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.     

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.     

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.     

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?相似文献   

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   

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.     

Impact of various solid carriers and spray drying on pre/post compression properties of solid SNEDDS loaded with glimepiride: in vitro-ex vivo evaluation and cytotoxicity assessment

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of glimepiride is reported with the aim to achieve its oral delivery. Lauroglycol FCC, Tween-80, and ethanol were used as oil, surfactant, and co-surfactant, respectively as independent variables. The optimized composition of SNEDDS formulation (F1) was 10% v/v Lauroglycol FCC, 45% v/v Tween 80, 45% v/v ethanol, and 0.005% w/v glimepiride. Further, the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, dissolution, and diffusion. Both, liquid and solid-SNEDDS have shown release of more than 90% within 10?min. Results of permeation studies performed on Caco-2 cell showed that optimized SNEDDS exhibited 1.54 times higher drug permeation amount and 0.57 times lower drug excretion amount than that of market tablets at 4?hours (p?p?>?.05, i.e. 0.74). The formulation was found stable with temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline glimepiride was observed in amorphous state in solid SNEDDS when characterized through DSC, PXRD, and FT-IR studies. The study revealed successful formulation of SNEDDS for glimepiride.     

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.     

Enhanced oral bioavailability of tacrolimus in rats by self-microemulsifying drug delivery systems

A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of tacrolimus (TAC). The formulations of TAC-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. In order to inhibit the efflux of P-glycoprotein (P-gp) for tacrolimus, which is the substrate of P-gp, the excipients which show the inhibition effect to P-gp, such as tocopheryl polyethylene glycol succinate (TPGS) and Cremophor EL40, were chosen in the SMEDDS formulations. According to particle size and the rate of self-emulsification, two optimized formulations were selected: Miglyol 840 as oil phase, Transcutol P as cosurfactant, TPGS as surfactant (TPGS-SMEDDS) or Cremophor EL40 as surfactant (Crem-SMEDDS), respectively. The ratio of oil phase, surfactant and cosurfactant is 1:7.2:1.8. The mean droplet size distribution of the optimized SMEDDS was less than 20?nm. The in vitro dissolution test indicated a significant improvement in release characteristics of TAC. The prepared SMEDDS was compared with the homemade solution by administering the hard capsule to fasted rats. The absorption of TAC from TPGS-SMEDDS and Crem-SMEDDS form resulted in about sevenfold and eightfold increase in bioavailability compared with the homemade solution. Our study illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as TAC by the oral route.     

Self-nanoemulsifying drug delivery system of docosahexanoic acid: development,in vitro,in vivo characterization

Context: Docosahexanoic acid (DHA) is an essential omega-3 fatty acid for normal brain development and its use has increased considerably in recent years.

Objective: The aim of this study is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of DHA for improved palatability, dispersibility and bioavailability.

Methods: The SNEDDS were prepared and evaluated for miscibility, employing different combinations of olive oil and soyabean oil as oil phase, Span 80, Span 20, soya phosphatidylcholine, Labrafil M 1944 CS as surfactants while Tween 80, PEG 400, Cremophor RH40 and propylene glycol as cosurfactants. Thermodynamically stable SNEDDS were characterized for dispersibility, self-emulsification time, droplet size, zeta potential along with sensory analysis. The optimized formulation was subjected to ex vivo and in vivo evaluation such as intestinal permeability, memory performance test, brain concentration and histopathology studies.

Results: The optimized SNEDDS formulation showed emulsification time of 27?±?4.7?s with droplet size of 17.6?±?3.5?nm and zeta potential of??37.6?±?0.5?mV. Intestinal absorption study depicted 18.3%, 21.5%, 41.5%, 98.7% absorption of DHA with SNEDDS-based formulation in comparison to 8.2%, 15.1%, 28.8%, 46.1% absorption of DHA with oil-based marketed formulation after 0.5, 1, 2 and 4?h. DHA concentration in brain homogenate was found to be increased to 2.6-fold in comparison to DHA-marketed formulation. This could be ascribed to enhanced dispersibility and bioavailability of DHA from nanosized formulation.

Conclusion: The developed formulation led to enhanced dispersibility and bioavailability of DHA due to the formation of nanodroplets.     

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q₁₀, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q₁₀, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87?mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250?mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200?nm. From all formulations, except that of vitamin K2, >80–90% nutraceuticals dispersed in 5–10?min and there was no precipitation of compounds during the test period of 120?min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.     

Formulation of solid self-nanoemulsifying drug delivery systems using N-methyl pyrrolidone as cosolvent

Atorvastatin calcium (ATRC) is a poor water soluble drug used for treatment of hypercholesterolemia. This research is aimed to improve solubility and dissolution rate of ATRC by formulating into solid self-nanoemulsifying drug delivery system (S-SNEDDS) using N-methyl pyrrolidone (NMP) as cosolvent. Solubility of ATRC was determined in various vehicles. Ternary phase diagrams were constructed to identify stable nanoemulsion region. SNEDDS formulations were evaluated for robustness to dilution, thermodynamic stability study, % transmittance, self-emulsification time, globule size and transmission electron microscopy. The optimized liquid SNEDDS showed robust to all dilutions exhibiting no signs of phase separation or precipitation for 24?h. Liquid SNEDDS was transformed into S-SNEDDS using different adsorbents. Differential scanning calorimetry and scanning electron microscopy studies unravel the transformation of native crystalline state to amorphous state/solubilized state. In vitro dissolution study of S-SNEDDS was found to be significantly higher in comparison to that from plain drug, irrespective of pH (p?ex vivo permeation studies showed a 4.45-fold improvement in apparent permeability coefficient (P_app) from S-SNEDDS compared to plain drug. In conclusion, S-SNEDDS prepared using NMP as cosolvent provides an effective approach for improved oral delivery of ATRC.     

Ophthalmic vehicles containing polymer-solubilized tropicamide: "in vitro/in vivo" evaluation

Commercial 1.0% aqueous tropicamide (TR) eyedrops are buffered to pH 4.4-5.0 to produce sufficiently stable solutions of the weakly basic, poorly soluble drug. These acidic solutions, however, are irritants and may induce copious lachrimation, thus reducing the drug bioavailability. The aim of the present study was to evaluate some solubilizing agents for the preparation of 1.0% TR ophthalmic solutions adjusted at physiologically compatible pH, potentially showing increased eye tolerance, activity, and stability when compared with standard commercial eyedrops. The tested solubilizers were two non-ionic surfactants—Tyloxapol (TY) and Cremophor EL (CR)—and one polymer, Pluronic P85 (PL). Four stable 1% TR formulations, containing 3% TY, 7.5% CR, 15% PL, or 5% CR + 10% PL were submitted to mydriatic activity tests in rabbits. They improved to a small but statistically significant extent the AUC for mydriatic effect of TR in the test animals when compared with commercial 1.0% TR eyedrops.     

Ophthalmic Vehicles Containing Polymer-Solubilized Tropicamide: “In Vitro/In Vivo” Evaluation

ABSTRACT

Commercial 1.0% aqueous tropicamide (TR) eyedrops are buffered to pH 4.4–5.0 to produce sufficiently stable solutions of the weakly basic, poorly soluble drug. These acidic solutions, however, are irritants and may induce copious lachrimation, thus reducing the drug bioavailability. The aim of the present study was to evaluate some solubilizing agents for the preparation of 1.0% TR ophthalmic solutions adjusted at physiologically compatible pH, potentially showing increased eye tolerance, activity, and stability when compared with standard commercial eyedrops. The tested solubilizers were two non-ionic surfactants—Tyloxapol (TY) and Cremophor EL (CR)—and one polymer, Pluronic P85 (PL). Four stable 1% TR formulations, containing 3% TY, 7.5% CR, 15% PL, or 5% CR + 10% PL were submitted to mydriatic activity tests in rabbits. They improved to a small but statistically significant extent the AUC for mydriatic effect of TR in the test animals when compared with commercial 1.0% TR eyedrops.     

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.     

Solutol and Cremophor Products as New Additives in Suppository Formulation

ABSTRACT

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1–3%, which is related to the optimal additive quantity accumulated on the boundary surface.     

Solutol and cremophor products as new additives in suppository formulation

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1-3%, which is related to the optimal additive quantity accumulated on the boundary surface.     

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.     

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.     

Preparation and characterization of coenzyme Q10-Eudragit solid dispersion

A solid dispersion of Coenzyme Q10 and Eudragit L 100-55 was prepared using solvent evaporation method. Solid dispersion, physical mixture, and pure compound were then characterized using differential scanning calorimetry and powder x-ray diffraction. Solubility of CoQ10 in different surfactant media was measured, and a suitable dissolution medium was developed to compare the dissolution patterns of the solid dispersion, physical mixture, and the pure compound. Combining labrasol with different surfactants in dissolution media demonstrated an additive effect on CoQ10 solubility. The solubility of CoQ10 in a 4% Labrasol/2% Cremophor EL solution was 562 microg/ml, which was five times higher than the combined solubility in 5% Labrasol (91 microg/ml) and 5% Cremophor EL (7.8 microg/ml). Moderate change in the crystalline pattern of CoQ10 was observed, which was attributed to solvent displacement rather than the degree of crystallinity change. The dissolution test indicated that the in-vitro release of Coenzyme Q10 from its solid dispersion was much faster than its physical mixture, which in turn was faster than the pure drug. The amount of drug released in 12 hours from solid dispersion, physical mixture, and the pure drug was 100, 26.5 and 12.5% respectively. CoQ10 was photostable throughout the dissolution experiments.