Current Leads and Marketed Formulations for an Effective Treatment of Fungal Infections.

Severe antifungal infections, especially opportunistic fungal infections, are increasing tremendously in immunocompromised patients. This is basically because more patients enduring neoplastic diseases lead to the wide use of chemotherapy, thus causing immunosuppression. Patients with HIV infection, burns, pancreatitis and neutropenia are also amenable to fungal infections. Out of a plethora of antifungal drugs applied, Amphotericin B, being a broad-spectrum antimicrobial drug, has been the gold standard treatment for a diverse variety of fungal infections since the 1950s and visceral leishmaniasis since the 1960s. However, Amphotericin B has major constraints of poor bioavailability and kidney toxicity, due to which newer antifungal compounds are being used. This article discusses fungal and parasitic diseases and formulations for treating these ailments.

The Custom R Group Enumeration with Various R Group Libraries at Designated Sites on Amphotericin B.

BACKGROUND: Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups. METHODS: Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties. RESULTS: We identified fourteen hits with improved predicted aqueous solubility and cell permeability. CONCLUSION: Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.

Theranostic Applications of Nanomaterials in the Field of Cardiovascular Diseases.

A large percentage of people are being exposed to mortality due to cardiovascular diseases. Convention approaches have not provided satisfactory outcomes in the management of these diseases. To overcome the limitations of conventional approaches, nanomaterials like nanoparticles, nanotubes, micelles, lipid-based nanocarriers, dendrimers, and carbon-based nanoformulations represent the new aspect of diagnosis and treatment of cardiovascular diseases. The unique inherent properties of the nanomaterials are the major reasons for their rapidly growing demand in the field of medicine. Profound knowledge in the field of nanotechnology and biomedicine is needed for the notable translation of nanomaterials into theranostic cardiovascular applications. In this review, the authors have summarized different nanomaterials which are being extensively used to diagnose and treat the diseases, such as coronary heart disease, myocardial infarction, atherosclerosis, stroke and thrombosis.

Challenges and Opportunities of Nanotechnological based Approach for the Treatment of Tuberculosis.

Mycobacterium tuberculosis, because of its unique biochemical behavior and a complex host relationship, successfully evades the host immune system. Therefore, chemotherapy appears to be the first-line option for patients with tuberculosis. However, poor patient compliance with anti-tubercular treatment and variability in anti-tubercular drug pharmacokinetics are among the major driving factors for the emergence of drug resistance. The rising cases of extrapulmonary TB, cross-resistance patterns, high prevalence of tuberculosis and HIV co-infections make tuberculosis treatment more complicated than conventional multidrug therapy. Due to their distinct advantages like higher solubility, increased payload, controlled release profiles, tissue-specific accumulation, and lack of toxicity, nanoscale materials have immense potential for drug delivery applications. An appropriate selection of polymer and careful particle engineering further improves therapeutic outcomes with opportunities to overcome conventional anti-tubercular drugs' challenges. The present review introduces the prospect of using nanotechnology in tuberculosis (TB) chemotherapy and provides a comprehensive overview of recent advances in nanocarriers implied for delivering anti-tubercular drugs.

Recent advances in topical carriers of anti-fungal agents.

Fungal skin infections are the most common global issue for skin health. Fungal infections are often treated by topical or systemic anti-fungal therapy. Topical fungal therapy is usually preferred because of their targeted therapy and fewer side effects. Advanced topical carriers because of their distinct structural and functional features, overcome biopharmaceutical challenges associated with conventional drug delivery systems like poor retention and low bioavailability. Literature evidence indicated topical nanocarriers loaded with anti-fungal agents display superior therapeutic response with minimum toxicity. Nanocarriers often used for topical anti-fungal medication includes Solid-Lipid nanoparticles, Microemulsions, Liposomes, Niosomes, Microsponge, Nanogel, Nanoemulsion, Micelles etc. This review summarizes recent advances in novel strategies employed in topical carriers to improve the therapeutic performance of anti-fungal drugs.

Development and characterization of pellets for targeted delivery of 5-fluorouracil and phytic acid for treatment of colon cancer in Wistar rat.

The present study was designed to investigate the therapeutic efficacy of metal chelator and anticancer drug in the treatment of colorectal cancer (CRC). Pellets containing Phytic acid, 5- Fluorouracil (5-FU), Microcrystalline cellulose (MCC) PH 101, Hydroxypropyl Methylcellulose (HPMC) and Barium sulfate were prepared by using extrusion spheronization technique. Prepared pellets were coated with Eudragit S100 to achieve colon-specific drug delivery. Pellets were characterized for various pharmaceutical and micromeritic attributes. The in vivo therapeutic efficacy comprising of both pharmacokinetic and pharmacodynamic parameters was determined in Ehrlich ascites carcinoma (EAC) induced cancer animal model. Phytic acid and 5-FU combinations seem to exert higher cytotoxic activity via increased reactive oxygen species (ROS) level by chelating manganese. Further pharmacokinetic studies reveled approximately 50% lower Cmax in the finished formulation, indicates lower systemic exposure to the drug. X-ray radiography ensures the localized delivery of the encapsulated drug. Histopathological studies indicated no significant local toxicity compared to the uncoated formulation. Results inferred that the proposed combination has superior anticancer activity with minimum systemic and local toxicity and it opens a new avenue in the treatment of colorectal cancer.

Inhalational Drug Delivery in Pulmonary Aspergillosis.

Pulmonary infections have long represented one of the major threats to humans. These vary from acute to chronic conditions, depending upon the underlying disease of the airways. Pulmonary aspergillosis (PMAP) has raised vital concerns in the immunocompromised patients. The fungal infection is difficult to diagnose in the early stages, often making the disease more complicated. Currently, three classes of antifungal agents are available on the market for the treatment of pulmonary infections. These agents are available in oral and intravenous forms only, which limits the availability of therapeutic concentrations of drug in the lungs for longer durations. Consequently, this leads to therapeutic failure and/or resistance of the organism(s) towards the antifungal agents because the optimum amount of drug does not reach the infection site. To combat the issues associated with the conventional regimens, inhalation of antifungal agents is gaining importance because administration to the lungs offers huge advantages of localized and targeted delivery. A wide range of inhalational devices such as nebulizers, dry powder inhalers, and metered dose inhalers are available on the market to deliver drug molecules to the lungs effectively. However, their clinical utility is limited to conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis only. For a few decades, inhalation therapy has also been gaining importance to treat infectious diseases such as tuberculosis and aspergillosis, though more research efforts are required to make the transition from bench to bedside. The current review provides an explicit account of the potential role of inhalation drug delivery in PMAP.

Recent advances in aerosolised drug delivery.

Pulmonary route is extensively studied for the diagnosis and treatment of pulmonary and extra pulmonary disease conditions such as asthma, tuberculosis, emphysema, and bronchitis. Formulation design, inhalation device and particle size play key role in determining the aerosol performance. The lack of desired clinical outcome along with the problem regarding efficacy or any adverse drug effect may arise due to improper training and education in use of the device to control the actuation and aerosol inhalation. This review summarizes the difference in the mechanistic features of current marketed aerosol delivery devices with respect to mechanism of aerosol generation with possible advancements in the aerosol design. The delivery options in the pulmonary route and its merits together with the limitations are also discussed. An update is provided regarding the current research and clinical outcome of the use of inhalational technology.

Development of Nanofibrous Ocular Insert for Retinal Delivery of Fluocinolone Acetonide.

PURPOSE: Topical formulations are less effective in treating retinal inflammatory diseases due to poor avaliability of drug at target tissues. Nanofibers due to their unique structural features show great promise for drug delivery to retinal segment following topical application. AIM: The aim of the present study was to design preservative free controlled release ocular drug delivery system for improved drug availability at the target site with higher patient compliance. MATERIALS AND METHODS: The fluocinolone acetonide-loaded PCL nanofibers were prepared by electrospinning technique. Optimized formulation was chosen on the basis of outcome of inclusive in-vitro characterization, SEM, FTIR, XRD, in-vitro release, isotonicity, sterility, and biodegradibility. The relative efficacy of optimized formulation was investigated in rabbits against its marketed counter part. RESULTS: The prepared fibers were sterile, smooth, non-woven and they showed extended drug release behavior. Ocular and plasma kinetics showed therapeutic levels at the target site while minimizing systemic distribution. CONCLUSIONS: Preclinical results established that PCL nanofibers serve as a promising drug carrier for retinal segment.

Development and Characterization of Novel Medicated Nanofiber for the Treatment of Periodontitis.

Periodontitis is a common microbial infection that involves pocket formation due to the destruction of periodontal ligament. The present work is oriented to provide a holistic approach for the treatment of periodontitis comprising localized delivery of nanometric hydroxyapatite as a reinforcing filler and silver-metronidazole as periodontal pocket disinfectant adjunct to current periodontal therapy because of its broad-spectrum antimicrobial activity and low systemic toxicity. In the present work, electrospinning technique was used to prepare medicated nanofiber enriched with antibacterial-hydroxyapatite layers for dental application. The optimized formulation was characterized by SEM, FTIR, DSC, XRD, etc. Safety assessment and therapeutic potential of optimized formulation was evaluated in both in vitro and in vivo animal models. The newly synthesized complex (silver-metronidazole) exhibited higher antibacterial activity against the selected strain over the referenced silver and metronidazole. Results of in vitro studies suggested good compatibility of the metal complex with the polymer matrix. The drug release behavior from optimized formulation shows constant in vitro release behavior. Both in vitro and in vivo studies show broad-spectrum antimicrobial activity of the metal complex and demonstrate the potential of biomimetic nano-hydroxyapatite for filling periodontal defects. All these observations indicated that the above formulation could play a useful role in the treatment of periodontitis. Graphical Abstract ᅟ.

Advancement in the treatment of haemophilia.

Poor understanding of the pathophysiological mechanisms involved in Haemophilia is a major obstacle in accessing effective haemophilia disease management. Haemophilia is a life-frightening bleeding problem in which there are repeated bleeding episodes. Various approaches have been used, involves clotting factor replacement therapy for effective bleeding control in Haemophilia. Current advancements in the management of patients with haemophilia include altered pharmacokinetics clotting factor concentrates for better prophylaxis and management of haemophilia. This review sums up the prophylactic treatment, novel production techniques, other treatment techniques and the present position of gene therapy in the treatment of haemophilia.

Development and Characterization of Gastroretentive High-Density Pellets Lodged With Zero Valent Iron Nanoparticles.

The objective of the present study is to improve iron bioavailability using high-density gastroretentive pellets of zero valent iron nanoparticles (ZVINPs). ZVINPs were prepared by the chemical reduction method and were characterized for surface morphology, surface charge, and thermal properties. High-density gastroretentive pellets of iron nanoparticles were prepared using spheronization technique. Pellets were characterized for its micromeritic properties, in vitro drug release, and ex vivo permeability. The pharmacokinetic parameters, organ distribution, and toxicity of the optimized pellets were investigated in Wistar rats. In vivo results revealed more than 2-fold increases in oral bioavailability of iron by pellets compared to plane ferrous sulfate. Toxicological studies of the carriers indicated no evidence of liver damage in acute treatment; however, few complications were observed in chronic treatment groups. These results indicated that ZVINPs pellets successfully improve the oral iron bioavailability but need to obtain more information on repeated dose toxicity to initiate the clinical evaluation of investigational products.

Recent Advances in Nanosuspension Technology for Drug Delivery.

BACKGROUND: Discovery and development of BCS class 1 drugs through high throughput screening is one of the biggest challenge faced by formulation scientist. METHODS: There are a number of approaches that have been exploited to enhance the solubility and permeability of drugs. Among them, development of nanosuspension has offered several benefits. These techniques may increase effective surface area due to nanonization of drug particles and further increases saturation solubility and dissolution properties for improved bioavailability. Various development methods are patented which are cost effective and easy to scale up. CONCLUSION: Several unique features of nanosuspension make it a versatile delivery system for different routes of administration including oral, dermal, ocular, parenteral and pulmonary. The present review is focused on preparatory techniques and formulation considerations of nanosuspension. Brief information about evaluation parameters, applications of nanosuspension in drug delivery and patented and marketed products available is also discussed.

Non-invasive systemic drug delivery through mucosal routes.

Science of drug delivery has achieved tremendous milestones in the last few decades. Emergence of novel drug delivery techniques and the most popular nanotechnology directed the drug delivery to another level. Without any doubt, present technology holds the proficiency to approach even the intercellular targets. Between all these success auras, there lies wads of giant challenges. One such challenge is delivering the molecule directly to the blood stream. Parenteral route is considered as the most effective route for delivering active pharmaceutical substances, but is associated with major disadvantages of painful drug delivery. Modern drug delivery suggests several approaches to outstrip this painful phenomenon. In the present article, we represent a new systematic vision to understand the ability and desirability of mucosal sites to achieve painless drug delivery. Human mucosa presents supreme proximity to the blood circulation that one can even observe with naked eye. Advances in drug delivery provide numerous approaches to exploit the mucosa for systemic reach. However, the revolutionary success is still unapproachable, with an understandable reason of associated complexities and challenges. This manuscript summarizes the significance of each mucosal site, on the basis of anatomical-physiological grounds. Particular attention is given to rationalize the selection of disease and a suitable drug delivery approach for its treatment.

Efaverinz and nano-gold-loaded mannosylated niosomes: a host cell-targeted topical HIV-1 prophylaxis via thermogel system.

Sexual dissemination of Human Immunodeficiency Virus-1 (HIV-1) is the prime mode of its spread. Topical microbicidal approach has gained much attention, but no real success is observed till date, either due to toxicity or resistance of active moieties and the lack of efficient drug delivery approaches. In this research protocol, a unique combination approach of a standard drug moiety, that is, Efaverinz (EFV) and a nanometal, that is, gold nanoparticles (GNPs) was tried. Both these candidates were delivered through a mannosylated niosomal system, to exploit protein (lectins present on HIV host cells) - carbohydrate (oligosaccharides such as mannan present on HIV gp-120 receptor) interaction. GNPs (10.4 nm average size) were entrapped inside the aqueous core, whereas lipophilic EFV was loaded in the bilayer membrane. Results demonstrated a significant increase in antiviral activity when EFV was fired with GNPs. Delivery of this combination via mannosylated niosomes proved to be a perfect approach with exceedingly well potential compared to non liganded niosomal system. A thermosensitive gel vehicle was prepared and the loaded niosomes were dispersed in it to have a nanogel system. The optimized formulation was evaluated for its prophylactic activity and the results showed completely inhibited viral dissemination at folds dilution levels.

Structure Based Drug Design: Clinically Relevant HIV-1 Integrase Inhibitors.

HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyzes the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In the last two decades, a number of integrase inhibitors have been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents. This review article summarizes the structural insights required for the inhibition of the HIV1 integrase in the context of clinically relevant HIV1 integrase inhibitors. Additionally, the structural features required for overcoming HIV resistance have been discussed. These insights will update the ongoing design of novel antiviral inhibitors.

Nanofibers: An Effective Tool for Controlled and Sustained Drug Delivery.

BACKGROUND: Electrospun nonwoven nanofibers are emerging as a novel carrier for verity of drugs meant for treatment of infections, disorders and tissue engineering scaffolds. These systems may used widely in controlled release of drug that are beneficial for the health management. Nonwoven structures may provide great surface area, absorbable, simplistic processing and economical. For water loving small molecule drugs, their high water solubility and poor partition and compatibility issues with polymers make it long term release yet more challenging. METHODS: Several strategies have been explored to control the release of hydrophilic drugs with high drug payload in electrospun fibers. Various techniques like blending, co-axial electrospinning can be used to improve drug payload. RESULTS: Studies have suggested that electrospinning methods are important attributes of developed nanofibers. Further, types of polymers are also important contributory factor on drug load and release. This review gives an overview of nanofibers used for controlled and sustained release for drugs. CONCLUSIONS: This articles enlightened that physicochemical and biological properties of nanofibers may be regulated by changing processing and formulation parameters.

Recent advances in metal nanoparticles in cancer therapy.

Metal nanoparticles (NPs) may have the potential to overcome problems related to conventional chemotherapy. Metal NPs reported to play a beneficial and powerful role in cancer therapy providing better targeting, gene silencing and drug delivery. Functionalised metal NPs with targeting ligands offer a better control of energy deposition in the tumours. Apart from therapeutic benefits, metal NPs are also used as a diagnostic tool for the imaging of cancer cells. Metal NP-based therapeutic systems not only provide simultaneous diagnostic and therapy but also allow controlled and targeted drug release which helps to revolutionise cancer treatment and management. This review addresses the advancement of metal NPs in tumour therapy with a focus on those being explained into clinical settings.

Spray Dried Formulation of 5-Fluorouracil Embedded with Probiotic Biomass: In Vitro and In Vivo Studies.

The present study is utilizing the targeted therapeutic approach and antioxidant potential of selected probiotic biomass in mitigating toxic side effects of chemotherapeutic agents. Multicomponent carrier system consisting of 5-fluorouracil (5-FU) and selected probiotic strain with higher free radical scavenging activity was prepared using spray drying technique. Prepared spray dried microparticles were characterized for various physical, pharmaceutical, and biopharmaceutical properties including particle size, moisture content, entrapment efficiency, in vitro drug release, DSC, XRD, cell uptake, histopathology, and pharmacokinetic studies. In addition to the above, optimized formulation was subjected to in vivo targeting efficacy studies using radiographic technique. Optimized formulation meets the necessary physical requirement for pharmaceutical powder. X-ray studies revealed that the prepared spray dried formulations are able to target the colon. Pharmacokinetic endpoints with an extended t 1/2 and lower C max indicate lower systemic toxicity. Intact nature of colonic epithelium in experimental formulation clearly demonstrates the protective role of Lactobacillus rhamnosus in minimizing the harmful consequence induced by 5-FU. Existing outcomes provide the basis for a combination of targeted therapeutic approach with natural antioxidant capacity of potential probiotic strain which could help to mitigate the problems associated with traditional chemotherapy.