Oncology biosimilars: New developments and future directions.

Biologicals have become an integral part of cancer treatment both as therapeutic agents and as supportive care agents. It is important to know that biologics are large, complex molecular entities requiring extensive immunogenicity testing and pharmacovigilance strategies to ensure no immune response is evoked in the body. Oncology's pharmacological market is dominated by biologics; however, their high development and manufacturing costs are burdensome to health care systems. Biologics being the most expensive prescription drugs on the market limit the accessibility for necessary treatment in the case of many patients. As biologics patents expire, the development of biosimilars is underway in an effort to lower costs and enable patients to access new cancer therapies. Regulatory guidelines for biosimilars have now been established and are constantly being revised to address any issues, facilitating their robust development. Moreover, many scientific societies offer guidance to help stakeholders better understand current regulations and biosimilar's safety. Despite the potential cost benefits, lack of knowledge about biosimilars, and the possibility of immunogenicity have created an uncertain environment for healthcare professionals and patients. In this review, we provide an overview of relevant legislation and regulations, pharmacoeconomics, and stakeholder perceptions regarding biosimilars. The article also describes biosimilars in development, as well as the ones currently available on the market.

Pivotal role of nitrogen heterocycles in Alzheimer's disease drug discovery.

Alzheimer's disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.

Transdermal Delivery of Chemotherapeutics: Strategies, Requirements, and Opportunities.

Chemotherapeutic drugs are primarily administered to cancer patients via oral or parenteral routes. The use of transdermal drug delivery could potentially be a better alternative to decrease the dose frequency and severity of adverse or toxic effects associated with oral or parenteral administration of chemotherapeutic drugs. The transdermal delivery of drugs has shown to be advantageous for the treatment of highly localized tumors in certain types of breast and skin cancers. In addition, the transdermal route can be used to deliver low-dose chemotherapeutics in a sustained manner. The transdermal route can also be utilized for vaccine design in cancer management, for example, vaccines against cervical cancer. However, the design of transdermal formulations may be challenging in terms of the conjugation chemistry of the molecules and the sustained and reproducible delivery of therapeutically efficacious doses. In this review, we discuss the nano-carrier systems, such as nanoparticles, liposomes, etc., used in recent literature to deliver chemotherapeutic agents. The advantages of transdermal route over oral and parenteral routes for popular chemotherapeutic drugs are summarized. Furthermore, we also discuss a possible in silico approach, Formulating for Efficacy™, to design transdermal formulations that would probably be economical, robust, and more efficacious.

Physical Compatibility, Antimicrobial Activity, and Stability of Cefazolin Combined with Gentamicin or Ethanol in Sodium Citrate as a Catheter Lock Solution.

BACKGROUND: Catheters provide vascular access for patients requiring intravenous treatments, but frequently are a source of infection and/or thrombosis. Instilling a solution of an antimicrobial agent with an anticoagulant into the catheter lumen may salvage-infected catheters. OBJECTIVE: The aim is to evaluate the physical compatibility, antibacterial activity, and stability of varying combinations of cefazolin (10 mg/mL), 40% ethanol, 4% sodium citrate with or without gentamicin (1 mg/mL) as a catheter lock solution over 48 h. METHODS: Admixtures were prepared using aseptic technique and stored under four conditions with or without light at 25°C or 37°C. Prepared admixtures were assessed for physical compatibility, antimicrobial susceptibility, and chemical stability in triplicate at 0, 24 and 48 h. Admixture physical compatibility was determined by visual clarity, pH, and ultraviolet (UV) spectroscopy. Antibacterial activity was determined using the Kirby-Bauer disk diffusion method. The chemical stability of cefazolin and gentamicin were assessed using high performance liquid chromatography and UV spectroscopy, respectively. RESULTS: All admixtures maintained clarity for 48 h. All admixtures stored at 25°C and the admixture containing 10 mg/mL cefazolin-4% sodium citrate stored at 37°C sustained antimicrobial activity and were chemically stable. A significant change in pH, antimicrobial activity, cefazolin concentration (<95% of baseline), were observed in admixtures containing ethanol stored at 37°C after 24 h. Gentamicin concentrations remained stable throughout the study. CONCLUSION: The admixture of 10 mg/mL cefazolin-4% sodium citrate sustained antimicrobial activity over 48 h and was chemically stable. However, admixtures containing ethanol stored at 37°C showed incompatibility with decreased antibacterial activity and cefazolin degradation after 24 h.

Biomedical Applications of Electrospun Nanofibers: Drug and Nanoparticle Delivery.

The electrospinning process has gained popularity due to its ease of use, simplicity and diverse applications. The properties of electrospun fibers can be controlled by modifying either process variables (e.g., applied voltage, solution flow rate, and distance between charged capillary and collector) or polymeric solution properties (e.g., concentration, molecular weight, viscosity, surface tension, solvent volatility, conductivity, and surface charge density). However, many variables affecting electrospinning are interdependent. An optimized electrospinning process is one in which these parameters remain constant and continuously produce nanofibers consistent in physicochemical properties. In addition, nozzle configurations, such as single nozzle, coaxial, multi-jet electrospinning, have an impact on the fiber characteristics. The polymeric solution could be aqueous, a polymeric melt or an emulsion, which in turn leads to different types of nanofiber formation. Nanofiber properties can also be modified by polarity inversion and by varying the collector design. The active moiety is incorporated into polymeric fibers by blending, surface modification or emulsion formation. The nanofibers can be further modified to deliver multiple drugs, and multilayer polymer coating allows sustained release of the incorporated active moiety. Electrospun nanofibers prepared from polymers are used to deliver antibiotic and anticancer agents, DNA, RNA, proteins and growth factors. This review provides a compilation of studies involving the use of electrospun fibers in biomedical applications with emphasis on nanoparticle-impregnated nanofibers.

Ocular Drug Delivery Barriers-Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases.

Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed.

Development and Evaluation of a Novel Microemulsion of Dexamethasone and Tobramycin for Topical Ocular Administration.

PURPOSE: The purpose of this study was to develop and evaluate a novel dexamethasone- and tobramycin-loaded microemulsion for its potential for treating anterior segment eye infections. METHODS: The microemulsion was evaluated for pH, particle size, zeta potential, light transmittance, morphology, and in vitro drug release. Sterility of the microemulsion was evaluated by direct as well as plate inoculation methods. Anti-inflammatory activity of dexamethasone, bactericidal activity of tobramycin, and cytotoxicity of the microemulsion were assessed and compared to that of the marketed eye drop suspension (Tobradex®). Histological evaluation was performed in bovine corneas to assess the safety of microemulsion in comparison to Tobradex suspension. In addition, the stability of the microemulsion was studied at 4°C, 25°C, and 40°C. RESULTS: The pH of the microemulsion was close to the pH of tear fluid. The microemulsion displayed an average globule size under 20 nm, with light transmittance around 95%-100%. The aseptically prepared microemulsion remained sterile for up to 14 days. The cytotoxicity of the microemulsion in bovine corneal endothelial cells was comparable to that of the Tobradex suspension. The anti-inflammatory activity of dexamethasone and the antibacterial activity of tobramycin from the microemulsion were significantly higher than those of the Tobradex suspension (P < 0.05). Histological evaluation showed an intact corneal epithelium without any signs of toxicity, and the developed microemulsion was found to be stable at 4°C and 25°C for 3 months. CONCLUSION: In conclusion, the developed microemulsion could be explored as a suitable alternative to the marketed suspension for treating anterior segment eye infections.

Tanshinone IIA Inhibits VEGF Secretion and HIF-1α Expression in Cultured Human Retinal Pigment Epithelial Cells under Hypoxia.

PURPOSE: The current work intends to study the activity of tanshinone IIA on secretion of vascular endothelial growth factor (VEGF) and expression of hypoxia inducible factor 1α (HIF-1α) in human retinal pigment epithelial cells (ARPE-19 cells) under hypoxic condition. METHODS: The cytotoxicity of tanshinone IIA was tested in ARPE-19 cells by MTT assay. ARPE-19 cells were incubated with different concentrations of cobalt chloride (100, 150, and 200 µM) for 12 h, and levels of expressed HIF-1α and secreted VEGF were quantified through Western blot and ELISA, respectively. Further, ARPE-19 cells were pretreated for 1 h with different concentrations of tanshinone IIA (5, 10, 15, and 18 µM). After 1 h, the cells were subjected to hypoxic condition using 150 µM cobalt chloride for 12 h in the presence and absence of tanshinone IIA. The cells were then harvested, and the secreted VEGF and expressed HIF-1α was studied. RESULTS: Tanshinone IIA at concentrations of 5, 10, 15, and 18 µM did not show cytotoxicity in ARPE-19 cells. Chemical hypoxia induced by cobalt chloride caused a significant increase in VEGF level in a dose-dependent manner, and HIF-1α expression peaked at 150 µM. Based on the data, cobalt chloride concentration was maintained at 150 µM for further studies. Tanshinone IIA decreased the level of HIF-1α and VEGF secretion in a dose-dependent manner under hypoxic condition. CONCLUSION: Tanshinone IIA could be explored as a new potential candidate for treating wet AMD.

Dry Eye Disease: Present Challenges in the Management and Future Trends.

Dry eye disease (DED) is a tear film disorder resulting in hyperosmolarity of the tear film and inflammation of the ocular surface. DED is also referred to as keratoconjunctivitis sicca (KCS) and dry eye syndrome. DED represents a significant public health issue, particularly in older adults, and needs more research and attention. Despite the urgent need for safe and effective pharmacotherapies, there is currently only one approved medication, Restasis®, to tackle DED. In this review article, we present an overview of DED, classification, epidemiology, pathophysiology, diagnosis, and risk factors of DED. Special emphasis is placed on current treatment options for DED such as artificial tears, lipid-containing lubricants, liposomal spray, inserts, anti-inflammatory or immunosuppressant drops, antibiotics, dietary omega-3 essential fatty acids, autologous serum, intense-pulsed-light (IPL), punctual plugs, moisture-retaining eyeglasses, hydrophilic bandage contact lenses and secretagogues. The review also summarizes trends in DED treatment that are patented and are currently under investigation in clinical trials.