Nanocarriers for the treatment of glioblastoma multiforme: A succinct review of conventional and repositioned drugs in the last decade.

Glioblastoma multiforme is a very combative and threatening type of cancer. The standard course of treatment involves excising the tumor surgically, then administering chemotherapy and radiation therapy. Because of the presence of the blood-brain barrier and the unique characteristics of the tumor microenvironment, chemotherapy is extremely difficult and has a high incidence of relapse. With their capacity to precisely target and transport therapeutic medications to the tumor while overcoming the challenges provided by invasive and infiltrative gliomas, nanocarriers offer a potentially beneficial treatment option for gliomas. Drug repositioning or, in other words, finding novel therapeutic uses for medications that have received approval for previous uses has also recently emerged to provide alternative treatments for many diseases, with glioblastoma being among them. In this article, our goal is to shed light on the pathogenesis of glioma and summarize the proposed treatment approaches in the last decade, highlighting how combining repositioned drugs and nanocarriers technology can reduce drug resistance and improve therapeutic efficacy in primary glioma.

Developing a rapid analytical method for simultaneous determination of apigenin and gallic acid: validation and application in a nanoliposomal formulation.

OBJECTIVE: Apigenin and gallic acid are natural compounds that are useful as antioxidant, anti-inflammatory and anticancer agents, especially when used together in combination. Therefore, the development and validation of a simultaneous method of analysis for both compounds in pure form and when encapsulated in an advanced delivery system such as liposomes would be useful. METHODS: Analysis was performed using C18 column under isocratic conditions. The mobile phase was acetonitrile: water containing 0.2% orthophosphoric acid at a ratio of 67:33, flow rate 1 ml/min, and detection wavelength 334 nm for apigenin and 271 nm for gallic acid. RESULTS: The assay method was linear at the concentration range (5-600 µg/mL) with R2 of 1 for both drugs. The method was also shown to be precise and robust with RSD less than 2% with LOD (0.12, 0.1 µg/mL) and LOQ (4.14, 3.58 µg/mL) for apigenin and gallic acid respectively. The method was also applicable for the determination of the entrapment efficiency of both drugs when co-loaded in a nanoliposomal formulation. CONCLUSION: The described HPLC method was shown to be suitable, sensitive, and reproducible for the simultaneous identification and quantification of apigenin and gallic acid. The analytical results were accurate and precise, with good recovery, low limit of detection, and the chromatographic assay was accomplished in less than 3 min, suggesting the suitability of the method for routine analysis of both drugs in pharmaceutical formulations.

Simplex Lattice Design and Machine Learning Methods for the Optimization of Novel Microemulsion Systems to Enhance p-Coumaric Acid Oral Bioavailability: In Vitro and In Vivo Studies.

Novel p-coumaric acid microemulsion systems were developed to circumvent its absorption and bioavailability challenges. Simplex-lattice mixture design and machine learning methods were employed for optimization. Two optimized formulations were characterized using in vitro re-dispersibility and cytotoxicity on various tumor cell lines (MCF-7, CaCO2, and HepG2). The in vivo bioavailability profiles of the drug loaded in the two microemulsion systems and in the suspension form were compared. The optimized microemulsions composed of Labrafil M1944 CS (5.67%)/Tween 80 (38.71%)/Labrasol (38.71%)/water (16.92%) and Capryol 90 (0.50%)/Transcutol P (26.67%)/Tween 80 (26.67%)/Labrasol (26.67%)/water (19.50%), respectively. They revealed uniform and stable p-coumaric acid-loaded microemulsion systems with a droplet size diameter of about 10 nm. The loaded microemulsion formulations enhanced the drug re-dispersibility in contrast to the drug suspension which exhibited 5 min lag time. The loaded formulae were significantly more cytotoxic on all cell lines by 11.98-16.56 folds on MCF-7 and CaCo2 cells and 47.82-98.79 folds on HepG2 cells higher than the pure drug. The optimized microemulsions were 1.5-1.8 times more bioavailable than the drug suspension. The developed p-coumaric acid microemulsion systems could be considered a successful remedy for diverse types of cancer.

Enhancement of oral bioavailability of drugs using lipid-based carriers: a meta-analysis study.

Cancer is the disease of this era. Its therapy is moving through ups and downs not only due to poor effectiveness of many treating drugs, but also due to the serious side effects always evolving. In an attempt to overcome this problem, many systems, including lipid-based carriers, have been exploited for their oral delivery. Throughout this study, the meta-analysis tool was used to combine data from different studies and extract evidences that lipid-based carriers enhance the oral bioavailability. Consequently, increasing the efficiency and the reduction in side effects of drugs would follow. Accordingly, the usual parameter to indicate the bioavailability; the area under effect curve (AUC) was used where the lipid carriers have proven their superiority over conventional formulations. Interestingly, by comparing microemulsion/self-microemulsifying system (SMEDDS) versus liposomes/pro-liposomes as subgroups of the meta-analysis study, insignificant differences were recorded between them.

Fabrication of extended-dissolution divalproex tablets: a green solvent-free granulation technique.

Objective: Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short in vivo half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process.Methods: A lab scale high shear mixer granulator employing six meltable lipid binders (compritol®888 ATO, beeswax, gelucire®50/13, precirol® ATO5, stearyl alcohol, and geleol®) was used for the preparation of tablets. Quality control tests were performed on granules and tablets, and Box-Behnken's design was adopted to investigate the effect of binder concentration, impeller speed, and granulation time on the drug dissolution. Shelf and accelerated stability evaluation, taste assessment, and in vivo pharmacokinetic study were conducted on the selected batches.Results: Results revealed that DVS tablets were successfully prepared, and that the in vitro dissolution of the drug was inversely proportional to the binder concentration. Beeswax and compritol® tablets showed similar dissolution profiles to the marketed product Depakote® 500 ER tablets (F1 < 15 and F2 > 50). The selected batches showed lower moisture content (<2%) and successfully masked the bitter taste compared to uncoated tablets based on a hydrophilic matrix. The in vivo pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol® tablets of 95.6% and 118%, respectively, compared to the marketed product.Conclusion: The solvent free HMG process can be employed to formulate 24 h extended dissolution DVS tablets with masked bitter taste and high stability, and comparable or higher bioavailability than the marketed product.

Optimisation of the microencapsulation of lavender oil by spray drying.

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions. Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated. Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography-mass spectrometry. Results: Lavender microparticles of size 12.42 ± 1.79 µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12 mg w/w%), and encapsulation efficiency (77.89 w/w%). Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.

Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug.

PURPOSE: Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections. METHODS: Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations. RESULTS: Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC50 values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution. CONCLUSIONS: Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues. Graphical Abstract ᅟ.

Vesicular powder as carrier for doxycycline hydrochloride and metronidazole combination therapy.

In this study, vesicular proniosomal powder encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) combination therapy was developed using different types of spans, cholesterol (CH) and maltodextrin as a carrier. Proniosomal powder was free flowing and spherical in shape. The surfactant structure affected the entrapment efficiency of both drugs with highest value of Sp 60 proniosomes of 45.16% and 42.64% for DH and MT, respectively. Incorporation of CH influenced vesicle stability and permeability with optimum concentration of 10 mole%. Increasing the surfactant loading from 1 mM to 3 mM resulted in a significant decrease in the amount of drugs (mg) entrapped per mM lipid (from 9.95 to 1.13 and from 8.88 to 1.22 for DH and MT, respectively). Longer chain length surfactants produced larger vesicles. Surfactant hydrophilicity affected zeta potential. Both drugs were molecularly dispersed in the proniosomal powder with no chemical interaction with other components. Proniosomal powder was stable at 2-8 °C for three months.

Quercetin loaded cosm-nutraceutical electrospun composite nanofibers for acne alleviation: Preparation, characterization and experimental clinical appraisal.

In the cosmeceutical field, it is essential to develop topical delivery systems which would allow drugs to create a depot and permeate within the skin. The aim of the present study was to develop composite nanofibers of polyvinyl alcohol/quercetin/essential oils using the electrospinning technique, and assess their efficiency in acne alleviation. Quercetin was chosen due to its anti-inflammatory, anti-oxidant, and antibacterial activities. Nanofibers were characterized for their morphology, ex-vivo deposition/permeation, physical/mechanical integrity, thermal properties, and chemical characteristics. In addition, the anti-bacterial efficacy was tested on Propionibacterium acne (P. acne), and a cytotoxicity assay was carried out. Lastly, an experimental clinical trial was conducted on acne patients, where the percentage reduction of inflammatory, non-inflammatory and total acne lesions was taken as evaluation criterion. Results showed that quercetin was successfully loaded into the nanofibers which were homogenously dispersed. They showed a reasonable skin deposition percentage of 28.24% ± 0.012, a significantly higher antibacterial efficacy against Propionibacterium acne than quercetin alone, and were utterly safe on skin fibroblastic cells. Upon clinical examination on acne patients, the nanofibers showed 61.2%, 14.7%, and 52.9% reduction of inflammatory, comedonal, and total acne lesions respectively, suggesting a promising topical anti-acne delivery system.

Nose to brain delivery of melatonin lipidic nanocapsules as a promising post-ischemic neuroprotective therapeutic modality.

Ischemic stroke accounts for about 87% of all strokes, causing long-term disability in adults, and is the second leading cause of death worldwide. In search of new therapeutic modalities, the use of neuroprotective agents loaded in nanocarriers to be delivered by noninvasive means (i.e. via intranasal route) became a popular approach. In the current study, melatonin (MEL) was loaded in lipidic nanocapsules (LNCs) prepared using the phase inversion method, and characterized in terms of size, polydispersity, zeta potential, in vitro drug release, viscosity, storage stability, and ex vivo permeation across sheep nasal mucosa. Moreover, MEL-LNCs were tested for efficacy in cerebral ischemia/reperfusion (I/R/) injury model through histopathological assessment, and analysis of oxidative stress markers, pro-inflammatory cytokines, and apoptotic markers. Results showed that LNCs exhibited particle size ranging from 18.26 to 109.8 nm, negative zeta potential, good storage stability, spherical morphology, and a burst release followed by a sustained release pattern. LNCs exhibited 10.35 folds higher permeation of MEL than the drug solution across sheep nasal mucosa. Post-ischemic intranasal administration of MEL-LNCs revealed lowering of oxidative stress manifested by a decrease in malondialdehyde levels, and elevation of glutathione and superoxide dismutase levels, lowering of the inflammatory markers tumor necrosis factor-α, NO, myeloperoxidase, and significant inhibition of Caspase-3 activity as an apoptotic marker. Western blot analysis delineated a recovery of protein expression Nrf-2 and HO-1 with downregulation in the parent inflammatory markers nuclear factor kappa B p65, inducible nitric oxide synthase, Bax, and Cytochrome C expressions, and upregulation of B-cell lymphoma-2 Bcl-2, hence promoting neuronal survival. This was supported by histological evidence, revealing significant restoration of hippocampal neurons. In light of the above, it can be concluded that MEL-LNCs could be a promising delivery system for nose to brain delivery for treatment of cerebral ischemia.

Intranasally administered melatonin core-shell polymeric nanocapsules: A promising treatment modality for cerebral ischemia.

AIMS: The neurohormone melatonin (MEL) has been reported as a promising neuroprotective molecule, however it suffers pharmaceutical limitations such as poor solubility and low bioavailability, which hinder its pharmacological and clinical potential. In the current work, MEL was loaded in core-shell nanocarrier system; polymeric nanocapsules (PNCs), and assessed for its potential in cerebral ischemia reperfusion injury rat model when administered intranasally. KEY FINDINGS: Adopting a D-optimal factorial design, MEL-PNCs were successfully formulated using the nanoprecipitation technique. MEL-PNCs exhibited a particle size ranging from 143.5 to 444 nm, negative zeta potential values ranging from -24.2 to -38.7 mV, cumulative release % for MEL ranging from 36.79 to 41.31 % over 8 h period, with overall good storage properties. The selected MEL-PNCs formulation displayed 8-fold higher permeation than the drug solution across sheep nasal mucosa. MEL-PNCs administered intranasally decreased oxidative stress and hippocampal inflammation, and the histological examination revealed the significant restoration of hippocampal neurons. SIGNIFICANCE: MEL-PNCs administered intranasally could be a promising treatment modality in brain ischemia.

QbD approach of rapid disintegrating tablets incorporating indomethacin solid dispersion.

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.

Nobiletin-loaded composite penetration enhancer vesicles restore the normal miRNA expression and the chief defence antioxidant levels in skin cancer.

Skin cancer is one of the most dangerous diseases, leading to massive losses and high death rates worldwide. Topical delivery of nutraceuticals is considered a suitable approach for efficient and safe treatment of skin cancer. Nobiletin; a flavone occurring in citrus fruits has been reported to inhibit proliferation of carcinogenesis since 1990s, is a promising candidate in this regard. Nobiletin was loaded in various vesicular systems to improve its cytotoxicity against skin cancer. Vesicles were prepared using the thin film hydration method, and characterized for particle size, zeta potential, entrapment efficiency, TEM, ex-vivo skin deposition and physical stability. Nobiletin-loaded composite penetration enhancer vesicles (PEVs) and composite transfersomes exhibited particle size 126.70 ± 11.80 nm, 110.10 ± 0.90 nm, zeta potential + 6.10 ± 0.40 mV, + 9.80 ± 2.60 mV, entrapment efficiency 93.50% ± 3.60, 95.60% ± 1.50 and total skin deposition 95.30% ± 3.40, 100.00% ± 2.80, respectively. These formulations were selected for cytotoxicity study on epidermoid carcinoma cell line (A431). Nobiletin-loaded composite PEVs displayed the lowest IC50 value, thus was selected for the in vivo study, where it restored skin condition in DMBA induced skin carcinogenesis mice, as delineated by histological and immuno-histochemical analysis, biochemical assessment of skin oxidative stress biomarkers, in addition to miRNA21 and miRNA29A. The outcomes confirmed that nobiletin- loaded composite PEVs is an efficient delivery system combating skin cancer.

Pharmacokinetic/pulmokinetic analysis of optimized lung targeted spray dried ketotifen-dextran core shell nanocomplexes-in-microparticles.

A passive lung targeted system for controlled lung delivery of ketotifen (KT) was developed based on the green complexation of dextran sulphate (DS) and KT. Achieving deep lung deposition of high drug fraction, while evading lung defense mechanisms were set as goals. Optimized uniform negatively charged nanocomplexes (NC), <80 nm, were obtained at KT/DS weight ratio of 1:0.66 to 1:0.5 and 1% surfactant concentration with 90% drug complexation efficiency. The interaction between KT and DS and matrix formation were evidenced by Fourier-transform infrared (FT-IR) spectra and differential scanning calorimetry (DSC) studies. A respirable particle percent reaching 67.41 ±â€¯2.6% was obtained following co-spray drying NC containing poloxamer with leucine. A higher lung/plasma partitioning was obtained following pulmonary administration of selected nanocomplexes in microparticles (NCEMP) to rats compared to oral and intravenous (iv) routes. A new core shell nanocomplex formed of DS and KT as main substrates exhibited a potential for lung targeting of the anti-asthmatic drug.

Effect of some formulation parameters on flurbiprofen encapsulation and release rates of niosomes prepared from proniosomes.

Proniosomal gels or solutions of flurbiprofen were developed based on span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60), and span 80 (Sp 80) without and with cholesterol. Nonionic surfactant vesicles (niosomes) formed immediately upon hydrating proniosomal formulae. The entrapment efficiency (EE%) of flurbiprofen (a poorly soluble drug) was either determined by exhaustive dialysis of freshly prepared niosomes or centrifugation of freeze-thawed vesicles. The influence of different processing and formulation variables such as surfactant chain length, cholesterol content, drug concentration, total lipid concentration, negatively or positively charging lipids, and the pH of the dispersion medium on flurbiprofen EE% was demonstrated. Also, the release of the prepared niosomes in phosphate buffer (pH 7.4) was illustrated. Results indicated that the EE% followed the trend Sp 60 (C(18))>Sp 40 (C(16))>Sp 20 (C(12))>Sp 80 (C(18)). Cholesterol increased or decreased the EE% depending on either the type of the surfactant or its concentration within the formulae. The maximum loading efficiency was 94.61% when the hydrating medium was adjusted to pH 5.5. Increasing total lipid or drug concentration also increased the EE% of flurbiprofen into niosomes. However, incorporation of either dicetyl phosphate (DCP) which induces negative charge or stearyl amine (SA) which induces positive charge decreased the EE% of flurbiprofen into niosomal vesicles. Finally, in vitro release data for niosomes of Sp 40 and Sp 60 showed that the release profiles of flurbiprofen from niosomes of different cholesterol contents is an apparently biphasic release process. As a result, this study suggested the potential of proniosomes as stable precursors for the immediate preparation of niosomal carrier systems.

In vitro evaluation of proniosomes as a drug carrier for flurbiprofen.

The purpose of the present investigation is to formulate and evaluate proniosomal transdermal carrier systems for flurbiprofen. Proniosomes were prepared using various non-ionic surfactants, namely span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60) and span 80 (Sp 80) without and with cholesterol at percentages ranging from 0% to 50%. The effect of surfactant type and cholesterol content on drug release was investigated. Drug release was tested by diffusion through cellophane membrane and rabbit skin. Drug release from the prepared systems was compared to that from flurbiprofen suspensions in distilled water and HPMC (hydroxypropylmethylcellulose) gels. In case of Sp 20 and Sp 80, the added amount of cholesterol affected the preparation type to be either proniosomal alcoholic solutions or liquid crystalline gel systems. On the other hand, both Sp 40 and Sp 60 produced gel systems in presence or absence of cholesterol. Microscopic observations showed that either proniosomal solutions or gel formulations immediately converted to niosomal dispersions upon hydration. Due to the skin permeation barrier, rabbit skin showed lower drug diffusion rates compared to cellophane membrane. The proniosomal composition controlled drug diffusion rates to be either faster or slower than the prepared flurbiprofen suspensions in HPMC gels or distilled water, respectively. In conclusion, this study demonstrated the possibility of using proniosomal formulations for transdermal drug delivery.

Tracking the transdermal penetration pathways of optimized curcumin-loaded chitosan nanoparticles via confocal laser scanning microscopy.

Curcumin-loaded chitosan nanoparticles intended for transdermal delivery were successfully prepared, optimized and their fate, interaction and pathway through the skin were tracked. D-optimal response surface methodology was used for the nanoparticles optimization. Xy and z-stack confocal laser scanning microscopic images were used for the particles tracking after measuring the drug permeation through the skin using Franz diffusion cells. Very small particle sizes in the range of 33.85-199.23nm accompanied with low PDI values of 0.129-0.536 of the prepared curcumin-loaded chitosan nanoparticles were obtained. TEM images revealed the spherical and non-aggregating curcumin-loaded chitosan nanoparticles. The ex-vivo permeation studies have proven the ability of the prepared chitosan nanoparticles to deliver curcumin through the skin reaching fluxes viz 5.14±1.31µgcm-2h-1. The confocal laser scanning microscopy has proven that the appendageal route is the main route of penetration of the prepared nanoparticles and has demonstrated the localization of the chitosan nanoparticles within the hair follicles from which the drug diffuses to deep layers of the skin and beyond.

Curcumin-loaded ultradeformable nanovesicles as a potential delivery system for breast cancer therapy.

In the current study, the transdermal route has been investigated to deliver the poorly bioavailable drug; curcumin into the systemic circulation, aiming to target both superficial and subcutaneous tumors such as the breast tumors. Accordingly, different colloidal carriers viz. ultradeformable nanovesicles comprising various penetration enhancers were exploited. Curcumin-loaded deformable vesicles were prepared by the thin film hydration method followed by extrusion. Sodium cholate and Tween 80 were set as standard edge activators and Labrasol, Transcutol, limonene and oleic acid were the penetration enhancers that were evaluated for their efficacy in skin permeation. The particle size and zeta potential of the prepared vesicles were significantly affected by the type of surfactant/penetration enhancer. The polydispersity measurements showed uniform particle size distribution indicating the sufficiency of the extrusion cycles performed. Curcumin, as a hydrophobic molecule, was well accommodated within the lipid bilayers of the prepared vesicles with entrapment efficiency (EE%) percentages and drug loading percentages (DL%) as high as 93.91% and 7.04%, respectively. The ex-vivo permeation studies were performed on male albino mice skin mounted on Franz diffusion cells. Oleic acid and Transcutol exhibited comparable fluxes to sodium cholate and Tween 80 (∼16 µg cm-2 h-1), whereas the fluxes of Labrasol and limonene were significantly lower. Cytotoxicity studies were performed using MTT assay on human breast cancer cell lines (MCF-7 cells). The results of the MTT assay demonstrated that oleic acid ultradeformable nanovesicles scored an IC50 of 20 µg/ml which introduce these new curcumin-loaded nanovesicles as a successful delivery system for breast cancer therapy.

Quality by design: understanding the product variability of a self-nanoemulsified drug delivery system of cyclosporine A.

The objective of this work was to understand the product variability due to size and other characteristics of the SNEDDS by utilizing near infrared (NIR) and chemometric analysis, as well as several other well-known procedures. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region using CyA solutions in sweet orange oil (oily phase), Emulphor EL-620 (surfactant), and Capmul MCM-C8 (cosurfactant). The formulated SNEDDS were characterized by droplet size, turbidity, zeta potential, and Fourier transform infrared (FTIR) analysis. Drug release studies were performed by dissolution in conjunction with turbidimetry. Permeability studies were performed in a Franz diffusion cell assembly. The results indicated an optimum surfactant to cosurfactant ratio of 2:1. Above this ratio, the resultant nanoemulsions had a particle size of 10 nm and turbidity of 10 nephlometric units (NTU). All the prepared systems were positively charged. The FTIR spectra and the DSC thermograms obtained showed no incompatibility between the SNEDDS ingredients. Turbidity time profiles revealed three distinctive regions: lag phase, plateau, and pseudolinear phase. Emulsification rate was obtained from the corrected slope of the pseudolinear phase of the profile. Permeability data indicated that the product variability is more with smaller droplet size. The size of the droplets showed good correlation with NIR spectral data by partial least square (PLS) regression plots. In conclusion, this study demonstrated the ability to understand the impact of nanodroplets size on the SNEDDS variability by different product analyzing tools.

Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function.

Quality by design (QBD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A very useful component of the QBD is the understanding of factors and their interaction effects by a desired set of experiments. The present project deals with a case study to understand the effect of formulation variables of nanoemulsified particles of a model drug, cyclosporine A (CyA). A three-factor, three-level design of experiment (DOE) with response surface methodology (RSM) was run to evaluate the main and interaction effect of several independent formulation variables that included amounts of Emulphor El-620 (X(1)), Capmul MCM-C8 (X(2)) and 20% (w/w) CyA in sweet orange oil (X(3)). The dependent variables included nanodroplets size (Y(1)), nanoemulsions turbidity (Y(2)), amounts released after 5 and 10min (Y(3), Y(4)), emulsification rate (Y(5)) and lag time (Y(6)). A desirability function was used to minimize lag time and to maximize the other dependent variables. A mathematical relationship, Y(5)=9.09-0.37X(1)+0.37X(2)-0.45X(3)+0.732X(1)X(2)-0.62X(1)X(3)+0.3X(2)X(3)+0.02X(1)(2)-0.28X(2)(2)+0.471X(3)(2) (r(2)=0.92), was obtained to explain the effect of all factors and their colinearities on the emulsification rate. The optimized nanodroplets were predicted to yield Y(1), Y(2), Y(3), Y(4), Y(5) and Y(6) values of 42.1nm, 50.6NTU, 56.7, 107.2, 9.3%/min and 3.5min, respectively, when X(1), X(2), and X(3) values were 36.4, 70 and 10mg, respectively. A new batch was prepared with these levels of the independent variables to yield Y(1)-Y(6) values that were remarkably close to the predicted values. In conclusion, this investigation demonstrated the potential of QBD in understanding the effect of the formulation variables on the quality of CyA self-nanoemulsified formulations.