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This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets) as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1), swelling pressure of the superdisintegrant (X2), and the surface area of Aerosil as a glidant (X3). Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for preand post-compression characteristics. The prepared ODmini- tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2) and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

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. [ABSTRACT FROM AUTHOR]

This study aimed at employing Plackett–Burman design in screening formulation variables that affect quality of matrix-type simvastatin (SMV) transdermal film. To achieve this goal, 12 formulations were prepared by casting method. The investigated variables were Eudragit RL percentage, polymer mixture percentage, plasticizer type, plasticizer percentage, enhancer type, enhancer percentage and dichloromethane fraction in organic phase. The films were evaluated for physicochemical properties andex vivoSMV permeation. SMV initial, delayed flux, diffusivity and permeability coefficient were calculated on the delayed flux phase with constraint to minimize the initial flux and approaching steady-state flux. The obtained results revealed flat films with homogeneous distribution of SMV within the films. Thickness values changed from 65 to 180 μm by changing the factors’ combinations. Most of the permeation profiles showed sustained release feature with fast permeation phase followed by slow phase. Analysis of variance (ANOVA) showed significant effects (p < 0.05) of the investigated variables on the responses with Prob > Fvalues of 0.0147, 0.0814, 0.0063 and 0.0142 for the initial and delayed fluxes, permeability coefficients and diffusivities, respectively. The findings of screening study showed the importance of the significant variables to be scaled up for full optimization study as a promising alternative drug delivery system. [ABSTRACT FROM AUTHOR]

Through the integration of orthogonal central composite design and desirability function, this work aimed to explore the potential of quality by design in understanding the formulation of phospholipid-stabilized tacrolimus nanodispersions by microfluidization. The influence of homogenization pressure, microfluidization time and phospholipid concentration (X1–X3) on nanodispersion performance was studied. Nanodispersions were characterized by differential scanning calorimetric (DSC), X-ray diffractometer (XRD) and Fourier transform infrared (FTIR) analysis. Moreover, masking the unpalatable taste of tacrolimus and reducing the gastric complications were also evaluated. FTIR analysis indicated its interaction with phospholipid. DSC and XRD analysis revealed the amorphous transformation of tacrolimus within nanodispersions. The dissolution was enhanced by 35 folds and 15 folds after 0.5 and 2 h, respectively. Maximum tacrolimus content, yield, polydispersity index, percentages dissolved after 0.5 and 2 h of 99.3%, 100%, 0.864, 39.7% and 95.3%, respectively, with particle size of 160 nm were obtained atX1,X2 andX3 values of 20 000 psi, 6 min and 30%, respectively. The Euclidean distance values demonstrated masking the unpalatable taste and taste perversion to stimuli of tacrolimus in its optimized nanodispersion. Moreover, the ulcerative indices following raw tacrolimus and its optimized nanodispersion oral administration were 6.73 and 2.45, respectively, to indicate that nanodispersion was significantly less irritating to the gastric mucosa. [ABSTRACT FROM PUBLISHER]

Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HI V drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/acetonitrile pH 7.4 (95:5 v/v). The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 µL with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtainedresult showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that calibration curves were linear with r² > 0.9995 over the analytical range of 1-10 µg/mL. Inter- and intraday accuracy and precision values ranged from 95% to 101% and 0.3% to 2.6%, respectively. The method was determined to be specific and robust. Regarding the potential of the prepared vectors to potentiate tenofovir permeability through the Caco-2 model, a 10-fold increase in tenofovir apparent permeability was observed compared to its oral solution. In conclusion, this novel and validated method was successfully applied to characterize both in vitro encapsulation efficiency and Caco-2 permeability transport for the pharmaceutical assessment of novel tenofovir formulations. [ABSTRACT FROM AUTHOR]

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm withn = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation. [ABSTRACT FROM PUBLISHER]

Efficacy of central nervous system-acting medications is limited by its localization and ability to cross the blood–brain barrier (BBB); therefore, the crux is in designing delivery systems targeted to cross the BBB. Toward this objective, this study proposed pegylated and glycosylated citalopram hydrobromide (Cit-HBr) liposomes as a delivery approach for brain targeting. The multicomponent liposomes were evaluated for drug encapsulation, vesicular size, size distribution, conductivity and drug release characteristics. Moreover, the interaction among the employed components was evaluated by Fourier transform infrared, differential scanning calorimetric and X-ray diffraction analysis. Through a systematic screening design of formulation and process variables in the optimization phase, an improvement of Cit-HBr loading, fine vesicular size with narrow size distribution, greater stability and sustained release features were achieved. The compatibility studies unveiled a significant interaction between Cit-HBr and dicetyl phosphate to control drug encapsulation and release properties. The optimization process showed a minimal range of design space to achieve the preset desirability; more precisely dicetyl phosphate, polyethylene glycol, N-acetyl glucosamine and freeze–thaw cycles of 3%, 5%, 4% and 2 cycles, respectively, were used. Using brain endothelial cell models, the optimized formulations showed an acceptable cell viability with preserved monolayer integrity and an enhanced flux and permeability. Thus, this study has proposed an optimized pegylated and glycosylated vector that is a promising step for brain targeting. [ABSTRACT FROM AUTHOR]

The aim of the current study was to investigate the effects of formulation parameters on the disintegration, water absorption and dissolution characteristics of cyclosporine A (CyA) loaded self-emulsifying drug delivery system (SEDDS) in an orodispersible compacts. Its taste masking efficiency was also attempted using an electronic tongue. ODTs were prepared by freeze-drying liquid SEDDS and synthetic amorphous silica suspension followed by direct compression. The influences of the compression forces and super-disintegrant were evaluated to optimize tablet characteristics. The liquid SEDDS was characterized by vesicular size of 48.5 nm, polydispersity index of 0.95, turbidity of 40.7 NTU and rapid CyA dissolution and emulsification rate. The results of micrometric studies demonstrated an acceptable flow, hardness and friability to indicate good mechanical strength of ODTs. The interaction and Pareto charts demonstrated a greater effect of low compression force to increase the porosity and facilitate the disintegration rather than the deformation action of the super-disintegrant. Super-disintegrant level was the most important factor affecting the dissolution parameter followed by the compression force then their interaction effect. Moreover, as indicated by Euclidean distance values and discrimination indices, the unpalatable taste and aversion taste of CyA to stimuli were masked in its optimized SEDDS incorporated ODTs. [ABSTRACT FROM AUTHOR]

The aim was to investigate the potential of proliposomes to improve the permeability of tenofovir, anti-HIV, for oral delivery. Tenofovir was incorporated into phosphatidylcholine proliposomes and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using aqueous drug solutions as reference. Five batches of proliposomes were prepared with different stearylamine levels and characterized in terms of vesicular morphology, drug encapsulation efficiency (EEF), drug leakage, vesicular sizing and surface charges. Cytotoxicity of the reconstituted liposomes was evaluated by the MTT assay. The obtained results showed that increasing the incorporated percentage of stearylamine led to an increase in drug encapsulation, a slower drug leakage and larger liposomes formed. Compared to the drug solutions at corresponding concentrations, the proposed formulations showed a positive relationship ( R2 = 0.9756) for the influence of increasing the stearylamine percentage on reduction of mitochondrial activity. Regarding the drug permeability, enhancements of apparent permeability by 16.5- and 5.2-folds were observed for proliposomes formulations with 5% and 15% stearylamine, respectively. A good correlation was observed between the Caco-2 and dialysis models that might indicate passive diffusion as well as paracellular transport as suggested mechanisms for drug absorption. Cationic proliposomes offered a potential formulation to improve the permeation of tenofovir. [ABSTRACT FROM AUTHOR]

The development of rapid disintegrating tablets (RDT) requires the use of highly soluble components to support the intended use of these products. In an attempt to prepare RDT of indomethacin, its solid dispersion with polyvinyl pyrrolidone K25 (PVP) was incorporated in a fast disintegrating matrix. Drug polymer interactions were investigated using X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Indomethacin 1:1 solid dispersion with PVP was used to prepare its RDT. Two factors at 3 levels full factorial design were employed as a statistical approach to optimize the amount of superdisintegrant (Ac-di-sol) and hardness value regarding the desired disintegration and release characteristics. Drug to carrier ratio was the controlling factor for dissolution improvement. XRD and FTIR data revealed a remarkable interaction between the drug and the carrier that might be responsible for the dissolution enhancement. Multiple regression analysis revealed a significant effect of the polynomial terms for obtaining rapid disintegrating tablets. It was inferred that the hardness value is the most important factor controlling the disintegration time and the release characteristics. In conclusion, this study demonstrated that quality by design (QbD) is a potential paradigm for understanding the quality and optimizing the formulation of RDT containing indomethacin solid dispersion. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to develop solid dispersion (SD) formulation of cyclosporine (CyA) using polyethylene glycol (PEG-6000) to enhance its dissolution rate followed by nondestructive method for the prediction of both drug and carrier. SD formulations were prepared by varying the ratio of CyA and PEG-6000 by solvent evaporation technique and characterized by dissolution, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), powder X-ray diffraction (PXRD), near infrared (NIR) and near infrared chemical imaging (NIR-CI). Dissolution data revealed enhanced dissolution of CyA when compared with pure CyA. DSC results showed that the crystallinity of PEG-6000 has decreased as indicated by decrease in the enthalpy of fusion and melting peak in the formulations. FTIR data demonstrated no chemical interaction between drug and carrier. The surface morphology of SD formulations was similar to PEG-6000 particle. NIR-CI disclosed homogeneity of SD matrix as indicated by symmetrical histograms with smaller values of skewness. Similar to NIR, a multivariate peak evaluation with principal component analysis and partial least square (PLS) were carried out with PXRD spectral data. PLS models with both techniques showed good correlation coefficient and smaller value of root mean square of errors. The accuracy of model for predicting CyA and PEG-6000 in NIR and PXRD data were 5.22%, 5.35%, 5.27%, and 2.10%, respectively. In summary, chemometric applications of non-destructive method sensors provided a valuable means of characterization and estimation of drug and carrier in the novel formulations. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess drug contents in poly(dl-lactide-co-glycolide) (PLGA) based nanoparticles of a model protein, cyclosporine A (CyA). A 6-factors 12-runs designed set of experiments with Plackett–Burman (PB) screening was applied in order to examine the effects of drug loading (X1), polymer loading (X2), emulsifier concentration (X3), stirring rate (X4), type of organic solvent (X5), and ratio of organic to aqueous phases' volumes (X6), on drug entrapment efficiency (EFF). After omitting the factors with nonsignificant influences on EFF, a reduced mathematical relationship, EFF = 48.34 + 7.3X1 – 29.95X3, was obtained to explain the effect of the significant factors on EFF. Using two different sets for calibration and validation, the developed NIR calibration model was able to assess CyA contents within the 12 PB formulations. NIR spectral imaging was capable of clearly distinguishing the 12 formulations, both qualitatively and quantitatively. A good correlation with a coefficient of 0.9727 was obtained for constructing a quantile-quantile plot for the actual drug loading percentage and the % standard deviation obtained for the drug loading prediction using the hyperspectral images. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1180–1192, 2010 [ABSTRACT FROM AUTHOR]

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6–11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety. [ABSTRACT FROM AUTHOR]

The primary objective of the research study is to investigate Glucose (GLUT) transporter targeting of the drug (Citalopram-Hbr) for increased permeability across the Blood-Brain Barrier (BBB). The current study reports the development, physicochemical characterization, cytotoxicity analysis and in-vitro BBB permeability assessment of the Citalopram-Hbr liposomal formulations. Rat Primary Brain Microvascular Endothelial Cells (RPBECs) were used for cytotoxicity analysis and drug permeability testing. Five N-Acetyl Glucosamine (NAG) coated PEGylated multilamellar liposomal formulations were prepared and tested. Permeability of the liposomal formulations was evaluated in RPBECs monolayer. The particle size of the formulations ranged from 13 to 4259 nm. Entrapment efficiency was 50-75%. Cytotoxicity analysis indicated viability (>90%) for all five formulations (0.3–1.25 mg/ml). Apparent drug permeability (Papp) of the formulations ranged from 5.01 × 104 to 15 × 104 cm/min. The study demonstrated successful preparation of NAG-coated PEGylated multilamellar liposomal formulations with high drug entrapment efficiency. Cytotoxicity data indicated that the formulations were well tolerated by the cells up to a concentration of 1.25 mg/ml. Transport study data demonstrated that RPBMECs monolayers can be employed as a robust screening tool for future drug transport studies targeting GLUT transporter on the BBB. The drug permeability values provide a promising preliminarily proof that NAG-coated liposomal formulations can be an effective tool for BBB-GLUT transporter targeting. [ABSTRACT FROM AUTHOR]

[Display omitted] For proportionally formulated intermediate strengths of a topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. The current study aims to assess the proportionality of tretinoin release rates across multiple strengths of tretinoin topical gels when manufactured using two different methods to understand the impact of formulation design on drug product microstructure and tretinoin release rate. Two groups of tretinoin gels of 0.04 %, 0.06 %, 0.08 % and 0.1 % strengths were manufactured. Gels in Group I were prepared by incorporating 4–10 % g/g of 1 % w/w tretinoin-loaded microparticles into a gel base. Gels in Group II were manufactured using 10 % g/g of the microparticles that were loaded with increasing amounts (0.4–1 % w/w) of tretinoin. The two groups of gels were characterized by evaluating microstructure using a polarized microscope, rheology using an oscillatory rheometer, and drug release using Vison® Microette™ Hanson vertical diffusion cells. The microscopic images were used to discriminate between the two groups of gels based on the abundance of microparticles in the gel matrix observed in the images. This abundance increased across gels of Group I and was similar across gels of Group II. The rheology parameters, namely viscosity at a shear rate of 10 s−1, shear thinning rate, storage, and loss modulus, increased across gels of Group I, and were not significantly different across gels of Group II. The release rate of tretinoin from the drug products was proportional to the nominal strength of the drug product in both Group I and Group II, with a correlation coefficient of 0.95 in each case, although the absolute release rates differed. Overall, changing the formulation design of tretinoin topical gels containing porous microparticles may change the physicochemical and structural properties, as well as the drug release rate of the product. Further, keeping the formulation design consistent across all strengths of microparticle-based topical gels is important to achieve proportional release rates across multiple strengths of a given drug product. [ABSTRACT FROM AUTHOR]

Graphical abstract Experimental setup of in vitro lipolysis testing of nimodipine loaded SEDDS; and effect of formulation variables on lipolysis responses. Abstract The objective of the current study was to optimize for the first time the formulation variables of self-emulsified drug delivery system (SEDDS) based on drug solubilization during lipolysis under a biorelevant condition of digestion such as lipase activity, temperature, pH, fed-fasting state, etc. Nimodipine (ND), a BCS class II, was used as a model drug to prepare the SEDDS. Various oils, surfactants, and cosurfactants were screened for their solubilization potential of ND. Area of self-emulsification was identified using various ternary phase diagrams. Box-Behnken design was employed to investigate effects of formulation variables on various dispersion, emulsification, and lipolysis characteristics of SEDDS. Among 26 candidate formulations, highest ND solubility of 12.72%, 11.09% and 11.2% w/w were obtained in peppermint oil as the oily phase, Cremphor EL as the surfactant and PEG400 as the cosurfactant, respectively. Cremphor EL was the most significant factor to decrease SEDDS droplet size to 30.16 nm. On the other hand, increasing the oil concentration was found to significantly increase the polydispersity index up to 0.31. A faster emulsification rate of 3.37%/min was obtained at higher Cremphor El/PEG 400 ratio. Increasing the percentage of lipid components of SEDDS resulted in lower rate of lipolysis with less recovery of ND in aqueous phase. Under fed state, percentage of lipolysis of optimized formulation was less than that observed under fasted state. However, lowest rate and percentage of lipolysis were observed in lipolysis media without phospholipids and bile salts. Hence, this study demonstrated that in vitro lipolysis could be used as a surrogate approach to distinguish effects of formulation variables on fate of SEDDS upon digestion. Further studies are in progress to identify the lipolytic products of the employed excipients by LC-MS/MS. [ABSTRACT FROM AUTHOR]

Critical physicochemical characteristics of microparticles in topical drug products. [Display omitted] Drug release from microparticle-based topical gels may affect their bioavailability, safety and efficacy. This work sought to elucidate spatial distribution of the drug within the microparticle matrix and how this impacts the product's critical performance attributes. The purpose of this research was to inform the development of in vitro characterization approaches to support a demonstration of bioequivalence. Drug-free microparticles were loaded with tretinoin or drug-loaded microparticles were separated from purchased Retin-A Micro® (tretinoin) topical gel drug products. The resultant microparticles were analyzed for tretinoin content, drug loading efficiency, morphology, surface topography, surface pore size distribution, particle size distribution and tretinoin release. The solid-state characteristics and chemical interaction of tretinoin with the microparticles were also investigated. Microparticles loaded with tretinoin made in-house and those separated from Retin-A Micro® (tretinoin) topical gel were spherical, polydisperse and free of aggregates. The surface porosity of the microparticles was ∼19.8% with an average pore size of ∼327 nm. Microparticles loaded with tretinoin in-house were smaller in size and exhibited faster drug release than those separated from Retin-A Micro® (tretinoin) topical gel. Tretinoin release was found to increase with an increase in the drug loading. Based on XRD and DSC data, tretinoin was present in an amorphous state. The FTIR spectra indicated a disappearance of carbonyl band of microparticles and shifting of the hydroxyl band of tretinoin due to hydrogen bonding. The extent of drug loading and the solid-state interaction of tretinoin with the microparticles may be critical for drug release. Additional characterization of the drug products is necessary to understand the effect of the factors examined in this work on the bioavailability and efficacy of tretinoin gels. [ABSTRACT FROM AUTHOR]