Self Emulsifying Delivery System of Cissus quadrangularis: Evidence of Enhanced Efficacy and Promising Pharmacokinetic Profile in the Management of Osteoporosis.

Treatment therapies used to manage osteoporosis are associated with severe side effects. So worldwide herbs are widely studied to develop alternative safe & effective treatments. Cissus quadrangularis (CQ) has a significant role in bone health and fracture healing. It is documented that its extracts increase osteoblastic differentiation & mineralization. Currently, Cissus quadrangularis is available in the form of tablets in the market for oral delivery. But these conventional forms are associated with poor bioavailability. There is a need for a novel drug delivery system with improving oral bioavailability. Therefore, a Cissus quadrangularis-loaded self-emulsifying drug delivery system (CQ-SEDDS) was developed which disperses rapidly in the gastrointestinal fluids, yielding nano-emulsions containing a solubilized drug. This solubilized form of the drug can be easily absorbed through lymphatic pathways and bypass the hepatic first-pass effect. The emulsification efficiency, zeta potential, globule size, in-vitro dissolution, ex-vivo, in-vivo and bone marker studies were performed to assess the absorption and permeation potential of CQ incorporated in SEDDS. CQ-SEDDS with excipients Tween 80, Cremophor RH40, Transcutol HP & α-Tocopherol acetate had shown about 76% enhancement in the bioavailability of active constituents of CQ. This study provided the pre-clinical data of CQ-SEDDS using osteoporotic rat model studies.

Steroidal nanoformulations for the treatment of uveitis: potential, promises and future perspectives.

BACKGROUND: Intraocular inflammation, commonly referred to as uveitis, is a prevalent ocular disease. The categorization of uveitis may be based on the prevailing anatomical site, which includes anterior, intermediate, and posterior uveitis. There exists a significant body of evidence indicating that T cells play a pivotal role in the pathogenesis of autoimmune uveitis. In addition to the presence of T cells, an elevation in levels of inflammatory cytokines and a reduction in regulatory cytokines were also noted. The primary pharmacological interventions for uveitis comprise of corticosteroids, methotrexate, anti-vascular endothelial growth factor (VEGF) agents, anti-tumor necrosis factor-alpha (TNF-α) antibodies, and sirolimus. These medications offer prompt alleviation for inflammation. Nevertheless, prolonged administration of corticosteroids invariably leads to unfavorable adverse reactions. The traditional topical corticosteroids exhibit certain limitations, including inadequate transcorneal permeation and low corneal retention, leading to reduced ocular bioavailability. Consequently, there is a growing inclination towards the creation of innovative steroid drug delivery systems with the aim of reducing the potential for adverse effects, while simultaneously enhancing the drug's corneal permeation and retention. CONCLUSION: This review is an attempt to compile all the research work done so far in this field and provides a brief overview of the global efforts to develop innovative nanocarrier-based systems for corticosteroids.

Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.

A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min-1 flow rate, λmax of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.

Systematically Optimized Imiquimod-Loaded Novel Hybrid Vesicles by Employing Design of Experiment (DoE) Approach with Improved Biocompatibility, Stability, and Dermatokinetic Profile.

The present research work explored the possibility of harnessing the benefits of vesicular carriers for overcoming imiquimod-associated complaints or side effects. Hybrid vesicles were prepared by the most common and easily scalable method, i.e., thin film hydration. The chaffing of myriad of factors, both process and material related, affecting the desirable attributes of conceived vesicles, was performed through Taguchi design. Based upon the analysis of Pareto chart and prior experiences, concentration of phospholipid and poloxamer 407 was selected for optimization by 2 levels, 13 run central composite design (CCD). The optimized hybrid vesicles contained 1% w/v phospholipid and 3% w/v poloxamer 407. The optimized hybrid vesicles were incorporated into the 3% w/v carbopol 940 gel and characterized for morphology, physicochemical properties, and rheological behavior. The release (%) and skin retention (% of total dose) across rat skin from gel at same amount of formulation was more than Imiquad®. The gel delivered the loaded cargo, preferably, in the viable region of skin and formed local depot in confocal microscopic studies. The gel followed one compartment open body dermatokinetic model in rat skin. There was not any harmful effect on the mice skin after repeated applications. The gel was stable at room conditions for 1 year.

Oral Delivery of Methylthioadenosine to the Brain Employing Solid Lipid Nanoparticles: Pharmacokinetic, Behavioral, and Histopathological Evidences.

The present study aimed to orally deliver methylthioadenosine (MTA) to the brain employing solid lipid nanoparticles (SLNs) for the management of neurological conditions like multiple sclerosis. The stearic acid-based SLNs were below 100 nm with almost neutral zeta potential and offered higher drug entrapment and drug loading. Cuprizone-induced demyelination model in mice was employed to mimic the multiple sclerosis-like conditions. It was observed that the MTA-loaded SLNs were able to maintain the normal metabolism, locomotor activity, motor coordination, balancing, and grip strength of the rodents in substantially superior ways vis-à-vis plain MTA. Histopathological studies of the corpus callosum and its subsequent staining with myelin staining dye luxol fast blue proved the potential of MTA-loaded SLNs in the remyelination of neurons. The pharmacokinetic studies provided the evidences for improved bioavailability and enhanced bioresidence supporting the pharmacodynamic findings. The studies proved that SLN-encapsulated MTA can be substantially delivered to the brain and can effectively remyelinate the neurons. It can reverse the multiple sclerosis-like symptoms in a safer and effective manner, that too by oral route.

Beta-carotene-Encapsulated Solid Lipid Nanoparticles (BC-SLNs) as Promising Vehicle for Cancer: an Investigative Assessment.

Beta-carotene (BC), a red-colored pigment found in plants and animals, is one of the most extensively investigated carotenoids due to its provitamin-A, antioxidant, and anticancer properties. The anticancer activity of BC through oral administration is severely affected due to its low bioavailability and oxidative degradation. The present study aimed to formulate and characterize solid lipid nanoparticles (SLNs) of BC for enhanced bioavailability and therapeutic efficacy. Beta-carotene-loaded solid lipid nanoparticles (BC-SLNs) were prepared employing different combinations of glyceryl monostearate and gelucire. The characterization studies were performed for particle size, morphology, release behavior, and stability. BC-SLNs were also studied for in vitro cytotoxicity in human breast cancer cell lines (MCF-7) and pharmacokinetic studies in Wistar rats. The cytotoxicity studies confirmed that encapsulation of BC within the lipid bilayers of nanoparticles did not affect its anticancer efficacy. An improved anticancer activity was observed in BC-SLNs as compared to the free BC. BC-SLNs enhanced the bioavailability of BC on oral administration by sustaining its release from the lipid core and prolongation of circulation time in the body. Similarly, area under the curve (AUCtotal) enhanced 1.92-times more when BC was incorporated into SLNs as compared to free BC. In conclusion, solid lipid nanoparticles could be an effective and promising strategy to improve the biopharmaceutical properties of carotenoids for anticancer effects.

Effective Topical Delivery of H-AgNPs for Eradication of Klebsiella pneumoniae-Induced Burn Wound Infection.

The aim of the present study was to explore the therapeutic efficacy of microemulsion-based delivery of histidine-capped silver nanoparticles in eradicating Klebsiella pneumoniae-induced burn wound infection. The developed microemulsion was characterized on the basis of differential light scattering, phase separation, refractive index, and specific conductance. Emulgel was prepared and characterized on the basis of thixotropy, texture, differential scanning calorimetry, and release kinetics. Emulgel was further evaluated in skin irritation and in vivo studies, namely full-thickness K. pneumoniae-induced burn wound infection treatment via topical route. Efficacy of treatment was evaluated in terms of bacterial load, histopathology, wound contraction, and other infection markers. The developed emulgel provided significant in vivo antibacterial activity of histidine-capped silver nanoparticle preparations via topical route and resulted in reduction in bacterial load, wound contraction, and enhanced skin healing as well as decrement of inflammatory markers such as malondialdehyde, myeloperoxidase, and reactive nitrogen intermediate compared to untreated animals. The present study encourages the further employment of histidine-capped silver nanoparticles along with microemulsion-based drug delivery system in combating antibiotic-resistant topical infections.

Fullerenol-Based Intracellular Delivery of Methotrexate: A Water-Soluble Nanoconjugate for Enhanced Cytotoxicity and Improved Pharmacokinetics.

Derivatization of fullerenes to polyhydroxylated fullerenes, i.e., fullerenols (FLU), dramatically decreases their toxicity and has been reported to enhance the solubility as well as cellular permeability. In this paper, we report synthesis of FLU as nanocarrier and subsequent chemical conjugation of Methotrexate (MTX) to FLU with a serum-stable and intracellularly hydrolysable ester bond between FLU and MTX. The conjugate was characterized for physiochemical attributes, micromeritics, drug-loading, and drug-release and evaluated for cancer cell-toxicity, cellular-uptake, hemocompatibility, protein binding, and pharmacokinetics. The developed hemocompatible FL-MTX offered lower protein binding vis-à-vis naïve drug and substantially higher drug loading. The conjugate offered pH-dependent release of 38.20 ± 1.19% at systemic pH and 85.67 ± 3.39% at the cancer cell pH. FLU-MTX-treated cells showed significant reduction in IC50 value vis-à-vis the cells treated with pure MTX. Analogously, the results from confocal scanning laser microscopy also confirmed the easy access of the dye-tagged FLU-MTX conjugate to the cell interiors. In pharmacokinetics, the AUC of MTX was enhanced by approx. 6.15 times and plasma half-life was enhanced by 2.45 times, after parenteral administration of single equivalent dose in rodents. FLU-MTX offered enhanced availability of drug to the biological system, meanwhile improved the cancer-cell cytotoxicity, sustained the effective plasma drug concentrations, and offered substantial compatibility to erythrocytes.

Preclinical Explorative Assessment of Celecoxib-Based Biocompatible Lipidic Nanocarriers for the Management of CFA-Induced Rheumatoid Arthritis in Wistar Rats.

Celecoxib (CXB), a COX-2 inhibitor, is primarily indicated for long-term treatment of rheumatoid arthritis (RA). The effective therapeutic efficacy of CXB on RA via oral administration shows adverse systemic complications, and therefore, local application of CXB has been recommended. The aim of the present study was to develop and characterize solid lipid nanoparticles (SLNs) with enhanced skin permeation potential of CXB. The particle size, polydispersity index (PDI), and percentage drug entrapment (PDE) of the developed SLNs (CXB-SLNs) were found to be 240 nm, < 0.3, and ~ 86% respectively. The developed SLNs exhibited sustained release up to 70% at the end of 48 h. Drug permeation was found to be 45% for SLN gel and 31% for conventional gel. The dermatokinetic studies also confirmed enhanced permeation of CXB in the epidermis and dermis and revealed superiority of the developed SLN gel vis-à-vis the conventional gel. Further, in the CFA-induced arthritis rat model, % arthritis index (AI) of the CXB-SLN gel formulation was found to be very less (18.54%) as compared to untreated (187.34%) and conventional gel-treated (91.61%) animals. In conclusion, the current study can provide a suitable alternative for the development of an effective topical formulation of CXB in lipid nanocarriers.

Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes.

The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1ß, COX2, and MMP1) at both transcript and proteome level.

Systematically Optimized Ketoprofen-Loaded Novel Proniosomal Formulation for Periodontitis: In Vitro Characterization and In Vivo Pharmacodynamic Evaluation.

Various preclinical/clinical studies support the effectiveness of ketoprofen in periodontitis; however, the literature reveals that novel delivery systems have been less explored for the drug in periodontitis. The current investigation aims to explore the potential of a pro-vesicular approach-based proniosomal drug delivery of ketoprofen for its effectiveness and validation in experimental periodontal disease (EPD). Formulations were developed using I-optimal mixture design. Developed formulations were characterized for entrapment efficiency, vesicle size, and in vitro drug release. Selected proniosomal gels were evaluated for mucoadhesiveness, ex vivo drug permeation, and retention studies. Optimized proniosomal gel was evaluated for surface morphology, rheological behavior, texture studies, and pharmacodynamic activity in EPD. The results showed that ketoprofen-loaded proniosomal formulations formed a mucoadhesive hydrogel comprising spherical and flexible vesicles. Viscosity and texture studies showed good adhesion and smoothness, which are desired for enhanced permeation. The disease condition was improved with preserved bone resorption process, that too with intact cementum vis-à-vis marketed gel formulation, when evaluated in the EPD model. The results lead to the conclusion that proniosomes can act as a promising carrier and can be effectively used for improved ketoprofen delivery in periodontal pockets.

Delivery of Thermoresponsive-Tailored Mixed Micellar Nanogel of Lidocaine and Prilocaine with Improved Dermatokinetic Profile and Therapeutic Efficacy in Topical Anaesthesia.

The topical delivery of local anaesthetics has always been a difficult task due to the limited percutaneous absorption of local anaesthetic drugs across the various barriers of the skin. In this pursuit, a thermoresponsive mixed micellar nanogel (MMNG) system of lidocaine and prilocaine has been attempted in the current piece of work. The system relies on the ability to alter its phase state (sol-to-gel) for feasibility of the topical application in response to change in temperature. The composition of MMNG entails majorly of Pluronic® F127 and Tween 80 in a fixed combination so as to provide the desired thermoreversibility for the skin application. The gels were optimized with respect to phase transition temperature (T sol/gel), turbidity and viscosity. The optimized systems were then characterized for particle size, spreadability, syringeability, bioadhesive strength, ex vivo skin permeation, retention and dermatokinetic studies. The skin compatibility revealed that no histological changes were observed for optimized formulation, while the conventional system showed changes in the skin-tissues. Further, the enhanced intensity of anaesthetic effect was noted in an in vivo rabbit model and tail flick model in mice. The overall results suggest that the prepared MMNG system possesses the potential in providing an efficacious, safe and acceptable alternative therapeutic system for topical anaesthesia.

Biocompatible Phospholipid-Based Mixed Micelles for Tamoxifen Delivery: Promising Evidences from In - Vitro Anticancer Activity and Dermatokinetic Studies.

Tamoxifen (TAM) is frequently prescribed for the management breast cancer, but is associated with the challenges like compromised aqueous solubility and poor bioavailability to the target site. It was envisioned to develop phospholipid-based mixed micelles to explore the promises offered by the biocompatible carriers. Various compositions were prepared, employing soya lecithin, polysorbate 80, sodium chloride/dextrose, and water, by self-assembled technique. The formulations were characterized for micromeritics and evaluated for in vitro drug release, hemolysis study, dermatokinetic studies on rodents, and cytotoxicity on MCF-7 cell lines. Cellular uptake of the system was also studied using confocal laser scanning microscopy. The selected composition was of sub-micron range (28.81 ± 2.1 nm), with spherical morphology. During in-vitro studies, the mixed micelles offered controlled drug release than that of conventional gel. Cytotoxicity was significantly enhanced and IC50 value was reduced that of the naïve drug. The bioavailability in epidermis and dermis skin layers was enhanced approx. fivefold and threefold, respectively. The developed nanosystem not only enhanced the efficacy of the drug but also maintained the integrity of skin, as revealed by histological studies. The developed TAM-nanocarrier possesses potential promises for safe and better delivery of TAM.

Chitosan-Stearic Acid Based Polymeric Micelles for the Effective Delivery of Tamoxifen: Cytotoxic and Pharmacokinetic Evaluation.

Chitosan is a widely employed polysaccharide with positive zeta-potential and better tissue/cell adhesion. Its hydrophilicity, high viscosity, and insolubility at physiological pH are major hurdles in proper utilization of this macromolecule. Therefore, it was conjugated with biocompatible stearic acid and the conjugate was employed to develop polymeric micelles for delivery of tamoxifen to breast cancer cells. The conjugate was characterized by FT-IR and NMR, and the nanocarrier was characterized for micromeritics, surface charge, drug loading, and morphological attributes. The efficacy was evaluated by in vitro MTT studies, safety by erythrocyte compatibility, and biodistribution by in vivo pharmacokinetic studies. Despite better drug loading and sustained drug release, cytotoxicity on MCF-7 breast cancer cells was substantially enhanced and the pharmacokinetic profile was significantly modified. The AUC was enhanced manifolds along with reduced clearance. The findings are unique and provide an alternative to the conventional lipid-based nanocarriers for better dose delivery, tissue adhesion, and desired pharmacokinetic modulation.

Conjugation of Docetaxel with Multiwalled Carbon Nanotubes and Codelivery with Piperine: Implications on Pharmacokinetic Profile and Anticancer Activity.

Nanotechnology-based drug products are emerging as promising agents to enhance the safety and efficacy of established chemotherapeutic molecules. Carbon nanotubes (CNTs), especially multiwalled CNTs (MWCNTs), have been explored for this potential owing to their safety and other desired attributes. Docetaxel (DTX) is an indispensable anticancer agent, which has wide applicability in variety of cancers. However, the potential of DTX is still not completely harvested due to problems like poor aqueous solubility, low tissue permeability, poor bioavailability, high first pass metabolism, and dose-related toxicity. Hence, it was proposed to attach DTX to MWCNTs and coadminister it along with piperine with an aim to enhance the tissue permeation, anticancer activity, and bioavailability. The Fourier transform infrared, UV, and NMR spectroscopic data confirmed successful conjugation of DTX to MWCNTs and adsorption of piperine onto MWCNTs. The codelivery MWCNT-based system offered drug release moderation and better cancer cell toxicity than that of plain DTX as well as DTX-CNT conjugate. The pharmacokinetic profile of DTX was exceptionally improved by the conjugation, in general, and coadministration with piperine, in specific vis-à-vis plain drug. Hence, the dual approach of MWCNTs conjugation and piperine coadministration can serve as a beneficial option for enhancement of the performance of DTX in cancer chemotherapy.

QbD-oriented development and validation of a bioanalytical method for nevirapine with enhanced liquid-liquid extraction and chromatographic separation.

The present studies describe the systematic quality by design (QbD)-oriented development and validation of a simple, rapid, sensitive and cost-effective reversed-phase HPLC bioanalytical method for nevirapine in rat plasma. Chromatographic separation was carried out on a C18 column using isocratic 68:9:23% v/v elution of methanol, acetonitrile and water (pH 3, adjusted by orthophosphoric acid) at a flow rate of 1.0 mL/min using UV detection at 230 nm. A Box-Behnken design was applied for chromatographic method optimization taking mobile phase ratio, pH and flow rate as the critical method parameters (CMPs) from screening studies. Peak area, retention time, theoretical plates and peak tailing were measured as the critical analytical attributes (CAAs). Further, the bioanalytical liquid-liquid extraction process was optimized using an optimal design by selecting extraction time, centrifugation speed and temperature as the CMPs for percentage recovery of nevirapine as the CAA. The search for an optimum chromatographic solution was conducted through numerical desirability function. Validation studies performed as per the US Food and Drug Administration requirements revealed results within the acceptance limit. In a nutshell, the studies successfully demonstrate the utility of analytical QbD approach for the rational development of a bioanalytical method with enhanced chromatographic separation and recovery of nevirapine in rat plasma. Copyright © 2015 John Wiley & Sons, Ltd.

Benzyl Benzoate-Loaded Microemulsion for Topical Applications: Enhanced Dermatokinetic Profile and Better Delivery Promises.

Benzyl benzoate (BB) is one of the oldest drugs used for the treatment of scabies and is recommended as the "first-line intervention" for the cost-effective treatment of the disease. Though a promising candidate, its application is reported to be associated with irritation of the skin and eye, resulting in poor patient compliance. Hence, the present study aims to develop BB-loaded topical microemulsion for the safer and effective delivery of BB. Pseudo-ternary phase diagrams with BB as the oily phase itself, along with Tween 80 as surfactant, and mixture of phospholipid and ethanol as the co-surfactant along with aqueous solution as the external phase were constructed and various compositions were formulated. The optimized formulation was characterized for particle-size, zeta-potential, drug-content, globule-morphology pH, and refractive-index, whereas evaluated for skin permeation, retention, compliance, and dermatokinetics. The nanosized formulation offered threefold higher drug permeation vis-a-vis plain drug solution across LACA mice abdominal skin. The drug retention of the selected formulation was nearly twice of that from the marketed product, assuring depot formulation and sustained release. The skin histopathology revealed the non-irritant nature of the formulation, as no changes in the normal skin histology were observed. The dermatokinetic studies confirmed better permeation and enhanced skin bioavailability of BB to epidermis as well as dermis vis-à-vis the conventional product. The results indicate that the developed lipid-based microemulsion hydrogel can alleviate the concerns associated with BB and can provide a better and safer delivery option in substantial amounts to various skin layers.

Biocompatible lidocaine and prilocaine loaded-nanoemulsion system for enhanced percutaneous absorption: QbD-based optimisation, dermatokinetics and in vivo evaluation.

Barrier properties of the skin and physicochemical properties of the drugs are the main hiccups in delivering local anaesthetic molecules topically. The present work endeavours for systematic optimisation and evaluation of nanoemulsions (NEs) of local anaesthetic drugs, lidocaine and prilocaine, employing the systematic approach of Quality by Design. A 3(3) Box-Behnken design was employed for systematic optimisation of the factors obtained from screening studies employing Plackett-Burman design and risk assessment studies. The superior permeation rates, and higher concentrations of the drugs in skin layers from the optimised NE carriers, were achieved in permeation and dermatokinetic studies, when compared to marketed cream. Furthermore, rapid onset of action was demonstrated by the NE system in rabbit eye corneal reflex model and biocompatibility was confirmed from the absence of any marked skin change(s) in the normal skin histology. The developed NE systems demonstrated it as a promising carrier for topical delivery of lidocaine and prilocaine.

Lipid-based capsaicin-loaded nano-colloidal biocompatible topical carriers with enhanced analgesic potential and decreased dermal irritation.

Capsaicin (CP), a recent FDA-approved drug for the topical treatment of neuropathic pain, is associated with several side effects like irritation, burning sensation, and erythema, resulting in poor patient compliance. The present study is an attempt to study the effect of CP encasement in nano-lipoidal carriers (NLCs) on skin-transport characteristics, in vivo pharmacological performance, skin compliance, and stability of the finished product. The study also compares two methods of NLC preparation, namely microemulsification and rotary-evaporation for various attributes. The results demonstrated that microemulsion technique produced smaller nanoparticles vis-à-vis the rotary-evaporation method. Out of the various studied solid lipids, NLCs from stearic acid offered smallest size and the highest negative zeta potential. The NLC-gel offered higher skin permeation and skin retention of CP across LACA mice skin as compared with the conventional cream. The analgesic effect was observed to be enhanced substantially than that of the conventional cream when tested on a radiant mouse tail-flick model. The most alarming problems of skin-irritation and redness were successfully taken care by NLC-gel while the mice group receiving conventional cream showed marked changes in the skin histopathology. Besides the enhanced efficacy and decreased skin-irritation, the developed CP-NLCs also found to be stable and rheologically accepted formulation for the treatment of pain-associated disorders.

QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies.

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186 nm, zeta potential of - 23.6 mV, entrapment efficiency of 80.09%, and cumulative drug release at 12 h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0-72 h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.