Formulation by design of felodipine loaded liquid and solid self nanoemulsifying drug delivery systems using Box–Behnken design

Objective: To design and develop liquid and solid self-nanoemulsifying drug delivery systems (SNEDDS and S-SNEDDS) of felodipine (FLD) using Box–Behnken design (BBD).

Methods: Solubility study was carried out in various vehicles. Ternary phase diagram was constructed to delineate the boundaries of the nanoemulsion domain. The content of formulation variables, X1 (Acconon E), X2 (Cremophor EL) and X3 (Lutrol E300) were optimized by assessment of 15 formulations (as per BBD) for mean globule sizes in Millipore water (Y1), 0.1?N?HCl (Y2), phosphate buffer (pH 6.4) (Y3); emulsification time (Y4) and T_85% (Y5). The responses (Y1–Y5) were evaluated statistically by analysis of variance and response surface plots to obtain optimum points. The optimized formulations were solidified by adsorption to solid carrier technique using Aerosil 200 (AER).

Results and discussion: Transmission electron microscopy images confirmed the spherical shape of globules with the size range concordant with the globule size analysis by dynamic light scattering technique (<60?nm). The surface morphology of S-SNEDDS (before release) by scanning electron microscopy and atomic force microscopy indicated that SNEDDS are adsorbed uniformly on the surface of AER. The dried residue of S-SNEDDS (after release) revealed the presence of nanometric pores vacated by the previously adsorbed SNEDDS onto AER. Differential scanning calorimetry and X-ray powder diffraction studies illustrated the change of FLD from crystalline to amorphous state.

Conclusion: This study indicates that owing to nanosize, SNEDDS and S-SNEDDS of FLD have potential to enhance its absorption and may serve an efficient oral delivery.     

Formulation of Rosuvastatin-Loaded Self-Nanoemulsifying Drug Delivery System Using Box-Behnken Design

The objectives of present study were to understand the effect of formulation variables of self-nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin (RSV). Box-Behnken design in conjunction with desirability function was used to evaluate the main effect, interaction effect and quadratic effect of independent formulation variables that included amounts of Acconon 200 E6, Cremophor RH40, and Lipoxol 300. For a better understanding of the selected variables for the optimal performance of RSV SNEDDS, the models were presented as three-dimensional response surface graphs. A fresh batch of optimized formulations and were prepared with optimized levels of the independent variables to yield dependent variables (Y1–Y6) values that were remarkably close to the predicted values. Drug excipient compatibility studies using the Fourier transform infrared spectroscopy, differential scanning calorimeter and x-ray diffraction indicated the absence of any incompatibility between RSV and selected excipients. The transmission electron microscopy of selected optimized SNEDDS of RSV showed the spherical shape of globules with no signs of coalescence and precipitation of RSV. The study demonstrates the use of Box-Behnken design for the preparation of RSV SNEDDS. The desirable goals can be obtained by systematic formulation approach in minimum possible time.     

Glibenclamide-loaded self-nanoemulsifying drug delivery system: development and characterization

Objective: To develop and characterize self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble drug, glibenclamide (GBD). Methods: Solubility of GBD was determined in various vehicles. Phase diagrams were constructed to identify efficient self-emulsification region using oils, surfactants, and cosurfactants in aqueous environment. Formulations were assessed for drug content, spectroscopic clarity, emulsification time, contact angle, zeta potential, particle size, and dissolution studies. On the basis of similarity and dissimilarity of particle size distribution, formulations were further characterized using principal component analysis and agglomerative hierarchy cluster analysis. Results: Among the formulations prepared and evaluated, optimized formulation showed mean particle size between 15.65 and 32.70 nm after 24 hour postdilution in various media. Dilution volume had no significant effect on particle size. Transmission electron microscopy of these formulations confirmed the spherical shape of globules with no signs of coalescence of globules and precipitation of drug. The relevance of difference in t50% and percent dissolution efficiency were evaluated statistically by two-way ANOVA. Infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction studies indicated compatibility between drug, oil, and surfactants. Conclusions: The results of this study indicate that the self-nanoemulsifying drug delivery system of GBD, owing to nanosize, has potential to enhance its absorption and without interaction or incompatibility between the ingredients.     

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.     

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.     

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.     

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.     

Formulation and characterisation of a self‐nanoemulsifying drug delivery system of amphotericin B for the treatment of leishmaniasis

This study was aimed to develop a self‐nanoemulsifying drug delivery system (SNEDDS) for amphotericin B (AmB) potential use in leishmaniasis through topical and oral routes. Two formulations, formulation A and formulation B (FA and FB) of AmB loaded SNEDDS were developed by mixing their excipients through vortex and sonication. The SNEDDS formulation FA and FB displayed a mean droplet size of 27.70 ± 0.5 and 30.17 ± 0.7 nm and zeta potential −11.4 ± 3.25 and −13.6 ± 2.75 mV, respectively. The mucus permeation study showed that formulation FA and FB diffused 1.45 and 1.37%, respectively in up to 8 mm of mucus. The cell permeation across Caco‐2 cells monolayer was 10 and 11%, respectively. Viability of Caco‐2 cells was 89% for FA and 86.9% for FB. The anti‐leishmanial activities of FA in terms of IC₅₀ were 0.017 µg/ml against promastigotes and 0.025 µg/ml against amastigotes, while IC₅₀ values of FB were 0.031 and 0.056 µg/ml, respectively. FA and FB killed macrophage harboured Leishmania parasites in a dose‐dependent manner and a concentration of 0.1 µg/ml killed 100% of the parasites. These formulations have the potential to provide a promising tool for AmB use through oral and topical routes in leishmaniasis therapy.Inspec keywords: nanomedicine, drops, microorganisms, electrokinetic effects, cellular biophysics, drug delivery systems, monolayers, drugs, diseasesOther keywords: self‐nanoemulsifying drug delivery system, topical routes, oral routes, SNEDDS formulation, mucus permeation study, cell permeation, leishmaniasis treatment, amphotericin B, zeta potential, Caco‐2 cell monolayer, vortex, sonication, droplet size, Caco‐2 cell viability, antileishmanial activity, promastigotes, amastigotes, Leishmania parasites     

Crystalline and amorphous carvedilol-loaded nanoemulsions: formulation optimisation using response surface methodology

This study aimed to evaluate the crystalline and amorphous carvedilol along with their lipidic mixtures using various instrumental techniques and to use response surface methodology in conjunction with factorial design to establish the functional relationships between operating variables (capmul GMS 50?K and cremophor RH 40).

The response variables selected are spectroscopic absorbance (Y ₁), mean particle size in distilled water (Y ₂) and in phosphate buffer pH 6.8 (Y ₃), polydispersibility index (PDI) (Y ₄) and zeta potential (Y ₅).

The optimal formulations of crystalline and amorphous carvedilol-loaded nanoemulsions were composed of fixed levels, ?0.41 and ?0.42, of capmul GMS 50?K and cremophor RH 40, respectively. The predicted and observed values of Y ₁–Y ₅ for blank nanoemulsions showed the percentage bias error of ?12.12%, ?10.25%, ?18.47%, +14.81 and ?2.89, respectively. The bias percent ranged between ?2.70% and ?29.41% for the responses Y ₁–Y ₄ for both crystalline and amorphous carvedilol-loaded nanoemulsions, indicating high degree of prognosis. However, the bias percent values for the response variable Y ₅ were 294.2% and 262.6%, for the crystalline and amorphous carvedilol-loaded nanoemulsions, respectively, possibly due to cationisation of emulsion droplets. The transmission electron microscopy of selected optimal nanoemulsions showed the spherical shape of globules with no signs of coalescence and precipitation of drug.

This study demonstrates the use of factorial design for the preparation of nanoemulsions of crystalline and amorphous carvedilol. The desirable goals can be obtained by systematic formulation approach in the shortest possible time.     

Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

There is an increasing interest on self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of poorly water-soluble drugs. However, development of SNEDDS is often driven by empiric, pseudo-ternary diagrams and solubility of drugs, and it is lacking a systematic approach for evaluating impact of excipients on the performance of formulations as well as the fate of drug. The aim of this study was to rationalize the SNEDDS development procedure and to get a better understanding on the role of excipients on the SNEDDS. The formulations consist of soybean oil or rapeseed oil, Cremophor^® RH40, Maisine? 35-1 and ethanol. Response surface methodology (RSM) was used in the development of SNEDDS. Significant advantages of RSM were found in reducing the work load and determining the impact of excipients on formulation characteristics. The most significant factor in influencing droplet size was the co-surfactant Maisine? 35-1, the droplet size increased with increasing concentration of Maisine? 35-1. It suggests that Maisine? 35-1 has double functions in the SNEDDS; it functions as co-surfactant to improve the emulsification of oil, meanwhile it also works as the oil phase and results in larger droplets. A significant reduction in droplet size was interestingly observed when fenofibrate was loaded in the vehicles, probably due to the surface activity of fenofibrate, promoting the self-emulsifying process. It was evident that drug precipitation during lipolysis was not affected by the level of co-solvent ethanol in the formulation, while it had pronounced impact on drug solubilization during the initial dispersion stage.     

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin

Abstract

Objective: Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability.

Methods: In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin.

Results: As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague–Dawley rats, the optimized SNEDDS of curcumin–phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS.

Conclusion: The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.     

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability.

Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol? 90 (oil), Cremophor^® RH40 (surfactant), and Transcutol^® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits.

Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t_max, AUC_(0–12), and AUC_(0–∞) at p?<?.05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product.

Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.     

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.     

Development of meloxicam in situ implant formulation by quality by design principle

Objective: The focus of this study was to develop and optimize in situ implant formulation of meloxicam by quality by design (QbD) principle for long-term management of musculoskeletal inflammatory disorders.

Methods: The formulation was optimized by Box–Behnken design with polylactide-co-glycolide (PLGA) level (X₁), N-methyl pyrrolidone level (X₂) and PLGA intrinsic viscosity (X₃) as the independent variables and initial burst release of drug (Y₁), cumulative release (Y₂), and dissolution efficiency (Y₃) as the dependent variables. The formulation was physicochemically characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD). Pharmacokinetic studies of the optimized formulation were performed on Sprague--Dawley rats.

Results: Y₁ was significantly affected by X₂ and X₃. Y₂ was affected by X₁ and X₃ while Y₃ was affected by all three independent variables employed in the formulations. Responses for the optimized formulation were in close agreement with the values predicted by the model. SEM photomicrographs indicated uniform gel formulation. No chemical interaction between the components of formulation was observed by FT-IR and meloxicam was found to be present in the amorphous form in the gel matrix as revealed by PXRD. The maximum plasma concentration (C_max), time to achieve C_max and area under plasma concentration curve were significantly different from those of the solution formulation used as the control. Plasma concentration of meloxicam was maintained above its IC₅₀ concentration required for COX-2 inhibition for 23 days.

Conclusion: Meloxicam in situ implant may provide long-term management of inflammatory conditions with improved patient compliance and better therapeutic index.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

Development of zolmitriptan transfersomes by Box–Behnken design for nasal delivery: in vitro and in vivo evaluation

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box–Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X₁), amount of drug (X₂) and amount of tween 80 (X₃). The dependent responses were vesicle size (Y₁), flexibility index (Y₂) and regression coefficient of drug release kinetics (Y₃). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74?mg of lecithin (X₁), 98.37?mg of zolmitriptan (X₂) and 32.2?mg of Tween 80 (X₃) and had vesicle size of 93.3?nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1?µm. The formulations were found to be physically stable upon storage at room temperature up to 2?months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist^®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.     

Optimization of methotrexate loaded niosomes by Box–Behnken design: an understanding of solvent effect and formulation variability

Dermal drug delivery system which localizes methotrexate (MTX) in the skin is advantageous in topical treatment of psoriasis. The aim of the current study was to understand dilution effects and formulation variability for the potential formation of niosomes from proniosome gels of MTX. Box–Behnken’s design was employed to prepare a series of MTX proniosome gels of Span 40, cholesterol (Chol-X₁) and Tween 20 (T20-X₂). Short chain alcohols (X₃), namely ethanol (Et), propylene glycol (Pg) and glycerol (G) were evaluated for their dilution effects on proniosomes. The responses investigated were niosomal vesicles size (Y₁), MTX entrapment efficiency percent (EE%-Y₂) and zeta potential (Y₃). MTX loaded niosomes were formed immediately upon hydration of the proniosome gels with the employed solvents. Addition of Pg resulted in a decrease of vesicular size from 534?nm to 420?nm as Chol percentage increased from 10% to 30%, respectively. In addition, increasing the hydrophilicity of the employed solvents was enhancing the resultant zeta potential. On the other hand, using Et in proniosomal gels would abolish Chol action to increase the zeta potential value and hence less stable niosomal dispersion was formed. The optimized formula of MTX loaded niosomes showed vesicle size of 480?nm, high EE% (55%) and zeta potential of –25.5?mV, at Chol and T20 concentrations of 30% and 23.6%, respectively, when G was employed as the solvent. Hence, G was the solvent of choice to prepare MTX proniosomal gels with a maintained stability and highest entrapment.     

Computational design strategy: an approach to enhancing the transdermal delivery of optimal capsaicin-loaded transinvasomes

Abstract

The aim of this study was to design and develop simultaneous optimal transinvasome formulations (OTV) to enhance the transdermal delivery of capsaicin. Using a central composite experimental design with duplicate centroids, 10 model formulations of transinvasomes (TVs) were demonstrated. The lipid compositions of the TV formulations were determined as formulation factors (X_n) and response variables (Y_n), respectively. TV formulations containing a constant concentration of phosphatidylcholine, cholesterol, 0.15% capsaicin, and various percentages of d-limonene (X₁) and cocamide diethanolamine (X₂) were prepared. The physicochemical characteristics, e.g. the vesicle size, size distribution, zeta potential, entrapment efficiency, and skin permeability, of the TV formulations were experimentally investigated. The relationship among the formulation factor, the response variables, and the OTV was predicted using Design Expert^® software. The accuracy and reliability of the OTV predicted using computer software were experimentally confirmed and investigated as an experimental transinvasome formulation (ETV). The results indicated that the skin permeability of the ETV was close to the OTV and was significantly higher than that of conventional liposomes and commercial products. The response surfaces estimated by the computer software were helpful in understanding the complicated relationship among the formulation factor, the response variables, and the stability of the TV formulation.     

D-Optimal Mixture Design: Optimization of Ternary Matrix Blends for Controlled Zero-Order Drug Release From Oral Dosage Forms

ABSTRACT

The objective of the present study was to develop a tablet formulation with a zero-order drug release profile based on a balanced blend of three matrix ingredients. To accomplish this goal, a 17-run, three-factor, two-level D-Optimal mixture design was employed to evaluate the effect of Polyox? (X₁), Carbopol® (X₂), and lactose (X₃) concentrations on the release rate of theophylline from the matrices. Tablets were prepared by direct compression and were subjected to an in vitro dissolution study in phosphate buffer at pH 7.2. Polynomial models were generated for the responses Y₄ (percent released in 8 h) and Y₆ (similarity factor or f₂). Fitted models were used to predict the composition of a formulation that would have a similar dissolution profile to an ideal zero-order release at a rate of 8.33% per hour. When tested, dissolution profile of the optimized formulation was comparable to the reference profile (f₂ was 74.2, and n [release exponent] was 0.9). This study demonstrated that a balanced blend of matrix ingredients could be used to attain a zero-order release profile. Optimization was feasible by the application of response surface methodology, which proved efficient in designing controlled-release dosage forms.