid phase SMEDDS showed best self-emulsifying ability with regard to self-emulsifying time as well as droplet size and monodispersity of microemulsions obtained upon SMEDDS dilution with aqueous phase. Overall, incorporation of RSV in SMEDDS resulted in improved solubility (over 23-fold) and dissolution rate compared to crystalline RSV. All SMEDDS formulations were adequately viscous for filling into hard gelatin capsules (>150?mPa?s for empty SMEDDS; >400?mPa?s for RSV-loaded SMEDDS) and no leaking was observed during three months of storage.

Conclusion: The presented work indicates the promising potential of mixed lipid SMEDDS formulations for future development of SMEDDS with lower surfactant content and no added cosolvents for incorporation of RSV and other poorly soluble drugs.     

Self-microemulsifying smaller molecular volume oil (Capmul MCM) using non-ionic surfactants: a delivery system for poorly water-soluble drug

The main purpose of this work is to formulate self-microemulsifying drug delivery system (SMEDDS) using smaller molecular oil with Atorvastatin calcium as a model drug. Solubility of the selected drug was accessed in oils and surfactants. Percent transmittance (%T) test study was performed to identify the efficient self-microemulsifying formulations. Those formulations which showed higher value for %T were evaluated for droplet size, polydispersity index, ζ potential, refractive index and cloud point measurement. Effect of drug loading on droplet size, increasing dilution in different media, thermodynamic stability and in vitro dissolution was performed to observe the performance of the selected formulation. Further cytotoxicity and permeation enhancement studies were carried out on Caco2 cell lines. Of all the oils accessed for drug solubility, Capmul MCM showed higher solubility capacity for Atorvastatin calcium. Capmul MCM was better microemulsified using combination of Tween 20 and Labrasol surfactant. Droplet size was as low as 86.93?nm with polydispersity index and ζ potential at 0.195?±?0.011 and -7.27?±?3.11 mV respectively. The selected undiluted formulation showed refractive index values ranging from 1.40 to 1.47 indicating the isotropicity of the formulation. The selected formulation was robust to dilution in different media and thermodynamically stable. Dissolution profile was enhanced for the selected drug as compared to marketed formulation with t85% and DE values at 10?min and 80.15 respectively. Also cytotoxicity measurement showed minimum effect with good permeation enhancing capacity. Thus our study demonstrates the use of smaller molecular oil (Capmul MCM) for developing self-microemulsifying drug delivery system for better in vitro and in vivo performance.     

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S_mix, and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100?±?0.1% transmittance and 17.85?±?2.78?nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value ?5.88?±?1.14?mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.     

Solid self microemulsification of Atorvastatin using hydrophilic carriers: a design

Context: Atorvastatin has a limited advantage to formulate oral dosage forms.

Objective: To enhance the solubility of Atorvastatin and to design the suitable solid self-microemulsifying drug delivery systems (S-SMEDDS)

Materials and methods: The clear and transparent self-microemulsifying drug delivery system (SMEDDS) were formulated using coconut oil and isopropyl myristate as lipid phases; Tween 80 as surfactant; PEG 400 and glycerin as co-surfactant at 2:1, 3:1, 1:2 and 1:3 ratio. The pseudo ternary phase diagrams were constructed to identify the microemulsion region. The SMEDDS were evaluated for zeta potential, poly dispersity index, globule size, pH, viscosity and drug release. The solid SMEDDS were developed by employing adsorption and melt granulation methods. The S-SMEDDS were evaluated for micromeritics, morphology, solid state property, reconstitution ability, drug release and stability.

Results: The micro formulations formed with particle size of 25?nm had shown a 3-folds rise in drug release. The solid SMEDDS had reconstituted to a good microemulsion rapidly in 1–3?min, with a release of 94.62% at the end of 30?min and behaved as immediate releasing capsules. Their shelf-life was found to be 1.3 years.

Discussion: The 1:3 ratio SMEDDS had shown more drug release owing to their less particle size. The solid SMEDDS had shown an increased dissolution profiles than atorvastatin. The solid state of the drug had changed in formulation inferring their enhanced solubility.

Conclusion: The solid form of atorvastatin liquid SMEDDS had been formulated successfully with enhanced shelf life and solubility.     

The effect of component of microemulsion for transdermal delivery of nicardipine hydrochloride

Purpose: Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study. Methods: Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study. Results: The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content. Conclusions: The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53±1.87 μg/cm2/h and was expected to develop a transdermal delivery system.     

Comparative permeability studies with radioactive and nonradioactive risedronate sodium from self-microemulsifying drug delivery system and solution

The purpose of this work is to prepare a self-microemulsifying drug delivery system (SMEDDS) for risedronate sodium (RSD) and to compare the permeability with RSD solution. The solubility of RSD was determined in different vehicles. Phase diagrams were constructed to determine the optimum concentration of oil, surfactant, and cosurfactant. RSD SMEDDS was prepared by using a mixture of soybean oil, cremophor EL, span 80, and transcutol (2.02:7.72:23.27:61.74, w/w, respectively). The prepared RSD SMEDDS was characterized by droplet size value. In vitro Caco-2 cell permeability studies were performed for SMEDDS and solution of radioactive (^99?mTc-labeled RSD) and nonradioactive RSD. The experimental results indicated that RSD SMEDDS has good stability and its droplet size is between 216.68?±?3.79 and 225.26?±?7.65 during stability time. In addition, RSD SMEDDS has higher permeability value than the RSD solution for both radioactive and nonradioactive experiments. The results illustrated the potential use of SMEDDS for delivery of poorly absorbed RSD.     

Preparation,characterization and in vitro evaluation of microemulsion of raloxifene hydrochloride

Raloxifene hydrochloride (RLX) is a selective estrogen receptor modulator which is orally used for treatment of osteoporosis and prevention of breast cancer. The drug has low aqueous solubility and bioavailability. The aim of the present study is to formulate and characterize oil-in-water microemulsion systems for oral delivery of RLX. To enhance the drug aqueous solubility, microemulsion based on sesame oil was prepared. Sesame oil and Tween 80 were selected as the drug solvent oil and surfactant, respectively. In the first and second formulations, Edible glycerin and Span 80 were applied as co-surfactant, respectively. Pseudo-ternary phase diagrams showed that the best surfactant/co-surfactant ratios in the first and second formulations were 4:1 and 9:1, respectively. The particle size of all free drug-loaded and drug loaded samples were in the range of 31.25?±?0.3?nm and 60.9?±?0.1?nm, respectively. Electrical conductivity coefficient and refractive index of all microemulsion samples confirmed the formation of oil-in-water type of microemulsion. In vitro drug release profile showed that after 24?hours, 46% and 63% of the drug released through the first formulation in 0.1% (w/v) Tween 80 in distilled water as a release medium and phosphate buffer solution (PBS) at pH?=?5.5, respectively. These values were changed to 57% and 98% for the second formulation. Results confirmed that the proposed microemulsion system containing RLX could improve and control the drug release profile in comparison to conventional dosage form.     

Formulation and in vitro evaluation of self-emulsifying formulations of Cinnarizine

The main objectives of this study were to improve the aqueous solubility and to modify in vitro dissolution profile of hydrophobic drug using self-emulsifying drug delivery systems (SEDDS). SEDDS were formulated using Capmul PG-12, Cremophor RH 40 and Tween 20 at different weight ratios and incorporated with Cinnarizine. The drug incorporation into pre-concentrate and drug solubility in phosphate buffer (pH 7.2) were investigated. In addition, the mean droplet size and drug release profile of the SEDDS were also determined. The drug incorporation was over 120?mg per 0.5?g pre-concentrate regardless of the composition of the formulations. The solubility of Cinnarizine in phosphate buffer (pH 7.2) was at least 1500 μM in the SEDDS. Formulations with only 10% w/w Capmul PG-12 were less than 20?nm in mean diameter while those produced with at least 20% w/w Capmul PG-12 were more than 100?nm regardless of the ratios of Cremophor RH 40 to Tween 20. SEDDS showed a significant increase of the mean percentage drug release than pure drug (p?<?0.0001). In general, the SEDDS with 30% w/w of Capmul PG-12 provided the greatest enhancement in drug solubility in phosphate buffer as well as rapid drug release despite forming larger droplets upon emulsification. The combination of Capmul PG-12, Tween 20 and Cremophor RH 40 can produce SEDDS which can be used as an alternative dosage form for poorly water soluble drug.     

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire^® 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire^® 44/14 (oil), 40% Solutol^® HS 15 (surfactant), and 30% Transcutol^® P (cosurfactant) (w/w) with 80?mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20?±?1.43 and 33.34?±?2.15?nm, and the melting points of them were 35.6 and 36.8?°C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of C_max and AUC_0–t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.     

Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery

Aim: In this study, self-emulsifying drug delivery system (SEDDS) for oral delivery of opioid peptide dalargin were developed and characterized in vitro.

Methods: Dalargin lipophilicity was increased by O-esterification of tyrosine OH group, hydrophobic ion pairing, or a combination thereof. Distribution coefficients (log?D) of lipidized dalargin derivatives were determined. Then, dalargin was incorporated in chosen SEDDS, namely SEDDS-1, composed of 50% Capmul 907, 40% Cremophor EL, and 10% propylene glycol and comparatively more lipophilic SEDDS-2 composed of 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL, and 10% propylene glycol. Additionally, SEDDS were characterized regarding droplet size, polydispersity index (PDI), cloudy point, physical stability and stability against pancreatic lipase. Furthermore, mucus permeating properties of SEDDS and their ability to protect the incorporated dalargin against proteolysis by trypsin, α-chymotrypsin, elastase, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) were evaluated.

Results: The highest dalargin drug payload of 4.57% in SEDDS-2 was achieved when dalargin palmitate (pDAL) was ion paired with sodium dodecyl sulfate (SDS) in molar ratio 1:1. Moreover, SEDDS-1 and SEDDS-2 had a narrow droplet size distribution with average droplet sizes of 42.1 and 33.1?nm with PDI of 0.042 and 0.034, respectively. Lipolysis study showed that within 30?min 78.5% of SEDDS-1 and 92.1% of SEDDS-2 were digested. In addition, both SEDDS exhibited mucus permeating properties as well as a protective effect against enzymatic degradation by trypsin, α-chymotrypsin, elastase, SGF and SIF.

Conclusion: The results of this study suggest that the developed SEDDS could be considered for oral opioid peptide delivery.     

Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of Pueraria lobata isoflavone

The aim of our investigation was to develop and characterize self-microemulsifying drug delivery systems (SMEDDS) of Pueraria lobata isoflavone to improve its in vitro dissolution and oral absorption in beagle dogs. SMEDDS consisted of oil (ethyl oleate), a surfactant (Tween 80), and a cosurfactant (Transcutol P). In all the SMEDDS, the level of Pueraria lobata isoflavone was fixed at 20% w/w of the vehicle. The in vitro self-microemulsification properties and droplet size analysis of SMEDDS were studied following their addition to water under mild agitation. A pseudoternary phase diagram was constructed identifying the efficient self-microemulsification region. From these investigations, an optimized formulation was selected and its dissolution and bioavailability were compared with a tablet formulation in beagle dogs. The in vitro dissolution rate of puerarin from SMEDDS was more than threefold faster than that from Yufengningxin tablets (Pueraria lobata isoflavone tablets). A 2.5-fold increase in the relative bioavailability was observed for the SMEDDS compared with Yufengningxin tablets. The absolute bioavailability of the SMEDDS was 82.32 +/- 15.51%, which was significantly improved compared with that of Yufengningxin tablets. These results demonstrate the potential of SMEDDS as an efficient way of improving the oral absorption of Pueraria lobata isoflavone.     

Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Berberine hydrochloride (BBH), an important bioactive compound from Chinese Medicines with poor water solubility. Pseudoternary phase diagrams were constructed using oil, surfactant and co-surfactant types to identify the efficient self-microemulsification region. SMEDDS was characterized by morphological observation, droplet size, zeta-potential determination, stability, in vitro release and in vivo bioavailability study. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 40% (w/w) of ethyl linoleate and oleic acid (2:1), 35% (w/w) Tween-80 and 25% (w/w) glycerol. The SMEDDS of BBH could exhibit good stability. In vitro release test showed a complete release of BBH from SMEDDS was in 5 h. In vivo results indicated that the peak plasma concentration (C_max) and the area under the curve (AUC_{0→12 h}) of SMEDDS of BBH were higher than the commercial tablet by 163.4% and 154.2%, respectively. The relative bioavailability of SMEDDS of BBH was enhanced about 2.42-fold compared with the commercial tablet in rats. The study confirmed that the SMEDDS formulation could be used as a possible alternative to traditional oral formulations of BBH to improve its bioavailability.     

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state

Objective: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs).

Methods: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control.

Results: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5?min. Pharmacokinetic study showed that the AUC_(0–∞) and C_max for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption.

Conclusion: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.     

Preparation and in vitro evaluation of self-microemulsifying drug delivery systems containing idebenone

A new self-microemulsifying drug delivery system (SMEDDS) was developed to increase the dissolution rate, solubility, and, ultimately, bioavailability of a poorly water soluble drug, idebenone. Pseudoternary phase diagrams were used to evaluate the self-microemulsification existence area, and the release rate of idebenone was investigated. The mixtures consisting of Labrafac hydro or Labrafil 2609 (HLB values > 4) with the surfactant (Labrasol containing 80% Transcutol) and cosurfactant (Plurol oleique WL 1173) were found to be optimum formulations. Using the SMEDDS formulations of 5% to 20% of Labrafac hydro or Labrafil 2609 in combination with the surfactant/cosurfactant mixing ratio of 3, the microemulsion existence field was wider compared to the other SMEDDS formulations due to high affinity for the continuous phase. The in vitro dissolution rate of idebenone from SMEDDS was more than twofold faster compared with that of tablets. The developed SMEDDS formulation can be used as a possible alternative to traditional oral formulations of idebenone to improve its bioavailability.     

Development and characterization of self-microemulsifying drug delivery system of tacrolimus for intravenous administration

Tacrolimus (FK 506), a poorly soluble immunosuppressant is currently formulated in nonaqueous vehicle containing hydrogenated castor oil derivative for intravenous administration. Hydrogenated castor oil derivatives are associated with acute anaphylactic reactions. This proposes to overcome the problems of poor aqueous solubility of the drug and the toxicity associated with currently used excipients by the development of a new parenterally acceptable formulation using self-microemulsifying drug delivery system (SMEDDS). Solubility of FK 506 in various oils, surfactants, and cosurfactants was determined to identify SMEDDS components. Phase diagrams were constructed at different ratios of surfactants:cosurfactant (K(m)) to determine microemulsion existence area. Influence of oily phase content, K(m), aqueous phase composition, dilution, and incorporation of drug on mean globule size of microemulsions was studied. SMEDDSs were developed using ethyl oleate as oily phase and Solutol HS 15 as surfactant. Glycofurol was used successfully as a cosurfactant. Developed SMEDDS could solubilize 0.8% (wt/wt) FK 506 and on addition to aqueous phase could form spontaneous microemulsion with mean globule size < 30 nm. The resulting microemulsion was iso-osmotic, did not show any phase separation or drug precipitation even after 24 h, and exhibited negligible hemolytic potential to red blood cells.