Mayur M. Patel

Getting into the brain: approaches to enhance brain drug delivery.

Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies totransport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer’s disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.

Angiogenic targets for potential disorders

This review shall familiarize the readers with various fundamental aspects of angiogenesis. Angiogenesis is a feature of a limited number of physiological processes like wound healing, ovulation, development of the corpus luteum, embryogenesis, lactating breast, during immune response, and during Inflammation. It is driven by a cocktail of growth factors and pro‐angiogenic cytokines and is tempered by an equally diverse group of inhibitors of neovascularization. The properties and biological functions of angiogenic growth factors such as VEGF, FGF‐2, nitric oxide, MMP, angiopoietin, TGF‐β as well as various inhibitors such as angiostatin, endostatin, thrombospondin, canstatin, DII4, PEDF are discussed in this review with respect to their impact on angiogenic process. In recent years, it has become increasingly evident that excessive, insufficient, or abnormal angiogenesis contributes to the pathogenesis of many more disorders. A long list of disorders is characterized or caused by excessive or insufficient angiogenesis whereas several congenital or inherited diseases are also caused by abnormal vascular remodeling. It may be possible in the future to develop specific anti‐angiogenic agents that offer a potential therapy for cancer and angiogenic diseases.

Design, Development and Optimization of a Novel Time and pH-Dependent Colon Targeted Drug Delivery System

The aim of present study was to develop a time- and pH-dependent system for delivering mesalamine to the colon. The system consists of the core tablet of mesalamine which is compression coated with hydroxypropyl methylcellulose (HPMC K4M) (time-dependent factor). This is then coated with pH-dependent polymer Eudragit® L100. The simplex lattice design was adopted to optimize the independent variables i.e. amount of HPMC (X1), dextrose (X2) and polyvinyl pyrollidone (PVP) (X3) and to study their effect on the dependent variables i.e. lag time and time for 50% drug dissolution (t50). The results of the linear interactive model and graphical representation revealed that as the amount of HPMC increases, the lag time and t50 value also increases and as the amount of dextrose and PVP were increased the lag time and t50 value decreases.

Formulation and development of release modulated colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer

The objective of the present study was to develop a colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer. Efficacy of selective cyclooxygenase–2 inhibitors has been proven in colorectal cancer. Meloxicam is a selective cyclooxygenase–2 inhibitor with pH-dependent solubility. To achieve pH-independent drug release of meloxicam, pH modifying agents (buffering agents) were used. Meloxicam tablets containing polyethylene oxide were dually coated with ethyl cellulose containing hydrophilic material, polyethylene glycol as an inner coating layer and methyl acrylate, methyl methacrylate, and methacrylic acid copolymer (Eudragit® FS 30D) as outer coating layer for colon targeting. Optimized tablet formulations demonstrated good potential to deliver the drug to the colon by successfully exhibiting a lag time of 5 h during in vitro drug release study. An in vivo evaluation study conducted to ascertain pharmacokinetic parameters in rabbits revealed that the onset of drug absorption from the coated tablets (Tlag time = 4.67 ± 0.58 h) was significantly delayed compared to that from the uncoated tablets. The AUC0→t and AUC0→∞ for coated tablets were lower than of uncoated tablets, although the difference was not significant (p > 0.01). The roentgenography study revealed that the tablet remained intact, until it reached the colon (5 h), which demonstrates that the system can efficiently deliver the drug to the colon. This study demonstrated that a meloxicam-loaded colon targeted system exhibited promising targeting and hence may be used for prophylaxis of colorectal cancer.

Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood–brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

Design and Optimization of Colon-Targeted System of Theophylline for Chronotherapy of Nocturnal Asthma

The objective of the present work was to develop a delayed-onset controlled-release colon-targeted system of theophylline, and to achieve the chronotherapy of nocturnal asthma. The formulation consisted of a core tablet containing hydroxypropyl methylcellulose used for achieving controlled release of drug, and a Eudragit S100:ethyl cellulose (EC) coating capable of delaying the drug release. The system was optimized using a 3(2) full factorial design, wherein two factors [ratio of Eudragit S100:EC and the coating level (% w/w)] were evaluated for lag time, t(50) and t(80) . The optimum formulation consisted of Eudragit S100:EC in a 60:40 ratio and a coating level of 7.5% (w/w). Results showed that the tablets prepared according to the optimized values released no drug in the upper part of gastrointestinal tract; drug release was initiated at pH 6.4 (colon) after a lag time of 5 h. In vivo evaluation (pharmacokinetic studies and roentgenography) in rabbits revealed that the tablet remained intact until it reaches the colon and the drug release was initiated after a lag time of 5 h. Thus, it can be concluded that the developed system exhibited a promising colonic targeting and hence may be used for chronotherapy of nocturnal asthma.

Cutting-edge technologies in colon-targeted drug delivery systems.

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.

Getting into the colon: approaches to target colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the world and the second most common cause of cancer related deaths. Conventional treatment of CRC is comprised of drug (chemotherapeutic agents) administration by parenteral route, which delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Enormous research is going on worldwide for designing an alternative route of administration, among which oral colon-targeted drug delivery systems have gained immense attention amongst scientific community. Direct delivery of drugs at the site of action leads to an increase in the availability of drugs at the targeted region. This causes a reduction in the amount of drug required to exert same therapeutic effect, thus reducing the incidents of adverse effects. Various maneuvers (pH-dependent, time-dependent and microflora-activated systems) have been attempted by researchers for targeting drugs successfully to the colonic region by circumventing the upper part of gastrointestinal tract. This Editorial article aims to put forth an overview of the formulation technologies that have been developed for attaining colon specific drug delivery for the treatment of CRC.

Colon targeting: an emerging frontier for oral insulin delivery.

Subcutaneous administration of insulin is associated with several limitations such as discomfort, local pain, irritation, infections, immune reactions and lipoatrophy as well as lipohypertrophy manifestations at the injection site. To overcome these drawbacks, enormous research is currently going on worldwide for designing of an alternative noninvasive route of administration. Pulmonary and oral route seem to be the most promising ones, with respect to the market value. However, after the letdown by pulmonary delivery of insulin, oral colon targeted delivery of insulin has gained tremendous interest among researchers. Although bioavailability remains a challenge for oral colon specific delivery of insulin, the employment of protease inhibitors, permeation enhancers and polymeric delivery systems have proved to be advantageous to overcome the said problem. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the strategies employed for attaining non-erratic bioavailability of insulin, and to highlight some of the formulation technologies that have been developed for attaining oral colon-specific delivery of insulin.

Therapeutic opportunities of small interfering RNA

Formation of small interfering RNA (siRNA) occurs in two steps involving binding of the RNA nucleases to a large double‐stranded RNA (dsRNA) and its cleavage into fragments called siRNA. In the second step, these siRNAs join a multinuclease complex, which degrades the homologous single‐stranded mRNAs. The delivery of siRNA involves viral‐ and non‐viral‐mediated delivery systems; the approaches for chemical modifications have also been developed. It has various therapeutic applications for disorders like cardiovascular diseases, central nervous system (CNS) disorders, cancer, human immunodeficiency virus (HIV), hepatic disorders, etc. The present review gives an overview of the applications of siRNA and their potential for treating many hitherto untreatable diseases.