Development and Optimization of Self‐Nanoemulsifying Drug Delivery System with Enhanced Bioavailability by Box–Behnken Design and Desirability Function

The aim of our study was to characterize and optimize a self‐nanoemulsifying drug delivery system (SNEDDS) formulation by a three‐factor, three‐level Box–Behnken design (BBD) combined with a desirability function. The independent factors were the amounts of Capryol PGMC (X₁), Tween 20 (X₂), and Transcutol HP (X₃). The dependent variables were droplet size (Y₁), equilibrium solubility (Y₂), and cumulative percentage of drug released in 15 min (Y₃) from the SNEDDS formulation. The responses were fitted to a second‐order quadratic model and statistical validation of the fitted models was carried out by analysis of variance. Various response surface graphs and contour plots were constructed to understand the effects of different factor level combinations on the responses. The optimized SNEDDS formulation consisting of Capryol PGMC–Tween 20–Transcutol HP at proportions of 5:58.4:40 (w/w) was prepared and a comparison of the predicted values and experimental values was found to be in close agreement. Furthermore, an in vivo pharmacokinetic study of the optimized SNEDDS formulation showed a 2.2‐fold increase in relative oral bioavailability compared with that of the suspension. In conclusion, the BBD demonstrated its effectiveness in optimizing the SNEDDS formulation and in understanding the effects of formulation variables on the performance of SNEDDS.     

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet

Abstract

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5?mg VNP composed of Maisine? 35-1, Transcutol^® HP, and Cremophor^® EL was adsorbed on the solid carrier Aeroperl^®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel^®, HPMC-K4M, PVP-K30, and Lubripharm^®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 3²*2¹ full factorial design was adopted. The independent variables were: type of coating material (X₁), concentration of coating solution (X₂), and number of drills (X₃). The dependent variables included % release at 2?h (Y₁), at 4?h (Y₂), and at 8?h (Y₃). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry^® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.     

Formulation and optimization of alkaline extracted ispaghula husk microparticles of isoniazid – in vitro and in vivo assessment

Microparticles containing isoniazid were prepared by the emulsification internal ionic gelation method using a novel, alkaline extracted ispaghula husk as a wall forming material. A four-factor three-level Box–Behnken design was employed to study the effect of independent variables on dependent variables. Sodium alginate concentration (X₁), alkaline extraction of ispaghula husk (AEISP) concentration (X₂), concentration of cross-linking agents (X₃) and stirring speed (X₄) were four independent variables considered in the preparation of microparticles, while the particle size (Y₁) and entrapment efficiency (Y₂) were dependent variables. Optimized microparticles exhibited 83.43% drug entrapment and 51.53?µm particle size with 97.80% and 96.37% validity, respectively, at the following conditions – sodium alginate (3.55% w/v), alkaline extracted ispaghula husk (3.60% w/v), cross-linker concentration (7.82% w/v) and stirring speed (1200?rpm). The optimized formulation showed controlled drug release for more than 12?h by following Higuchi kinetics via non-Fickian diffusion. The gamma scintigraphy of the optimized formulation in Wistar rats showed that microparticles could be observed in the intestinal lumen after 1?h and were detectable in the intestine up to 12?h, with decreased percentage of radioactivity (t_1/2 of ^99mTc 4–5?h).     

Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization

Background: Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability.

Objective: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles.

Methods: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X₁) and surfactant (X₂) as the critical factor variables. The SNEDDS were optimized (OPT) using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats.

Results: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of K_a (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions.

Conclusion: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.     

Fabrication and evaluation of captopril modified-release oral formulation

The present research was directed towards fabrication of modified-release captopril oral formulation. A 3² full factorial design was employed for optimization using captopril to Compritol® ATO 888 ratio (X₁) and extragranular fraction of ethyl cellulose (X₂) as independent variables. The percentage drug released in 1?h (Y₁) and the time required to release 80% of the drug (Y₂) were selected as dependent variables. Eutectic blend of camphor and menthol was used as a solvent to facilitate the drug distribution in matrix. The optimized batch containing 50?mg captopril, 160?mg Compritol® ATO 888 and 220?mg ethyl cellulose was formulated by overlapping the contour plots of Y₁ and Y₂. The responses Y₁ and Y₂ of optimized batch were 25% and 520?min, respectively. The kinetics of drug release was best explained by Korsmeyer-Peppas model. The results of artificial neural network were superior in prediction power than the factorial design for both the responses (Y₁ and Y₂).     

Trans-resveratrol self-nano-emulsifying drug delivery system (SNEDDS) with enhanced bioavailability potential: optimization,pharmacokinetics and in situ single pass intestinal perfusion (SPIP) studies

Abstract

Trans-resveratrol (t-RVT) is a potent antioxidant. By virtue of extensive pre-systemic metabolism and existence of enterohepatic recirculation, t-RVT bioavailability is almost zero. The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides (LCTs) of t-RVT in an attempt to circumvent such obstacles. Equilibrium solubility studies indicated the choice of Lauroglycol FCC as lipid, and of Labrasol and Transcutol P as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X₁) and surfactant (X₂) as the critical factor variables. The SNEDDS were optimized using 3² central composite design (CCD) and the optimized formulation (OPT) located using overlay plot. The nanometer size range and high negative values of zeta potential depicted non-coalescent nature of the SNEDDS. Optimized formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT. Augmentation in the values of K_a (3.29-fold) and AUC (4.31-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT compared with pure drug. In situ perfusion (SPIP) studies in Wistar rats construed remarkable enhancement in the absorptivity and permeability parameters of SNEDDS vis-à-vis the pure drug. Successful establishment of level A of in vitro/in vivo correlation substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. The present study, therefore, reports the successful development of SNEDDS with distinctly enhanced bioavailability of t-RVT.     

Optimization and evaluation of lyophilized fenofibrate nanoparticles with enhanced oral bioavailability and efficacy

Abstract

The objective of this study was to enhance physiochemical properties as well as oral bioavailability of the poorly water soluble drug fenofibrate (FB), through preparation of amorphous solid dispersions (ASDs). ASDs were prepared via freeze drying using polyvinylpyrrolidone (PVP) K30 and poloxamer 188 as hydrophilic carriers. Formulations were optimized by 3² full factorial design (FFD) with PVP-K30 level (X₁) and poloxamer 188 level (X₂) as independent variables and particle size (Y₁), zeta potential (Y₂), drug content (Y₃) and dissolution rate (T90, [Y₄]) as dependent variables. Optimized FB nanoparticles were physicochemically evaluated and formulated into lyophilized sublingual tablets. Pharmacokinetic, pharmacodynamics and histological finding of optimized formulation were performed on rabbits. Y₁ and Y₄ were significantly affected by independent variables while Y₂ and Y₃ were not affected. Physicochemical characterization showed the drug was in amorphous state, nanometer range and pharmacophore of FB was preserved. Administration of optimized FB tablets to rabbits with fatty liver led to significant reduction (p?<?0.001) in serum lipids. Moreover, histological analysis of liver specimens confirmed the improved efficacy in animals with fatty liver. In this study, we confirmed that ASDs of FB had beneficial effects on managing fatty liver and serum lipids level in hyperlipidemic rabbits.     

Quality by design: understanding the formulation variables and optimization of metformin hydrochloride 750?mg sustained release tablet by Box–Behnken design

This study examined the formulation variables and optimization of a sustained-release metformin hydrochloride 750?mg tablet using a combination of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP K30), and glyceryl behenate with a computer optimization technique based on a response surface methodology (RSM) utilizing a polynomial equation. A three-factor, three-level Box?CBehnken design was used for the optimization procedure with the contents of HPMC (X ₁), PVP K30 (X ₂), and glyceryl behenate (X ₃) as independent variables. The drug release percentages at 1, 3, and 10?h were the target responses and were restricted to 25?C35?% (Y ₁), 55?C65?% (Y ₂), and 85?C100?% (Y ₃), respectively. The quadratic model fit the data well and the resulting equation was used to predict the responses in the optimal region. The optimized formulation was achieved with 165?mg HPMC, 40?mg PVP K30, and 22.5?mg glyceryl behenate, and the observed responses of the optimized formulation were very close to the values predicted using the RSM optimization technique. Furthermore, the drug release rate and dissolution curve shape of the optimized formulation were similar to those of the commercial product.     

Development and optimization of boswellic acid-loaded proniosomal gel

Context: Boswellic acids (BAs) are isolated from oleo gum of Boswellia serrata and are mainly used as potential anti-inflammatory, hypolipidemic, immunomodulatory, and antitumor agents. Pharmacokinetic investigations of BAs uncover its poor bioavailability through digestive system thus creates a need for improved therapeutic responses which can possibly be achieved by developing formulations through novel delivery system.

Objective: Present study was conducted to design topical BA-loaded proniosomal gel for the management of inflammatory disorders with enhanced bioavailability.

Materials and methods: Nonionic surfactant vesicles were prepared using the coacervation phase separation method. A central composite design was employed to statistically optimize formulation variables using Design-Expert software. Three independent variables were evaluated: amount of surfactant (X₁), amount of soya lecithin (X₂), and amount of cholesterol (X₃). The encapsulation efficiency percentage (Y₁) and particle size (Y₂) were selected as dependent variables.

Results and discussion: The optimum formulation (F10) displayed spherical bi-layered vesicles under transmission electron microscopy with optimum particle size of 707.9?nm and high entrapment efficiency as 98.52%. In vitro skin permeation study demonstrated the most sustained release of 84.83?±?0.153?mg/cm² in 24?h. Anti-inflammatory activity of the gel showed a significant (p < 0.001) higher percentage inhibition as compared to the marketed gel at the same dose.

Conclusion: The present study exhibited that BA-loaded proniosomal gel was better in terms of absorption, bioavailability, and release kinetics.     

Optimization of Formulation Components and Characterization of Large Respirable Powders Containing High Therapeutic Payload

The aim of the study was to optimize and characterize high therapeutic payload large respirable powders prepared by spray-drying technique for maximum fine particle fraction with minimum quantities of excipients. Influence of formulation components was optimized by a three-factor, five-level central composite design having different proportions of L-leucine (X₁), tobramycin sulfate (X₂), and poloxamer-188 (X₃) as the independent variables and fine particle fraction as a response variable (Y). Large respirable powders were characterized for particle size, size distribution, moisture, crystallinity, and morphology. In vitro aerosol performance of powders was determined by an eight-stage Andersen cascade impactor using the Rotahaler. Mathematical model elucidated for Y was Y = 56.2068 + 5.7481 X₁ - 3.0531 X₂ + 0.8468 X₃ + 1.1737 X₁ X₂ ? 0.5012 X₁ X₃ ? 0.7412 X₂ X₃ ? 0.7149 X₁² ? 1.9212 X₂² ? 1.6187X₃². The component of greatest influence on product performance (response variable) was found to be L-leucine. Lack of fit was not significant (p = 0.08), and regression equation predicted response for Y was in reasonably good agreement with experimental values (p = 0.01; R² = 0.92). The optimal model predicted with a fine particle fraction of 62.8 ± 2.6% with X₁, X₂, X₃ levels of 20, 45.71, and 5.51 respectively. Large respirable powders with TB load of 45.7% w/w were prepared; they had smooth surface texture, dimpled spherical shape, roundness value close to 1(1.048 ± 0.032) and were found to possess bulk tap densities of 0.04 g/cc, geometric particle sizes of 6–7 μm, and emitted dose of 92%. The results of the studies suggest that in vitro aerosol performance was affected significantly by small and deliberate change of specific formulation components and its proportions. It may be concluded that appropriate type and proportion of excipients is necessary to obtain maximum fine particle fraction of large respirable powders containing high therapeutic payloads.     

星点设计法优化盐酸小檗碱树脂复合胃黏附给药系统的研究

本文以离子交换树脂(IER)作为载体吸附盐酸小檗碱，通过包衣将其制成胃黏附微囊，并以胃黏附微囊的载药量，胃滞留时间和体外释药时间作为评价指标，对处方进行优化。考察不同型号载体与不同浓度、温度和pH值的药物溶液对IER载药量的影响；以卡伯姆934与IER的比例(X₁)、丙烯酸树脂(Eudragit)与IER的比例(X₂)、Eudragit RL与Eudragit RS的比例(X₃)为自变量，以制剂累计释放量85%的时间点(Y₁)、制剂在大鼠胃体外黏附滞留百分比(Y₂)为因变量，通过星点设计—效应面法优化胃黏附包衣处方。优化后载药工艺为在37 ℃、pH 5左右条件下，用IRP88离子交换树脂对1.0 mg·mL^-1盐酸小檗碱溶液载药；优化后的包衣液组成为X₁=0.75、 X₂=0.9、 X₃=0.6，所得制剂单位质量载药量高，可在300 min左右达到累计释放总量的85%，同时在所设计条件范围内胃黏附作用最强。     

Response Surface Methodology to Investigate the Iontophoretic Delivery of Tacrine Hydrochloride

No HeadingPurpose. The objective of this work was to apply response surface approach to investigate the main and interaction effects of delivery parameters for iontophoretic delivery of tacrine HCl in vitro.Methods. Iontophoresis was used to deliver tacrine HCl across rat skin. Experiments were performed according to Box-Behnken design to evaluate effects of drug concentration (X₁), current density (X₂), and donor buffer molarity (X₃) on cumulative drug delivered in 24 h (Y₁), 6 h (Y₂), iontophoretic flux (Y₃), and post-iontophoretic flux (Y₄).Results. Mathematical model for Y₁ was Y₁ = 0.653 + 0.163 * X₁ + 0.456 * X₂ – 0.156 * X₃ + 0.190 * X₁X₂ + 0.139* X₃X₃. Response surface plot indicated that at low level of X₂ (0.1mA/cm²), X₁ had little effect on Y₁. However, at high level of X₂ (0.5 mA/cm²), Y₁ significantly increased from 0.75 mg/cm² to 1.46 mg/cm² when X₁ increased from 1% to 9%. Regression equations predicted responses for Y₁ to Y₄, for optimal formulation, which were in reasonably good agreement with experimental values.Conclusions. Experimental design methodology revealed an interaction between drug concentration and current density, which would have been difficult to predict from one factor at a time classic experimental approach.     

Formulation Optimization of Propranolol Hydrochloride Microcapsules Employing Central Composite Design

A central composite design was employed to produce microcapsules of propranolol hydrochloride by o/o emulsion solvent evaporation technique using a mixture of cellulose acetate butyrate as coat material and span-80 as an emulsifier. The effect of formulation variables namely levels of cellulose acetate butyrate (X₁) and percentage of Span-80 (X₂) on encapsulation efficiency (Y₁), drug release at the end of 1.5 h (Y₂), 4 h (Y₃), 8 h (Y₄), 14 h (Y₅), and 24 h (Y₆) were evaluated using the F test. Mathematical models containing only the significant terms were generated for each response parameter using multiple linear regression analysis and analysis of variance. Both the formulation variables exerted a significant influence (P <0.05) on Y₁ whereas the cellulose acetate butyrate level emerged as the lone factor which significantly influenced the other response parameters. Numerical optimization using desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ for the optimized formulation was found to be 92.86±1.56% w/w, 29.58±1.22%, 48.56±2.56%, 60.85±2.35%, 76.23±3.16% and 95.12±2.41%, respectively which were in close agreement with those predicted by the mathematical models. The drug release from microcapsules followed first order kinetics and was characterized by Higuchi diffusion model. The optimized microcapsule formulation developed was found to comply with the USP drug release test-1 for extended release propranolol hydrochloride capsules.     

Formulation development of novel in situ nanoemulgel (NEG) of ketoprofen for the treatment of periodontitis

The aim of the present study was to formulate and evaluate in situ gelling syringeable nanoemulgels (NEGs) of ketoprofen for periodontal delivery. Application of 3-factor 3-level design was employed using the Box–Behnken experimental design for the optimization of nanoemulsion using three independent variables such as percent concentration (v/v) of oil (X₁), S_mix (mixture of surfactant and cosurfactant) (X₂) and water (X₃); while the particle size (nm) (Y₁), polydispersity index (Y₂) and zeta potential (mV) (Y₃) were used as dependent variables. The NEG was evaluated based on their drug content, pH measurement, mucoadhesion on the goat buccal mucosa, syringeability and inverted sol-gel transition temperature. The drug release data were analyzed for curve fitting based on the Korsmeyer–Peppas law, and the n-values of optimized A5 and A8 formulations were found 0.3721 and 0.3932, respectively, confirmed that both the formulations followed pseudo Fickian diffusion (n?<?0.43). The formulation A8 with the optimal drug release was identified as the best NEG formulation. Results of rheological, mucoadhesion and syringeability studies showed the suitability of desired sol-gel property for periodontal drug delivery. The Herschel–Bulkley model was the best fit model to explain the flow behavior of optimized formulation. Using the HET-CAM method, significantly lower in vitro toxicity was indicated the suitability of developed NEG for intra-pocket delivery.     

Understanding the Impact of Multi-factorial Composition on Efficient Loading of the Stable Ketoprofen Nanoparticles on Orodispersible Films Using Box-Behnken Design

The purpose of the present study was to prepare Orodispersible films (ODFs) loaded with ketoprofen nanoparticles (KT-NP). The Box-Behnken design was constructed in developing and optimizing the KTF-NP-ODFs. The effect of independent variables: Soluplus® concentration (X₁, stabilizer), Tween 80 concentration (X₂, surfactant), and KTF concentration (X₃, drug) were studied on the dependent variables: particle size (PS, Y₁), zeta potential (ZP, Y₂), and the polydispersity index (PDI, Y₃) of the NPs, as well as on the tensile strength (TS, Y₄) and permeability coefficient (PC, Y₅) of the KTF-NP-ODFs. Hydroxypropyl methylcellulose (HPMC E15) and polyethylene glycol (PEG 400) were used as the film former polymer and plasticizer, respectively, and their concentrations were kept constant for all formulations. KTF-NPs were prepared by antisolvent precipitation technology. This was followed by the addition of HPMC E15 and PEG 400 to prepare the ODFs using the solvent-casting method. The PS, PDI, and ZP for all the formulations were found in the range of 94 nm to 350 nm, 0.09 to 0.438, and -21.83 mV to -8.03 mV, respectively. The TS and PC of the prepared KTF-NP-ODFs were found between 1.21 MPa to 3.93 MPa and 3.12 × 10^?4 cm/h to 34.23 × 10^?4 cm/h, respectively. The amorphous nature of the KTF-NP in the ODFs was confirmed by the absence of characteristic crystalline peaks and endothermic events of KTF in X-ray diffraction (XRD) and modulated differential scanning calorimetry (mDSC), respectively. The optimized formulation showed ? 4 times higher permeability as compared to the pure KTF. In addition, the dissolution of pure KTF and the optimized KTF-NP-ODF in pH 1.2 at the end of 60 min was found to be ? 30% and ? 95%, respectively. Conclusively, KTF-NP-ODFs can be a promising drug delivery system to counter the issues related to dysphagia and bypass the common side effects, such as the gastric irritation associated with NSAIDs like KTF.     

Quality by design (QbD) approach for design and development of drug-device combination products: a case study on flunisolide nasal spray

Abstract

The objective of the present study was to design and develop drug-device combination product in particular flunisolide nasal spray (FNS) using quality by design (QbD) approach. Quality target product profile (QTPP) of FNS was defined and critical quality attributes (CQAs), i.e. viscosity (cp) (Y₁) and D₅₀ droplet size distribution (DSD) (μm) (Y₂) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tools. Plackett–Burman and Box–Behnken designs were used for screening the significant factors and optimizing the variables range, respectively. It was observed that viscosity (cp) (Y₁) was significantly impacted by formulation variables X₁: propylene glycol (PG) (%) and X₂: polyethylene glycol (PEG) 3350 (%), while D₅₀ DSD (μm) (Y₂) was significantly impacted by formulation variables X₁: PG (%), X₂: PEG 3350 (%) and device variable X₈: delivery volume (μl). A design space plot within which the CQAs remained unchanged was established at laboratory scale. In conclusion, this study demonstrated how QbD based development approach can be applied to the development of drug-device combination products with enhanced understanding of the impact of formulation, process and device variables on CQAs of drug-device combination products.     

α-Tocopherol as functional excipient for resveratrol and coenzyme Q10-loaded SNEDDS for improved bioavailability and prophylaxis of breast cancer

The present study evaluates the prophylactic efficacy of α-tocopherol (α-TOH), resveratrol (RES), and coenzyme Q10 (CoQ10) co-loaded self-nanoemulsifying drug delivery system (α-TOH-RES-CoQ10 SNEDDS) in 7,12-Dimethylbenz[a]anthracene (DMBA) induced breast cancer model. SNEDDS formulation components were rationally selected and optimized for maximum drug loading by applying the design of experiments and further evaluated for stability in simulated gastrointestinal fluids, functional stability of antioxidants, in vitro release, Caco-2 cell uptake, oral bioavailability and prophylactic anticancer activity. The SNEDDS demonstrated excellent stability in stimulated gastrointestinal fluids. The functional activity of antioxidants was confirmed by 2,2-diphenylpicrylhydrazyl (DPPH) scavenging assay wherein significantly (p?>?.05) higher antioxidant activity was observed in case of SNEDDS as compared with free antioxidants. Coumarin 6 (C-6)-loaded SNEDDS formulation demonstrated remarkably higher Caco-2 cell uptake in comparison with free C-6, indicative of efficient internalization of sub-micron SNEDDS droplets by Caco-2 cells. In line with Caco-2 cell uptake observations, α-TOH-RES-CoQ10-SNEDDS showed ～2.30- and ～3.64-fold increase in the AUC_0?∞ values of RES and CoQ10 in comparison with free antioxidants. Significantly lower (p?<?.001) tumor volume (～327?mm³) was found in case of animals treated with α-TOH-RES-CoQ10-SNEDDS in comparison with free antioxidant combination (～1070?mm³) and DMBA control (～1540?mm³) groups. Conclusively, the proposed strategy posed great potential in improving the prophylactic activity of antioxidants and hold promise for further exploration.     

Optimization of controlled release nanoparticle formulation of verapamil hydrochloride using artificial neural networks with genetic algorithm and response surface methodology

This study was performed to optimize the formulation of polymer–lipid hybrid nanoparticles (PLN) for the delivery of an ionic water-soluble drug, verapamil hydrochloride (VRP) and to investigate the roles of formulation factors. Modeling and optimization were conducted based on a spherical central composite design. Three formulation factors, i.e., weight ratio of drug to lipid (X₁), and concentrations of Tween 80 (X₂) and Pluronic F68 (X₃), were chosen as independent variables. Drug loading efficiency (Y₁) and mean particle size (Y₂) of PLN were selected as dependent variables. The predictive performance of artificial neural networks (ANN) and the response surface methodology (RSM) were compared. As ANN was found to exhibit better recognition and generalization capability over RSM, multi-objective optimization of PLN was then conducted based upon the validated ANN models and continuous genetic algorithms (GA). The optimal PLN possess a high drug loading efficiency (92.4%, w/w) and a small mean particle size (∼100 nm). The predicted response variables matched well with the observed results. The three formulation factors exhibited different effects on the properties of PLN. ANN in coordination with continuous GA represent an effective and efficient approach to optimize the PLN formulation of VRP with desired properties.     

Quality by design approach to understand the process of optimization of iloperidone nanostructured lipid carriers for oral bioavailability enhancement

Abstract

Context: The current work was carried out by exploring the principles of quality by design approach to develop an optimized nanostructured lipid carrier (NLC) formulation of poorly water soluble active iloperidone (ILO) through systematic statistical study. The potential of NLC for improving the oral bioavailability of ILO was also evaluated.

Objective: To understand the effect of formulation variables (critical parameters) on the performance characteristics (critical quality attributes) of NLC.

Materials and methods: A 3-factor, 3-level Box–Behnken factorial design was explored to predict the responses such as particle size (Y₁) and % entrapment efficiency (EE) (Y₂) when concentration of lipid (X₁), concentration of drug (X₂) and concentration of surfactant (X₃) were selected as independent variables.

Results and discussion: Particle size analysis revealed that all the batches were within the nanometer range. The % EE was found to be between 63% and 96%. In-vitro release study demonstrated sustained release profile of ILO NLC. The pharmacokinetic study in Wistar rats over the period of 24?h demonstrated 8.30-fold increase in oral bioavailability of ILO NLC as compared with ILO pure drug suspension.

Conclusion: The NLC formulation remarkably improved the oral bioavailability of ILO and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs.     

Chitosan microparticle preparation for controlled drug release by response surface methodology

The objectives were to investigate the effects of formulation variables on the release of drug and to optimize the formulation of chitosan microparticles loaded with drug for controlled release using response surface methodology. Chitosan microparticles were prepared by dropping a chitosan solution into sodium tripolyphosphate (TPP) through ionic cross-linking. The release behaviour of felodipine as a model drug was affected by preparation variables. A central composite design was used to evaluate and optimize the effect of preparation variables, chitosan concentration (X₁), the pH of the TPP solution (X₂) and cross-linking time (X₃) on the cumulative per cent drug release (Y) in 24 h. Chitosan concentration and cross-linking time affected negatively the release of felodipine, while the pH of the TPP did so positively and was the highest influential factor. The optimum rate of drug release, 100% in 24 h, was achieved at 1.8% chitosan concentration, a pH 8.7 for the TPP solution and 9.7 min cross-linking time.