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AbstractBackgroundThe combination therapy of Isotretinoin (ITR) and antibacterial formulations administered through topical route suffer from several limitations including reduced therapeutic efficacy and low patient-compliance.ExperimentThe present study aimed to develop biocompatible lipid-based mixed micelles of ITR in combination with Clindamycin phosphate (CLIN) employing self-assembly method to improve its skin delivery, photostability, biocompatibility and pharmacodynamic efficacy.ResultsThe MTT assay and cellular uptake studies showed non-cytotoxic effect to HaCat cell lines. The zone of inhibition studies conducted in Propionibacterium acnesprovides the first literature evidence to support the antimicrobial property of Isotretinoin and Tretinioin. The nano-sized carriers offered (19.3 ± 1.03 nm particle size with −3.12 mV zeta potential) enhanced permeation, skin retention, pre-clinical efficacy and significant skin biocompatibility. The testosterone-induced acne model proved superior pharmacodynamic efficacy of lab developed formulation vis-à-vismarketed products of both the drugs. The results were further confirmed by the histopathological studies of respective skin samples treated with different formulations.ConclusionThe lab developed lipid-based micellar formulation of ITR and CLIN offers a better strategy for the combined delivery of unstable molecules like ITR and CLIN in acne management.

ABSTRACTIntroduction: Analogous to nanocarriers such as nanoparticles, liposomes, nano lipoidal carriers, niosomes, and ethosomes, polymeric micelles have gained significance in the field of drug delivery. They have attracted scientists worldwide by their nanometric size, wide range of polymers available for building block synthesis, stability and potential to enhance the targeting and safety of drugs. Incorporation of drugs within the interior of polymeric micelles alters the drug pharmacokinetics, which generally results in increased efficiency.Areas covered: This review deals with the pharmacokinetics of various anti-neoplastic drugs loaded into micelles. The structure of polymeric micelles, polymers employed in their development and techniques involved will be discussed. This is followed by discussion on the pharmacokinetics of anti-cancer drugs loaded into polymeric micelles and the toxicity concerns associated.Expert opinion: Polymeric micelles are nanometeric carriers, with higher stability, polymeric flexibility and higher drug loading of poorly water-soluble drugs. These nanosystems help in increasing the bioavailability of drugs by encapsulating them within the hydrophobic core. The proper selection and design of the amphiphilic polymer for micelles is a crucial step as it decides the toxicity and the biocompatibility.

Since the discovery of liposomes, these vesicular carriers have attracted the researchers from all the vistas of the biomedical domain to explore and harness the potential benefits. Many novel drug delivery-based products have been approved by the United States Food and Drug Administration (USFDA) and other federal agencies of the globe, out of which the major share is of the liposomes and related carriers. Taking cognizance of it, the US-FDA has recently come up with ‘Guidance for Industry on Liposome Drug Products’. In cancer management, chemotherapy is the most frequently employed approach which is still not devoid of untoward challenges and side effects. In chemotherapy, the taxanes, esp. Docetaxel shares a huge percentage in the prescription pattern. Also, the first marketed liposomal product was encasing one drug of this category. Henceforth, the present review will highlight the advances in the delivery of taxanes, in particular docetaxel, with an emphasis on the need, success and pharmacoeconomic aspects of such vesicular-carrier mediated docetaxel delivery.

Thymoquinone (TQ), a potent bioactive of Nigella sativaplant, is highly hydrophobic molecule and thus associated with poor oral bioavailability. The present work proposes the phospholipid-nanoparticles (PLN) based delivery of TQ to enhance the low oral bioavailability and anti-inflammatory activity. TQ-loaded nanoparticles were prepared viamicro-emulsification technique employing different phospholipid concentrations and extensively characterized for particle size, surface charge, surface morphology, entrapment efficiency, and drug release kinetics. Further, the nanoparticles were assessed for oral bioavailability, and anti-inflammatory activity employing rat paw edema model. The optimized nanoparticle composition (F1) was nanosized (<100 nm) with spherical morphology coupled with narrow size distribution, higher drug entrapment efficiency (>70%), controlled drug release pattern, and negatively charged surface (zeta potential of −0.57 mV). After oral administration of a single dose of F1 formulation, showed approx. 226.6% relative bioavailability vis-à-vis plain TQ suspension. While, substantially higher reduction in the percent inhibition in paw edema in comparison to the pure drug suspension and diclofenac sodium, was observed in the inflammation model. The present work indicate that PLN could be an efficient nanodevices for the treatment of inflammatory disorders and promising carrier system to augment TQ oral bioavailability.

Successful delivery of a chemotherapeutic agent like bendamustine still remains a challenge in clinical conditions like chronic lymphatic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma. We have conjugated bendamustine to polyamidoamine (PAMAM) dendrimers after conjugating with N-(hydroxyethyl)maleimide (spacer) via an ester bond. The particle size of PAMAM–bendamustine conjugate was 49.8 ± 2.5 nm. In vitrodrug release resulted in sustained release with improved solution stability of drug up to 72 h. In a 24 h cytotoxicity study by MTT assay against human monoblastic leukemia cells (THP-1), the IC50 value for PAMAM–bendamustine was 32.1 ± 4.8 μM compared to 50.42 ± 3.4 μM and 2303 ± 106.5 μM for bendamustine and PAMAM dendrimer, respectively. Significantly higher cell uptake and apoptosis were observed in THP-1 cells by PAMAM–bendamustine conjugate which was confirmed by flow cytometry and confocal laser scanning microscopy. Preliminary in vivostudies undertaken included pharmacokinetics studies, organ distribution studies, and tumor inhibition studies. In healthy Wistar rat model (1CBM IV push model), the pharmacokinetic studies revealed that bioavailability and t1/2increased significantly, i.e., almost 8.5-fold (193.8 ± 1.116 vs 22.8 ± 0.158 μg mL–1/h) and 5.1-fold (0.75 ± 0.005 vs 3.85 ± 0.015 h), respectively, for PAMAM–bendamustine conjugate compared to pure bendamustine (p< 0.05), however, clearance and volume of distribution were found to be decreased compared to those of free drug. The study suggests that PAMAM–bendamustine conjugate was not only stable for the longer period but also least toxic and highly taken up by THP-1 cells to exert an anticancer effect at the reduced dose. Tumor inhibition and biodistribution studies in tumor-bearing BALB/c mice revealed that PAMAM–bendamustine conjugate was more effective than the pure drug and showed higher accumulation in the tumor.

The present investigation focuses on the development and evaluation of acyclovir-loaded flexible membrane vesicles (ACY-FMVs) and evaluates their targeting potential to localize the drug into skin layers. The drug-loaded FMVs were prepared by thin-film hydration method and characterized for various attributes including micromeritics, entrapment efficiency, vesicle shape, size, and degree of deformability. The values of particle size and zeta potential of the developed carrier system were found to be 453.7 nm and − 11.62 mV, respectively. The system was further incorporated into a hydrogel and evaluated for skin permeability and retention characteristics in comparison to marketed formulation. The developed formulation demonstrated enhanced retention of drug deep inside the skin layers which can probably decrease the frequency of application of the drug, thereby reducing its adverse effects. Skin irritancy studies performed on Lacamice skin proved the safety and non-irritant nature of ACY-FMVs. The pharmacodynamic studies on murine model for HSV-1 infection demonstrated immense potential and safety of topically applied ACY-FMVs. However, more intensive studies need to be pursued to explore and exploit the potential of lipid-based systems in anti-viral therapeutics. These preclinical findings provide a hope for corroborating the efficacy in clinical situations.

Psoriasis is a chronic skin disease characterized by inflammation caused by the activation of the immune system. Although the etiology of psoriasis is still unknown, the crosstalk between immune cells, dermal vascular cells, and epidermal keratinocytes has been shown as a critical process. Curiously, the overexpression of vascular endothelium growth factor (VEGF), which further propagates angiogenesis and cell proliferation, helps in the progression of the psoriasis plaque. Literature evidence shows the betterment of the psoriasis plaque when administering anti-VEGFA treatment. In our opinion, several other therapies targeting VEGF/VEGFR axis, such as employing peptides, RNAi and CRISPRi with nanocarriers as delivery strategy could redirect the therapeutic approach for the treatment of psoriasis. Collectively, this short communication highlights the significance of VEGFA, its downstream targets, and nanomedicines in the treatment of psoriasis. Nevertheless, continued research in this area could enable novel therapeutics and strategies to enter the market with a substantial social impact.

In the present study, water-soluble lysine-based C60-fullerene nanoconjugates (CF-LYS-TEG-MMF) were synthesized using a biodegradable linker for the better delivery of monomethyl fumarate (MMF) employing Prato reaction. CF-LYS-TEG-MMF resulted in enhanced cytotoxicity on neuroblastoma cells, meanwhile found to be substantially biocompatible to erythrocytes. The designed nanoconjugate exhibited a pH-based drug release pattern, minimizing the leaching of drug at plasma pH. However, the carrier offered maximum drug release at cancer cell pH, indicating huge promise in internalization of drug molecules at the site of target. The pharmacokinetics of MMF in rodents was significantly improved in terms of enhanced bioavailable drug fraction in the central compartment, reduced drug clearance, elevated plasma concentrations and prolonged biological residence of drug. Enhanced in vitro efficacy in SH-SY5Y neuroblastoma cells, improved erythrocyte compatibility, high drug loading, and conducive pharmacokinetic profile by CF-LYS-TEG-MMF offers a huge promise in brain drug delivery, dose reduction, and dosage-regimen alteration for the management of brain tumors employing MMF.

Aceclofenac (ACE) is one of the most popular anti-inflammatory drugs, frequently used for the pain relief in conditions like osteoarthritis, muscular pain, rheumatoid arthritis, periarthritis, spondylitis, sprain and alkylosing arthritis. However, being important non-steroidal anti-inflammatory agent (NSAID), still the polymorphic attributes of ACE are relatively less explored. Therefore, we aimed to study the polymorphic transitions of ACE employing various solvents and also to correlate with the biological transport of ACE.

Background: Now-a-days, numerous nanocarrier-based drug products for topical applications are present in the market and number of similar products are being researched. To estimate the amount of drug delivery to skin, the scientists have now established techniques for separation of skin layers for the determination of drug concentrations. This forms the basis of pharmacokinetics of drug(s) in skin, i.e., dermatokinetics. However, dermatokinetic modeling of topical products is still a colossal challenge. Assessment of bioavailability helps in determination of safety and efficacy of topical formulations. Objective: This article is an attempt to explore the usefulness and methodologies of dermatokinetics for nanocarriermediated topical delivery. It also showcases challenges in methodologies used for determination of dermatokinetic parameters along with advantages. Method: All the articles (research and review) used for writing the manuscript were collected from various search engines like Science Direct, Google Scholar, PubMed and Eureka Select using keywords like dermatokinetics, novel drug delivery systems, bioequivalence, bioavailability and topical delivery. Conclusion: As the methods used for determination of pharmacokinetics of oral and intravenous formulations are not useful for dermatokinetic assessment, various methods like tape stripping, microdialysis and vasoconstrictor assays are being used for dermatokinetic assessment. These methods are not only useful to determine the drug concentrations in skin layers, but can also be used to correlate the toxic effects of xenobiotics.

Dibenzoylmethane (DBM), a phytochemical agent, occurring as a minor constituent in the root extracts of liquorice has a potential for anti-photoaging effects. It acts as a UVA absorber that filters out and prevents the penetration of UV radiations into various cell components. In this study, DBM loaded o/w microemulsion (ME) was developed and evaluated for anti-photoaging effect in mice. The ME was evaluated for various physicochemical characteristics, stability, ex-vivoskin permeation studies and in vivoevaluation in mice model of UV-radiation induced photodamage. The mean globule size of DBM loaded ME was found to be 35.550 ± 4.879 nm. The mean cumulative amount permeated/area and skin retention of DBM in 24 h from the ME was 6.81 and 5.16 folds higher, respectively as compared to the conventional cream of DBM. In vivoanti-photoaging effect on mice skin was evaluated in terms of visual scoring, pinch test, biochemical estimations and histopathological studies. Results clearly demonstrated the promising efficacy of ME formulation in preventing wrinkles, lesions and other macroscopic and microscopic changes associated with chronic UV exposure. Hence, it can be concluded that DBM ME can be used effectively used as sunscreen agent to protect against the damaging effect of UV rays.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely prescribed drug for chronic inflammatory conditions like osteoarthritis (OA), a highly prevalent musculoskeletal disorder of adults, projected to affect about 60 million people of total world population by 2020. The chronic oral administration of diclofenac is linked with many gastrointestinal complications like ulceration, bleeding and perforation. These issues paved the way for the development of a structurally similar drug Aceclofenac, which proved to be a safer and more efficient alternative. In spite of better tolerability of Aceclofenac, the oral use of it is not completely free from typical NSAID like side effects. Thus in this context, it becomes mandatory to explore the potential of newer delivery approaches. Amongst the varied newer carrier-systems, microemulsion systems, lipidic colloidal carrier systems and many other supramolecular systems promise to improve the delivery. They tend to place the molecules to the desired target site or in the vicinity without disturbing the unaffected normal surrounding tissues and also ensure enhanced permeation into the skin. The current investigation highlights and deals with the different conventional and novel approaches used thus far in oral delivery of Aceclofenac, their limitations and recent shift towards non oral routes.

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-visplain 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.

Methotrexate (MTX) has shown remarkable therapeutic effects against a variety of cancers. However, it is related to various challenges like dose-influenced side effects, compromised bioavailability, and poor tissue penetration. Henceforth, a poly-(lactic-co-glycolic acid) (PLGA)-based d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) conjugated MTX self-assembled nanoparticulate system was developed. The synthesized conjugate (MTX-PLGA-TPGS) was affirmed by FT-IR and NMR spectroscopy, and the developed self-assembled nanoparticles were characterized for particle size, zeta potential, surface charge, drug loading and drug entrapment. The evaluation studies included drug release at the plasma and cancer cell pH, compatibility with erythrocytes, plasma protein binding, in-vitrocytotoxicity on cancer cell lines, confocal laser scanning microscopy, and in-vivopharmacokinetics. The FT-IR and 1H NMR confirmed the successful conjugation of the two macromolecules. The developed nanoparticulate system offered controlled drug release in a pH-dependent manner, releasing the maximum drug at the pH of cancer cells. The developed systems were not only found to be biocompatible with erythrocytes but also offered substantially enhanced cytotoxicity on MDA-MB-231 cells. The confocal laser scanning microscopy confirmed higher cellular uptake and pharmacokinetics in rodents offered markedly elevated AUC and substantially retarded elimination from the central compartment. The findings vouch for the immense promise of the designed nanosystem in enhancing the efficacy, permeation, safety and reducing the dose and dosing frequency of a well-established BCS class IV drug candidate.

Acne, a common skin disease in teenagers, is caused by Propionibacterium acnes(P. acnes). Isotretinoin (ITR) is though reported to have immense antiacne potential, yet there are hardly any reports vouching its antimicrobial activity. The present study, therefore, was undertaken to study the antimicrobial activity of ITR and evaluate the effect of its encasement in nanocarriers on its minimum inhibitory concentration (MIC). The nanocarriers were also evaluated for the skin transport characteristics. MICs of pure drug and entrapped drug in nanolipid carriers (ITR-NLCs) and in solid lipid nanoparticles (ITR-SLNs) were determined by broth dilution method against clindamycin phosphate as the reference antibiotic. It was observed that ITR possessed marked antimicrobial activity against anaerobic pathogen, P. acnes. Nanocarriers loaded with ITR, that is, SLNs and NLCs, enhanced the antimicrobial activity even at lower concentrations vis-à-visthe drug alone and improved drug transport potential vis-à-visthe commercial gel. The unique findings could be the result of effective adhesion of ITR-loaded nanocarriers to the bacterial membranes and release of drug directly to the target. Besides establishing ITR as an antimicrobial agent against acne-causing bacteria, the current work ratifies immense potential of nanocolloidal carriers like SLNs and NLCs to treat acne in a more efficient manner.

Numerous oral treatment options have been reported for neurological diseases, particularly Alzheimer's disease (AD). Berberine (BRB), a promising phytoactive drug, has been successfully explored for effective therapeutic management of AD and other neurodegenerative disorders. However, it poses formidable challenges of exceedingly poor oral bioavailability of 0.68%, primarily owing to its poor intestinal permeation, extremely low aqueous solubility, and extensive P-glycoprotein efflux transport. The present studies, accordingly, were undertaken to develop the galactose-tethered nanostructured lipidic carriers of BRB for efficient brain uptake. NLCs were systematically developed and optimized using QbD paradigms, and thoroughly characterized for particle size, zeta potential, morphology, entrapment efficiency and in vitrodrug release. U-87 cell lines studies indicated augmentation in cellular permeability and uptake of the galactosylated NLCs. Oral bioavailability was found to be highly significantly enhanced with over 8.21-folds and 3.56-folds (p < 0.001 each) improvement in the values of AUC48hand Cmax, respectively, along with substantial elevation in brain drug levels too (p < 0.05 to p < 0.001). Also, tmaxwas found to be notably increased by 1.41-folds (p < 0.05), indicating extended release characteristics of the galactosylated NLCs. Studies on brain homogenates exhibiting distinctly superior biochemical parameters, and behavioural studies demonstrating marked cognitive potential in β-amyloid treated rats further substantiated their promising utility in the management of AD. High degree of Level A linear correlations were established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) BRB and its NLC formulations. Stability studies at 5 °C indicated robustness of galactosylated NLCs for 6 months. The current preclinical findings, accordingly, offer distinctive potential of the developed NLCs in enhanced drug efficacy, extended duration of action and effective therapeutic management of AD.

The objective of the study was to develop novel chitosan-based nanoconjugate intended for intravenous drug delivery to enhance the therapeutic efficacy of the docetaxel. Nanoparticles were prepared using the dialysis method, characterized using various spectroscopic studies like IR, NMR, and Mass, and evaluated for various drug delivery attributes. The designed carrier presented a particle size of 231 ± 0.92 nm with PDI value less than 0.3 which attributes the homogeneity of the polydisperse phase. The developed system not only offered 64.77% of entrapment efficacy and 35.23% of drug loading, but also found to be compatible with the erythrocytes. On the MDA-MB-231 invasive cancer cell lines, the efficacy of the developed system was far superior to the naïve drug and the developed system was able to enhance the bioavailable fraction in the plasma of rats’ vis-à-visplain drug. The findings are encouraging and provide a system which not only enhanced the efficacy of DTX against MDA-MB-231 cells, but also improved its hemocompatability and bioavailability.

In the present study, polyethylene glycol-linked conjugate of carbon nanotubes with Mangiferin was synthesized and characterized by means of Fourier transform infrared and nuclear magnetic resonance spectroscopic techniques. Studies for the determination of particle size, polydispersity index and zeta potential were performed. Morphological characterization was performed using transmission electron microscopy. Phytochemical conjugated nanotubes were also evaluated for hemo-compatibility, protein binding capacity and in-vitrodrug release. Cytotoxicity studies and flow cytometry were performed on U-87 cell lines. Drug release studies confirmed a spatiotemporal pattern of release at the cancer cell pH. Cytotoxicity studies proved that there was 1.28 folds decrease in the IC50value indicating effective anticancer activity, whereas hemolytic profile established the safety. Flow cytometry confirmed effective induction of apoptosis with minimum necrosis by the nano-conjugate vis-à-visthe naïve drug. The pharmacokinetic study showcased that there was 4 times escalation in the area under the curve, i.e., bioavailability of the drug after the conjugation to that of plain mangiferin. From the obtained results, it can be concluded that these functionalized nanocarriers are capable of the effective and safer delivery of phytochemicals to the brain cancerous cells.