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Protein kinases, a class of enzymes that govern various biological phenomena at a cellular level, are responsible for signal transduction in cells that regulate cellular proliferation, differentiation, and growth. Protein kinase enzyme mutation results in abnormal cell division leading to a pathological condition like cancer. Tyrosine kinase (TK) inhibitors, which helps as a potential drug candidate for the treatment of cancer, are continuously being developed. Majority of these drug candidates are being administered as conventional oral dosage form, which provides limited safety and efficacy due to non-specific delivery and uncontrolled biodistribution resulting into the adverse effects. A controlled drug delivery approach for the delivery of TK inhibitors may be a potential strategy with significant safety and efficacy profile. Novel drug delivery strategies provide target-specific drug delivery, improved pharmacokinetic behaviour, and sustained release leading to lower doses and dosing frequency with significantly reduced side effects. Along with basic aspects of tyrosine kinase, this review discusses various aspects related to the application of tyrosine kinase inhibitors in clinical oncological setting. Furthermore, the limitations/challenges and formulation advancements related to this class of candidates particularly for cancer management have been reviewed. It is expected that innovations in drug delivery approaches for TK inhibitors using novel techniques will surely provide a new insights for improved cancer treatment and patients' life quality.

Introduction: Solid lipid nanoparticles (SLNs) are solid core lipid nanocarriers, which can hold both hydrophilic and hydrophobic drugs. They can be made up of biocompatible ingredients and therefore are one of the preferred choices for drug delivery. Surface modifications of SLNs may further provide unique features to them like mucoadhesiveness or targeting capability.Areas covered: In this review, the authors have covered areas from the basic introduction of SLNs to its applications in controlled drug delivery. More specifically, the authors have covered patents disclosed related to the SLNs for the period 2014-2019; however, a summary of patents of 2008-2013 is also included.Expert opinion: SLNs have been explored for development of compositions/formulations with improved therapeutics or cosmetic applications or for nutraceutical applications. Targeted SLNs compositions have been patented as evidenced from the literature; however, not such types of enough SLNs formulations have been claimed for the same.

Background: Nanopharmaceuticals serve as emerging forms of modern medicines, which include nanomedicines, nanosimilars, nanotheranostics, nanodevices, and many more. In the last two decades, a large number of nano-based products have reached the market and are being used clinically. Objectives: Unlike conventional pharmaceutical products, nanopharmaceuticals behave differently both in vitro and in vivo, and therefore, the development of their generic versions needs special attention to replicate the similar drug release pattern leading to an identical therapeutic outcome. Further, drug-device combinations and 3D products are the latest advancements in precision medicine delivery and development. Methods: The regulatory guidelines for these products are being framed at many stages by various regulatory agencies like USFDA/EMA and still are in infancy at the moment if we look at wider perspectives and applications of nanomedicine. Results: For a formulation scientist, it is much needed that well-explained and directive guidelines should be made available before leading to the development of the generic versions of these nano-cargos. Conclusion: Here, in this review, we have summarized the silent features of the regulatory perspectives related to nanotechnology based next generation therapeutics and diagnostics.

Background Transdermal drug delivery represents an extremely attractive and innovative route across the skin owing to the possibility for achieving systemic effect of drugs. The present scenario demands a special focus on developing safe medicine with minimized toxic adverse effects related to most of the pharmacologically active agents. Transdermal drug delivery would be a focal paradigm which provides patient convenience, first-pass hepatic metabolism avoidance, local targeting and reduction in toxic effect related to various categories of drugs like, analgesics, antiinflammatory, antibiotics, antiviral, anaesthetic, anticancer etc. Even this route has challenges due to highly organized structure of skin which acts as a main barrier to penetration of drug via the skin. Method Several alternative possible strategies are available which overcome these barriers, including use of penetration enhancer, eletroporation, iontophoresis and various nanotechnologically developed nanocarrier systems. The latest one includes employing liposome, dendrimers, nanoparticles, ethosome, carbon nanotube and many more to avoid associated limitations of conventional formulations. Numerous transdermal products such as Estrasorb, Diractin, VivaGel®, Daytrana®, Aczone, Sileryst® are available in the market having a novel strategy to achieve higher penetration of drugs. This encourages formulation fraternity to develop structurally deformable and stable nanocarriers as an alternative approach for controlled and reliable drug delivery across the skin barrier. Discussion In this review, we will discuss nanocarriers mediated approaches that come-up with the solutions to the different challenges towards transdermal drug delivery, its clinical importance and latest insight to research in it. Conclusion The reports presented in this review confirm the wide application of nanocarriers for transdermal delivery of drug/gene.

Phytoconstituents have some limitations like poor bioavailability, stability issues and hence limited therapeutic efficacy upon administration. Such issues can be warranted using the controlled delivery of these molecules with the help of novel drug delivery systems especially nano-sized carrier systems. A wide range of biomaterial and their suitable engineering into a nanocarrier navigate them to the target site. In this chapter, we have covered the aspects of various nanosystems that are being used for the delivery of chemopreventive agents like polymeric nanoparticles, solid lipid nanoparticles, vesicular systems (liposomes and phytosomes), metallic nanoparticles (iron, gold, silver, and silica), nanocapsules, and hybrid nanosystems.

Cancer is a leading cause of human death throughout the world. The lack of specificity associated with conventional anti-cancer therapeutics leads to several side effects in addition. Cancer initiation and progression involve complex and multi carcinogenesis processes along with diverse cellular physiological system activities like cell signaling and apoptosis. An erratic microenvironment and drug resistance mechanism of cancer cells further causes failure of the most conventional chemotherapy regimen. Such limitations of the conventional cancer therapy advocate well engineered and smart therapeutics for cancer treatment. An ideal cancer treatment needs a customized and specialized drug delivery technology, which is capable to eradicate even a last cancer cell that may be responsible for the relapse of disease. Targeted nanocarriers (NCs) navigate the loaded therapeutics towards the specific site of action with the reduced adverse effects on the healthy cells. This review presents an overview of various molecular mechanisms and cellular alterations associated with cancer cell development and how targeted formulations can be designed for cancer therapy. A brief focuses on the applications of nanotechnology to exploit these mechanisms and molecular ports for the development of a novel targeted formulation for cancer treatment has also been discussed.

Chitosan, a cationic polymer, is very well utilized for numerous applications, including drug delivery. This polymer has been routinely explored for drug delivery through ocular route, because of its charge-based character and mucoadhesive properties. Chitosan and its different derivatives have been explored for controlled delivery of drugs, proteins, and peptides. Because of its well-established safety issue as reported in the literature for ocular delivery purposes, it has become the choice of the formulation development scientist either alone or in combination with other polymers/lipids, etc. This chapter deals with progress and recent reports published for the readers who are interested for polysaccharides-based ocular drug delivery and chitosan as an alternative option for the same.

Controlled delivery of a bioactive to specific organ, cellular and sub-cellular level is a desired feature of a drug carrier system. In order to achieve this goal, formulation scientists search for better alternatives of biomaterials to deliver the therapeutics in more precise and controlled manner in vivo. Zein, a plant protein obtained from corn, is a useful biomaterial for several industrial applications including agriculture, cosmetics, packaging and pharmaceuticals. Being a hydrophobic protein, which is biodegradable, biocompatible, economic to use and with generally regarded safe "GRAS" status, it is an attractive biomaterial for human use. Novel biomedical applications of zein such as controlled and targeted delivery of bioactives and tissue engineering are the current research interests of the scientific fraternity. Here we attempt to review the literature on zein as a biopolymer for drug/vaccine/gene delivery and its applicability in tissue engineering.

In clinical practices, solution of dorzolamide hydrochloride (DH) and timolol maléate (TM) is recommended for the treatment of glaucoma. However, low drug-contact time and poor ocular bioavailability of drugs due to drainage of solution, tear turnover and its dilution or lacrimation limits its uses. In addition, systemic absorption of TM may induce undesirable cardiovascular side effects. Chitosan (CS) is a polycationic biodegradable polymer which provides sustained and local delivery of drugs to the ocular sites. Hyaluronic acid (HA) also provides synergistic effect for mucoadhesion in association with chitosan. In the present study, hyaluronic acid modified chitosan nanoparticles (CS-HA-NPs) loaded with TM and DH were developed and characterized. The CS-HA-NPs were evaluated for size, shape, zeta potential, entrapment efficiency, and mucoadhesive strength. The in vitro release study was also performed in PBS pH 7.4. The ocular irritation potential of CS-HA-NPs was estimated using draize test on albino rabbits. A significant reduction in IOP level was obtained using CS-HA-NPs as compared to plain solution of drug and a comparable higher reduction in IOP level was observed as to CS-NPs. These results suggest that HA potentialy enhance the mucoadhesiveness and efficiency of CS-NPs and may be promising carrier for ocular drug delivery.

Controlled drug delivery to eye is one of the most challenging fields of pharmaceutical research. Low drug-contact time and poor ocular bioavailability due to drainage of solution, tear turnover and its dilution or lacrimation are the problems associated with conventional systems. In addition, anatomical barriers and physiological conditions of eye are also important parameters which control designing of drug delivery systems. Nanosized carriers like micro/nano-suspensions, liposome, niosome, dendrimer, nanoparticles, ocular inserts, implants, hydrogels and prodrug approaches have been developed for this purpose. These novel systems offer manifold advantages over conventional systems as they increase the efficiency of drug delivery by improving the release profile and also reduce drug toxicity. Conventional delivery systems get diluted with tear, washed away through the lacrimal gland and usually require administering at regular time intervals whereas nanocarriers release drug at constant rate for a prolonged period of time and thus enhance its absorption and site specific delivery. This review presents an overview of the various aspects of the ocular drug delivery, with special emphasis on nanocarrier based strategies, including structure of eye, its barriers, delivery routes and the challenges/limitations associated with development of novel nanocarriers. The recent progresses in therapy of ocular disease like gene therapy have also been included so that future options should also be considered from the delivery point of view. Recent progress in the delivery of proteins and peptides via ocular route has also been incorporated for reader benefit.

Hydroxyapatite (HA) has been extensively investigated as scaffolds for tissue engineering, as drug delivery agents, as non-viral gene carriers, as prosthetic coatings, and composites. Recent studies in our laboratory demonstrated the immunoadjuvant properties of HA when administered with malarial merozoite surface protein-119 (MSP-119). HA nanoceramic carrier was prepared by co-precipitation method that comprises of sintering and spray-drying technique. Prepared systems were characterized for crystallinity, size, shape, and antigen loading efficiency. Small size and large surface area of prepared HA demonstrated good adsorption efficiency of immunogens. Prepared nanoceramic formulations also showed slower in vitro antigen release and slower biodegrability behavior, which may lead to a prolonged exposure to antigen-presenting cells and lymphocytes. Furthermore, addition of mannose in nanoceramic formulation may additionally lead to increased stability and immunological reactions. Immunization with MSP-119 in nanoceramic-based adjuvant systems induced a vigorous immunoglobulin G (IgG) response, with higher IgG2a than IgG1 titers. In addition considerable amount of IFN-g and IL-2 was observed in spleen cells of mice immunized with nanoceramic-based vaccines. On the contrary, mice immunized with MSP-119 alone or with alum did not exhibit a significant cytotoxic response. The antibody responses to vaccine co-administered with HA was a mixed Th1/Th2 compared to the Th2-biased response obtained with alum. The prepared HA nanoparticles exhibit physicochemical properties that appear promising to make them a suitable immunoadjuvant to be used as antigen carriers for immunopotentiation.

The pH-sensitive liposomes have been extensively used as an alternative to conventional liposomes in effective intracellular delivery of therapeutics/antigen/DNA/diagnostics to various compartments of the target cell. Such liposomes are destabilized under acidic conditions of the endocytotic pathway as they usually contain pH-sensitive lipid components. Therefore, the encapsulated content is delivered into the intracellular bio-environment through destabilization or its fusion with the endosomal membrane. The therapeutic efficacy of pH-sensitive liposomes enables them as biomaterial with commercial utility especially in cancer treatment. In addition, targeting ligands including antibodies can be anchored on the surface of pH-sensitive liposomes to target specific cell surface receptors/antigen present on tumor cells. These vesicles have also been widely explored for antigen delivery and serve as immunological adjuvant to enhance the immune response to antigens. The present review deals with recent research updates on application of pH-sensitive liposomes in chemotherapy/diagnostics/antigen/gene delivery etc.

The pH-sensitive liposomes have been extensively studied in recent years as an advantageous alternative to conventional liposomes in effective targeting and accumulation of anticancer drugs in tumors. pH-sensitive liposomes usually contain phosphatidylethanolamine and stabilizing amphiphiles and can destabilize under acidic conditions of the endocytotic pathway. The drug loaded is thought to be delivered into the cytoplasm, probably through destabilization of or fusion with the endosome membrane. This fusogenic property makes the pH-sensitive liposomes more efficient in delivering anticancer drugs than conventional liposomes. The intra-cellular release of drug/gene/diagnostic agents can be achieved without altering their therapeutic efficacy by means of the endosomal escape phenomenon. Cell surface targeting ligands, including antibodies, can be appended on the surface of pH-sensitive liposomes to target specific receptors on tumor cells. This chapter provides an introduction to pH-sensitive liposomes and examples of their therapeutic interest as smart drug-delivery systems.

Breast cancer is a multifarious and heterogeneous disease. Identification of molecular alterations of surface/intracellular proteins particularly involved in proliferation and growth of breast cancer cells provides opportunities for the development of new targets for therapy. Several ligands that are routinely employed in targeted delivery to breast cancer cells have been found to be immunogenic. Therefore, endogenous bioligands may serve as a better option, which may be bio-competent and non-immunogenic, including estrogens. Membrane-associated estrogen binding sites are highly over-expressed in cancers of endocrine origin, such as breast. The selective high density of these receptor portals can be utilized for targeted breast cancer therapy. Numerous estrogen-chemotherapeutic agent conjugates have been successfully utilized for targeted drug/DNA delivery. Recently, nanocarrier(s) anchored with estrogens as site-directing ligands for the delivery of bioactive(s) have been exhaustively investigated for breast cancer therapy. This review presents a detail account of how estrogens, anti-estrogens, and their derivatives can be used for site-specific delivery of bioactive(s) to breast cancer cells. The sequential emergence of various estrogen-anticancer drug conjugates is highlighted. Additionally, carrier systems that utilize estrogens/anti-estrogens as ligands for purpose-specific site-selective novel drug delivery platforms have been reviewed and revisited in terms of their realistic clinical applications in breast cancer treatment.

Publisher Summary This chapter deals with aspects related to proteins and peptide delivery to or through the ocular route for treatment of local and systemic disorders. The main challenge in ocular delivery is to circumvent the protective barriers of the eye so that the therapeutic molecule can penetrate into the bio-milieu quantities sufficient to treat ophthalmic diseases or to exert its pharmacological action. Although conventional drug delivery systems such as solutions, suspensions, gels, ointments, and inserts have been investigated for controlled ocular delivery, they suffer from problems such as poor drainage of instilled solutions, tear turnover, poor corneal permeability, nasolacrimal drainage, systemic absorption, and blurred vision. Advanced drug delivery systems have been developed with the intention of optimizing and controlling delivery of ocular therapeutics to the target sites, either by increasing its penetration across the mucosa or by prolonging the contact time of the carrier with the ocular surface, and have shown promising results. Most of the proteins and peptides that have been delivered to the eye have been for the treatment of local ocular disorders. Although the ocular route is not the preferred route for systemic delivery of proteins due to limitations such as the poor permeability through a membrane of these large, hydrophilic molecules, metabolism (enzymatic degradation), and low capacity for transport, some significant efforts have been made in this area.

The present study was designed to develop a novel liposomal system containing dequalinium chloride (DEQ) as a charge-imparting constituent. Liposomes were prepared by cast film method with EPC:chol:DEQ molar ratio of 7:1:2. The novel liposomes were characterised for surface morphology, size and size distribution, entrapment efficiency and in vitro release study. Effect of osmotic shock was performed for establishment of liposomal bilayer stability and results demonstrated that incorporation of dequalinium chloride to the liposomal bilayer hindered the movement of entrapped solute. The hemolysis study was performed for estimation of its toxicological behaviour, if any. Cell-uptake studies showed that developed carrier could be useful for higher penetration in the cells compared to conventional liposomes. This being the first finding of its kind could open up a new era for the use of bolaamphiphiles like DEQ as an integral part of well established carrier like liposomes to provide them additional stability and efficacy.