Development of Nanomedicines and Nano-Similars: Recent Advances in Regulatory Landscape.

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.

Recent advances in search of oral heparin therapeutics.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant.

Estrogen-anchored pH-sensitive liposomes as nanomodule designed for site-specific delivery of doxorubicin in breast cancer therapy.

The present investigation reports the development of nanoengineered estrogen receptor (ER) targeted pH-sensitive liposome for the site-specific intracellular delivery of doxorubicin (DOX) for breast cancer therapy. Estrone, a bioligand, was anchored on the surface of pH-sensitive liposome for drug targeting to ERs. The estrone-anchored pH-sensitive liposomes (ES-pH-sensitive-SL) showed fusogenic potential at acidic pH (5.5). In vitro cytotoxicity studies carried out on ER-positive MCF-7 breast carcinoma cells revealed that ES-pH-sensitive-SL formulation was more cytotoxic than non-pH-sensitive targeted liposomes (ES-SL). The flow cytometry analysis confirmed significant enhanced uptake (p < 0.05) of ES-pH-sensitive-SL by MCF-7 cells. Intracellular delivery and nuclear localization of the DOX was confirmed by fluorescence microscopy. The mechanism for higher cytotoxicity shown by estrone-anchored pH-sensitive liposomal-DOX was elucidated using reactive oxygen species (ROS) determination. The in vivo biodistribution studies and antitumor activities of formulations were evaluated on tumor bearing female Balb/c mice followed by intravenous administration. The ES-pH-sensitive-SL efficiently suppressed the breast tumor growth in comparison to both ES-SL and free DOX. Serum enzyme activities such as LDH and CPK levels were assayed for the evaluation of DOX induced cardiotoxicity. The ES-pH-sensitive-SL accelerated the intracellular trafficking of encapsulated DOX, thus increasing the therapeutic efficacy. The findings support that estrone-anchored pH-sensitive liposomes could be one of the promising nanocarriers for the targeted intracellular delivery of anticancer agents to breast cancer with reduced systemic side effects.

Chitosan nanoconstructs for improved oral delivery of low molecular weight heparin: In vitro and in vivo evaluation.

The aim of present study was to investigate the potential of mucoadhesive polymer chitosan (CS) and N-trimethyl chitosan (TMC) based nanoparticulate systems for oral bioavailability enhancement of low molecular weight heparin (LMWH). The TMC was synthesized by methylation of chitosan followed by characterization using infrared spectroscopy and (1)H-NMR spectroscopy. The IR and NMR spectra of TMC confirmed the presence of trimethyl groups and estimated the degree of quaternization for TMC about 46%. TMC nanoparticles were then prepared by ionic gelation method. The developed CS-NPs and TMC-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency, in vitro release behavior and storage stability at different temperature and simulated gastrointestinal tract conditions. The fluorescent microscopy study confirmed the higher particle uptake of TMC-NPs by gastrointestinal epithelium in comparison to the CS-NPs. The concentration of LMWH in the systemic circulation followed by oral administration of formulations was estimated using FXa chromogenic assay. A significant increase (p<0.05) in the oral bioavailability of LMWH was observed with TMC-NPs than both CS-NPs as well as plain LMWH solution. These findings suggested that TMC nanoparicles hold promise for oral delivery of LMWH and clinical applicability for the treatment of vascular disorders like deep vein thrombosis and pulmonary embolism, etc.

Biomimetic solid lipid nanoparticles for oral bioavailability enhancement of low molecular weight heparin and its lipid conjugates: in vitro and in vivo evaluation.

Low molecular weight heparin (LMWH) is an anionic oligosaccharide macromolecule, which is commonly administered via parenteral routes for the treatment of vascular disorders like deep vein thrombosis (DVT) and pulmonary embolism (PE). Oral heparin delivery can tremendously improve the treatment of such disorders but is restricted due to its large size and anionic character. The present investigation describes synthesis of LMWH-lipid conjugates and their encapsulation in phosphatidylcholine stabilized biomimetic solid lipid nanoparticles (SLNs) for LMWH's oral bioavailability enhancement. Briefly, LMWH was conjugated with different saturated lipids of varying chain length (stearic acid, palmitic acid and myristic acid) using carbodiimide chemistry. The conjugation was confirmed with IR and (1)H NMR spectroscopy. The LMWH-lipid conjugate loaded SLNs were characterized for various parameters like shape, size, zeta potential, entrapment efficiency and in vitro release behavior in different simulated GIT pH mediums. The GIT toxicity of LMWH-lipid conjugate loaded SLNs to different tissues of intestinal epithelium was observed using H&E staining followed by microscopic observation at cellular level. The LMWH-lipid conjugate loaded SLNs were found to be safe for oral administration. The plasma concentration of LMWH was estimated using anti-FXa chromogenic assay. A significantly higher bioavailability (p < 0.05) of LMWH was observed using LMWH-lipid conjugates loaded SLNs in comparison to LMWH loaded SLNs and free LMWH. The order of different conjugates in bioavailability enhancement was LMWH-stearic acid > LMWH-palmitic acid > LMWH-myristic acid. This strategy holds promise for future applications of oral delivery of LMWH conjugates in the form of SLNs particularly for the treatment of cardiovascular disease like DVT and PE.

Recent advances in mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymeric carriers.

IMPORTANCE OF THE FIELD: The mucosal delivery of vaccines provides the basis for induction of humoral, cellular and mucosal immune responses against infectious diseases. The delivery of antigens to and through mucosal barriers always remains challenging due to adverse physiological conditions (pH and enzymes) and biological barriers created by tight epithelial junctions restricting transportation of macromolecules. Mucoadhesive and biodegradable polymers offer numerous advantages in therapeutic delivery of proteins/antigens particularly through the mucosal route by protecting antigens from degradation, increasing concentration of antigen in the vicinity of mucosal tissue for better absorption, extending their residence time in the body and/or targeting them to sites of antigen uptake. Furthermore, antigen can be delivered more effectively to the antigen presenting cells by anchoring the ligand having affinity on the surface of carrier for the receptors present on the mucosal epithelial cells. AREAS COVERED IN THIS REVIEW: The present review covers various polymeric carriers, which allow the possibility of modification and manipulation of their properties, thereby, enhancing the effectiveness of mucosal vaccines. This article reviews the recent literature and patents in the field of vaccine delivery using mucoadhesive polymeric carriers. WHAT THE READER WILL GAIN: The reader will gain insights into various natural polymers, synthetic polymers and ligand derived polymeric carrier systems studied to enhance mucosal immunization. TAKE HOME MESSAGE: Biodegradable polymeric carriers represent a promising approach for mucosal delivery of vaccine.

Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development, characterization, and evaluation.

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.

Advances in effective vaccine development against hepatitis B: focus on mucosal vaccine delivery strategies.

Hepatitis B virus causes chronic necroinflammatory liver disease, which is known as hepatitis B. This inflammatory condition may further aggravate liver cirrhosis or hepatocellular carcinoma. Currently available conventional hepatitis B vaccine contains one of the viral envelope proteins, hepatitis B surface antigen, which develops a humoral immune response and hence protects against the infection. However, it fails in developing the desired cellular immune response, which is one of the most important bioresponses contributing to virus elimination from infected hepatocytes. At the same time, moderate humoral response developed following conventional vaccination do not protect the mucosal surfaces through serosal response. The mucosa is a predominant entry site for most of the infectious pathogens. Several strategies, including the use of adjuvants, development of surface functionalized novel antigen carriers and mucosal immunization for example, have been explored to investigate their role in addressing the limitations associated with the current hepatitis B vaccine. This review focuses on recent advances that have been made in order to develop an effective vaccine against hepatitis B.