Oral self-emulsifying delivery systems for systemic administration of therapeutic proteins: science fiction?

Abstract

Objective: The aim of this study was to develop self-emulsifying drug delivery systems (SEDDS) for oral delivery of therapeutic proteins through hydrophobic ion pairing.

Method: Horseradish peroxidase (HRP), a model protein, was ion paired with sodium docusate to increase its hydrophobicity. The formed enzyme - surfactant complex was incorporated into SEDDS, followed by permeation studies across Caco-2 cell monolayer and freshly excised rat intestine.

Results: Hydrophobic ion pairs (HIP) were formed between HRP and sodium docusate with the efficiency of 87.49?±?1.35%. The formed complex maintained 60.97?±?1.48% of the original enzyme activity. The ion pair was subsequently loaded into SEDDS with a payload of 0.1% (mass per cent, m/m). The obtained emulsion formed by SEDDS had a droplet size in the range from 20 to 200?nm with negative zeta potential. Permeation mechanism of the enzyme was energy-dependent and the encapsulation of the HIP complex in SEDDS enhanced the permeation of the enzyme through the Caco-2 cell monolayer and freshly excised rat intestine by 4 times and 2.5 times compared to the free enzyme, respectively.

Conclusion: According to these findings, hydrophobic ion pairing followed by incorporation to SEDDS might be considered as a potential strategy for oral delivery of therapeutic proteins.     

Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations

Abstract

The objective of this study was to develop self-emulsifying drug delivery system (SEDDS) to improve solubility and enhance the oral absorption of the poorly water-soluble drug, nevirapine. This lipid-based formulation may help to target the drug to lymphoid organs where HIV-1 virus resides mainly. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SEDDS were investigated in detail. Two SEDDS (F1 and F2) were prepared and characterized by morphological observation, droplet size and zeta potential determination, cloud point measurement and in vitro diffusion study. The influence of droplet size on the absorption from formulations with varying concentration of oil and surfactant was also evaluated from two self-emulsifying formulations. Oral bioavailability of nevirapine SEDDS was checked by using rat model. Results of diffusion rate and oral bioavailability of nevirapine SEDDS were compared with marketed suspension. The absorption of nevirapine from F1 and F2 showed 1.92 and 1.98-fold increase (p?<?0.05) in relative bioavailability, respectively, compared with that of the suspension. There was no statistical significant difference (p?<?0.05) between F1 and F2 in their AUC and C_max. This indicated that there was apparent poor correlation between the droplet size and in vivo absorption. However, nevirapine in SEDDS showed higher ex vivo stomach and intestinal permeability and in vivo absorption than the marketed suspension, suggesting that the SEDDS may be a useful delivery system for targeting nevirapine to lymphoid organs.     

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view

Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5–6 years are analyzed for an up to date compilation.     

Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems

Purpose

The aim of the study was to create novel mucoadhesive drug delivery systems by incorporating amphiphilic hydrophobically modified, thiolated and preactivated polymers (preactivated thiomers) into self-emulsifying drug delivery systems (SEDDS).

Methods

L-Cysteine methyl ester was covalently attached to the polymeric backbone of Pemulen TR-2 and preactivated using 2-mercaptonicotinic acid (2-MNA). These thiomers were incorporated in a concentration of 0.3% (w/v) into SEDDS. The size distribution and the zeta potential of the emulsions were evaluated by dynamic light scattering. Mucoadhesive properties of thiomers-SEDDS spiked with FDA (fluorescein diacetate) were examined utilizing rheological measurement, permeation studies and in vitro residence time study on porcine mucosa. Cell viability tests were additionally performed.

Results

734 ± 58 μmol L-Cysteine methyl ester and 562 ± 71 μmol 2-MNA could be attached per gram polymer of Pemulen TR-2. Emulsions exhibited a droplet size range between 180 and 270 nm. Blank SEDDS possessed a zeta potential value between ?5.7 and ?8.6 mV, whereas thiomers-SEDDS between ?14.6 and ?17.2 mV. Viscous modulus of thiomer and preactivated thiomer containing SEDDS-mucus mixture was 8-fold and 11-fold increased in comparison to reference. The amount of FDA permeated the mucus layer was 2-fold lower in case of thiomers-SEDDS compared to blank SEDDS. A prolonged residence time was observed for thiomers-SEDDS over 45 min. During cell viability studies no severe toxic effects were detected.

Conclusion

The novel developed SEDDS with incorporated thiomers might be a promising tool for mucoadhesive oral drug delivery.

     

Development and optimization of nanoemulsion gel for topical delivery of imiquimod

In the present study, we aimed to formulate, optimize and characterize nanoemulsion-based gel of imiquimod for its topical administration and to improve the drug permeation. Nanoemulsions were prepared by the aqueous phase titration method and spontaneously formed by mixing specific fractions of oil phase:S_mix:water. The nanoemulsion formulations were optimized by response surface methodology (RSM) using mixture design, Scheffe model. The formulated nanoemulsion was incorporated into 0.5% Carbopol 934 (w/v) to enhance convenience in superficial application of the drug. The nanoemulsions were characterizedin terms of droplet size, zeta potential, TEM, DSC and in vitro drug permeation. The vesicle size was 113.6 nm with polydispersity index of 0.251. The zeta potential was 34 mV. The spherical droplet shape was confirmed by TEM analysis. The drug permeation from the diffusion membrane was 73.67% in 6 h for the optimized formulation. An optimized nanoemulsion gel formulation of imiquimod was successfully developed with improved permeation using experimental design technique. The developed formulation could be further explored as a potential alternate to currently available topical formulations for the treatment of genital warts.     

Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery

Introduction: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years.

Areas covered: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach.

Expert opinion: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.     

Development and in vitro evaluation of an oral SEDDS for desmopressin

Abstract

Context: Self-emulsifying drug delivery systems (SEDDS) are among most promising tools for improving oral peptide bioavailability.

Objective: In this study, in vitro protective effect of SEDDS containing desmopressin against presystemic inactivation by glutathione and α-chymotrypsin was evaluated.

Materials and methods: The partitioning coefficient (log P) of desmopressin was increased via hydrophobic ion pairing using anionic surfactants. Solubility studies were performed to select the appropriate solvents for SEDDS preparation. Subsequently, droplet size and emulsification properties of 22 SEDDS formulations were evaluated. Moreover, the peptide-surfactant complex was dissolved in two chosen SEDDS formulations. Finally, SEDDS containing desmopressin were characterized regarding lipase stability, toxicity, and in vitro protective effect toward glutathione and α-chymotrypsin.

Results: Desmopressin log P was increased from initial ?6.13 to 0.33 using sodium docusate. The resulting desmopressin docusate complex (DES/AOT) was incorporated in two different SEDDS formulations, containing Capmul 907 P as main solvent. DES/AOT-SEDDS-F4 (containing 0.07% w/w DES/AOT) was composed of 50% Capmul 907P, 40% Cremophor RH40, and 10% Transcutol. The comparatively more hydrophilic formulation DES/AOT-SEDDS-F15 (containing 0.25% w/w DES/AOT) consisted of 20% Capmul 907P, 40% Acconon MC8-2, and 40% Tween 20. Both formulations were stable toward digestion by lipase and protected desmopressin toward α-chymotrypsin degradation. Moreover, DES/AOT-SEDDS-F4 also protected the peptide from thiol/disulfide exchange reactions with glutathione and was not cytotoxic at a concentration of 0.375% (w/w).

Conclusion: DES/AOT-SEDDS-F4 protected desmopressin from in vitro glutathione and α-chymotrypsin degradation. DES/AOT-SEDDS-F4 was metabolically stable and nontoxic. Therefore, it could be considered as a potential delivery system for oral desmopressin administration.     

In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system

In order to characterize the in situ intestinal permeability and in vivo oral bioavailability of celecoxib (CXB), a poorly water-soluble cyclooxygenase (COX)-2 inhibitor, various formulations including the self-emulsifying drug delivery system (SEDDS) and supersaturating SEDDS (S-SEDDS) were compared. The S-SEDDS formulation was obtained by adding Soluplus as a precipitation inhibitor to SEDDS, composed of Capryol 90 as oil, Tween 20 as surfactant, and Tetraglycol as cosurfactant (1:4.5:4.5 in volume ratio). An in situ single pass intestinal perfusion study in rats was performed with CXB-dissolved solutions at a concentration of 40 μg/mL. The effective permeability (P_eff) of CXB in the control solution (2.5 v/v% Tween 20-containing PBS) was 6.39 × 10^?5 cm/s. The P_eff value was significantly increased (P < 0.05) by the lipid-based formulation, yielding 1.5- and 2.9-fold increases for the SEDDS and S-SEDDS solutions, respectively, compared to the control solution. After oral administration of various formulations to rats at the equivalent dose of 100 mg/kg of CXB, the plasma drug level was measured by LC–MS/MS. The relative bioavailabilities of SEDDS and S-SEDDS were 263 and 355 %, respectively, compared to the CXB suspension as a reference. In particular, S-SEDDS revealed the highest C_max and the smallest T_max, indicating rapid and enhanced absorption with this formulation. This study illustrates the potential use of the S-SEDDS formulation in the oral delivery of poorly water-soluble compounds.     

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro,in vivo and in situ intestinal permeability studies

Abstract

The main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed C_max1, C_max2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2- and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p?<?0.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.     

Distribution of thiolated mucoadhesive nanoparticles on intestinal mucosa

It was the aim of the present study to evaluate and compare the distribution of thiolated mucoadhesive anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) nanoparticles on intestinal mucosa. Modifications of these polymers were achieved by conjugation with cysteine (PAA-Cys) and 2-iminothiolane (CS-TBA). Nanoparticles (NP) were prepared by ionic gelation and labelled with the strong hydrophilic fluorescent dye Alexa Fluor 488 (AF 488) and hydrophobic fluorescein diacetate (FDA). Unmodified and modified CS and PAA NP were examined in vitro in terms of their mucoadhesive and mucus penetrating properties on the mucosa of rat small intestine. To investigate the transport of NP across the mucus layer, their diffusion behaviour through natural porcine intestinal mucus was studied through a new diffusion method developed by our group. Lyophilised particles displayed 526 μmol/g (CS) and 513 μmol/g (PAA) of free thiol groups and a zeta potential of 20 mV (CS) and -14 mV for PAA NP. Nanoparticle distribution on rat intestine suggested that mucoadhesion of thiolated NP is higher than the diffusion into the intestinal mucosa. Modified particles displayed more than a 6-fold increase in mucoadhesion compared to unmodified ones. The rank order with regard to mucoadhesion of all particles was: CS-TBA>PAA-Cys>CS>PAA, whereas CS-TBA showed 2-fold higher mucoadhesive properties compared to PAA-Cys NP. Diffusion through intestinal mucus was much higher for unmodified than for thiolated as well as for anionic compared to cationic particles. Overall, it was shown that thiolated particles of both anionic and cationic polymers have improved mucoadhesive properties and could be promising carriers for mucosal drug delivery.     

Disruption of the mucus barrier by topically applied exogenous particles

The mucus barrier is well established as a formidable barrier to exogenous substances and forms the first line of defense for mucosal surfaces. Drugs and particle systems are known to be significantly hindered via a variety of interactions with mucus, and some efforts have been reported that can mitigate these interactions. We investigated topically applied particulate systems (nano and micro) for their potential to interact with mucus and influence on the diffusion of model drugs across the mucus barrier. Functionalized polystyrene nanoparticles and microparticles and diesel particulate matter were topically applied to established in vitro mucus models. Particle treated mucus was then assessed, compared to controls, for drug permeation rates. The average permeation rate of drugs increased 2-fold following the application of particles to mucus compared to permeation of the same drug through mucus alone. In some cases permeation enhancement of small model drugs was over 5 times that of controls. Assessment of particle physicochemical properties also indicated that significant interactions occurred between mucus and the particles as determined by zeta potential changes and size changes. Collectively this work supports the hypothesis that topically applied particles interact with the mucus barrier causing disruption of this barrier allowing for increased drug permeation. These findings have implications for improved drug delivery and enhanced environmental exposure to exogenous substances.     

SEDDS of gliclazide: Preparation and characterization by in-vitro,ex-vivo and in-vivo techniques

In the study, self emulsifying drug delivery system (SEDDS) of gliclazide, a poorly soluble drug, was developed and evaluated by in-vitro, ex-vivo and in-vivo techniques. Oil and surfactant were screened out according to their solubilizing capacity. Among the tested components Transcutol HP and Tween-80 showed good solubilizing capacity. These two components were used in different ratios to prepare gliclazide SEDDS. The SEDDS formulations were transparent and clear. Droplet size of the emulsion was determined by Laser Diffraction Technology of Malvern. Formulation F1 containing 1:1 (m/m) mixture of Transcutol HP/Tween-80 showed minimum mean droplet size (50.959 μm). In-vitro drug release from F1 was higher (99% within 20 min) than other formulations. The developed SEDDS was also evaluated for ex-vivo permeability profile by using chicken intestinal sac. Formulation F1 showed optimal drug diffusion. In-vivo performance of SEDDS was evaluated in albino mice using plasma glucose level as a pharmacodynamic marker parameter. The test formulation (F1) showed significant reduction in plasma glucose level, after oral administration. So SEDDS may be an alternative technique for the oral administration of gliclazide.     

Self-emulsifying drug delivery systems for improving oral absorption of ginkgo biloba extracts

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. We found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. Ginkgo biloba extract (GBE) has become a widely used herbal remedy for increasing cognitive function in elderly people. The main purpose of our work is to prepare SEDDS for improving oral absorption of GBE. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region, and particle size distributions of resultant emulsions were determined. The optimized formulation for bioavailability assessment consisted of 45% Tween 80-Cremophor EL35 (1:1, w/w), 10% 1, 2-propanediol, and 45% ethyl oleate. The mean droplet size distribution of the optimized SEDDS was approximately 100 nm when diluted with 500-fold volume of the distilled water. The in vitro dissolution rates of the active components of GBE SEDDS form were significantly faster than those of the GBE tablets. After single oral administration of 800 mg GBE as SEDDS or tablets to fasted dogs, the relative bioavailability of SEDDS for bilabolide and ginkgolide A and B was 162.1, 154.6, and 155.8% compared with the reference tablets, respectively. Our results suggested the potential and promising use of SEDDS for the efficient delivery of the sparingly soluble drugs or traditional Chinese medicines, such as GBE by oral administration.     

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.     

An ion pairing approach to increase the loading of hydrophilic and lipophilic drugs into PEGylated PLGA nanoparticles

The aim of this study was to enhance the loading of dalargin (enkephalin derivatives) a hydrophilic drug and loperamide HCl (non-opiate antidiarrheal agent) a lipophilic drug candidates within PEGylated nanoparticles. A novel nanoencapsulation method based on the concept of s/o/w and ion pairing followed by solvent diffusion was adopted. The copolymers with three different mPEG densities (5%, 12% and 17%) were employed separately in combination with two different grades of dextran sulphate (DS) 5000 and 500,000 MW in the preparations. Nanoparticles prepared from copolymers with increasing mPEG densities, showed an insignificant (p > 0.05) increasing trend of drug loading, this was however significantly increased when DS5000 was included in the preparations. The particle size remains unchanged after dalargin loading, with no significant (p > 0.05) alteration in the neutral zeta potential compared to that of the preparations without DS5000. Considering that a dalargin ion pair could also have a neutral charge, it was not advisable to conclude its incorporation, as the size remain unchanged, which would otherwise increase if an ion pair was incorporated within the core of nanoparticles. Therefore, it was expected that a dalargin ion pair might be located outside the core as a separate particulate entity or reside in the hydrophilic shell of the nanoparticles. A loperamide HCl ion pair showed significant (p < 0.05) increase in size when incorporated; at the same time it provided a neutral zeta potential despite adding negatively charged DS5000 in the preparation, hence it seemed encapsulated. Inclusion of DS500,000 in the preparation further increased the drug loading of dalargin and loperamide HCl. However, a significant (p < 0.05) negative zeta potential was noted in both cases which suggested that excess charge was still available on the surface of nanoparticles which could trap further amounts of drug on the surface rather than inside the core of nanoparticles. During in vitro evaluation of drug loaded nanoparticles, dalargin released as quickly as free drug, when loperamide HCl showed almost burst free sustained release profile with respect to the release of their free drug solutions, suggested that ion pairing approach was more pronounced for loperamide HCl formulation.     

Self-Emulsifying Drug Delivery Systems for Improving Oral Absorption of Ginkgo Biloba Extracts

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. We found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. Ginkgo biloba extract (GBE) has become a widely used herbal remedy for increasing cognitive function in elderly people. The main purpose of our work is to prepare SEDDS for improving oral absorption of GBE. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region, and particle size distributions of resultant emulsions were determined. The optimized formulation for bioavailability assessment consisted of 45% Tween 80-Cremophor EL35 (1:1, w/w), 10% 1, 2-propanediol, and 45% ethyl oleate. The mean droplet size distribution of the optimized SEDDS was ～100 nm when diluted with 500-fold volume of the distilled water. The in vitro dissolution rates of the active components of GBE SEDDS form were significantly faster than those of the GBE tablets. After single oral administration of 800 mg GBE as SEDDS or tablets to fasted dogs, the relative bioavailability of SEDDS for bilabolide and ginkgolide A and B was 162.1, 154.6, and 155.8% compared with the reference tablets, respectively. Our results suggested the potential and promising use of SEDDS for the efficient delivery of the sparingly soluble drugs or traditional Chinese medicines, such as GBE by oral administration.     

Fabrication,in-vitro characterization,and enhanced in-vivo evaluation of carbopol-based nanoemulsion gel of apigenin for UV-induced skin carcinoma

The aim of this study was to develop a potential novel formulation of carbopol-based nanoemulsion gel containing apigenin using tamarind gum emulsifier which was having the smallest droplet size, the highest drug content, and a good physical stability for Skin delivery. Apigenin loaded nanoemulsion was prepared by high speed homogenization method and they were characterized with respect to morphology, zeta potential, differential scanning calorimeter study, and penetration studies. In-vitro release studies and skin permeation of apigenin loaded nanoemulsion by goat abdominal skin was determined using Franz diffusion cell and confocal laser scanning microscope (CLSM). The cytotoxicity of the reported formulation was evaluated in HaCaT Cells (A) and A431 cells (B) by MTT assay. The nanoemulsion formulation showed droplet size, polydispersity index, and zeta potential of 183.31?nm, 0.532, and 31.9?mV, respectively. The nanoemulsions were characterized by TEM demonstrated spherical droplets and FTIR to ensure the compatibility among its ingredients. CLSM showed uniform fluorescence intensity across the entire depth of skin in nanocarriers treatment, indicating high penetrability of nanoemulsion gel through goatskin. The nanoemulsion gel showed toxicity on melanoma (A341) in a concentration range of 0.4–2.0?mg/ml, but less toxicity toward HaCaT cells. The carbopol-based nanoemulsion gel formulation of apigenin possesses better penetrability across goatskin as compared to marketed formulation. Hence, the study postulates that the novel nanoemulsion gel of apigenin can be proved fruitful for the treatment of skin cancer in near future.     

Olive oil and clove oil-based nanoemulsion for topical delivery of terbinafine hydrochloride: in vitro and ex vivo evaluation

In this article, formulation studies for terbinafine hydrochloride nanoemulsions, prepared by high-energy ultrasonication technique, are described. Pseudo-ternary phase diagram was constructed in order to find out the optimal ratios of oil and surfactant/co-solvent mixture for nanoemulsion production. Clove and olive oils were selected as oil phase. Based on the droplet size evaluation, maximum nanoemulsion region were determined for formulation development. Further characterization included polydispersity index (PDI), zeta potential, Fourier transform infrared (FT-IR) spectroscopy, morphology, pH, viscosity, refractive index, ex vivo skin permeation, skin irritation, and histopathological examination. Droplet sizes of optimized formulations were in colloidal range. PDI values below 0.35 indicated considerably homogeneous nanoemulsions. Zeta potential values were from 13.2 to 18.1 mV indicating good stability, which was also confirmed by dispersion stability studies. Ex vivo permeation studies revealed almost total skin permeation of terbinafine hydrochloride from the nanoemulsions (96–98%) in 6 hours whereas commercial product reached only 57% permeation at the same time. Maximum drug amounts were seen in epidermis and dermis layers. Skin irritation and histopathological examination demonstrated dermatologically safe formulations. In conclusion, olive oil and clove oil-based nanoemulsion systems have potential to serve as promising carriers for topical terbinafine hydrochloride delivery.     

Development and characterization of liquid and solid self-emulsifying drug delivery system of fexofenadine

Fexofenadine, the active metabolite of terfenadine, a well known and effective H1 receptor antagonist, is administered by the oral route. The objective of present investigation was to develop and characterize a liquid self-emulsifying drug delivery system (SEDDS) and a solid SEDDS by using bioenhancer excipients like Tween 80 and Labrasol which are known for their inhibiting action on CYP450 and P-glycoprotein pump. Solubility of fexofenadine was determined in various vehicles, including oils, surfactants and co-solvents. Various evaluation parameters (emulsification study, particle size, poly-dispersibility index, % drug release, etc.) were carried out to find out optimized liquid SEDDS formulation. Optimized liquid formulations were converted in solid SEDDS by simple and convenient physical adsorption technique. Solid SEDDS was characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transport infra-red spectroscopy. The optimized liquid SEDDS formulation contained 29 % Captex 200P/Capmul MCM C8 EP as oil, 47 % Labrasol/Tween 80 as a surfactant and 24 % Ethanol as a co-solvent. The optimized liquid and solid SEDDS showed higher drug release than pure API powder. DSC and XRD results of solid SEDDS confirmed that the drug presented in the formulation was in an amorphous state. The prepared liquid SEDDS and solid SEDDS containing bio-enhancer excipients increased the in vitro dissolution rate of fexofenadine compared to pure drug and has potential to increase bioavailability by blocking Pgp efflux pump and CYP450 hepatic metabolism.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.