Drug delivery to the central nervous system (CNS) is one of the most challenging fields of research and development for pharmaceutical and biotechnology products. A number of hydrophilic therapeutic agents, such as antibiotics, anticancer agents, or newly developed neuropeptides do not cross the blood brain barrier (BBB) after systemic administration. The BBB is formed by the tight junctions at the brain capillary endothelial cells, which strictly control drug transfer from blood to brain. Drug modification, osmotic opening of cerebral capillary endothelium, and alternative routes for administration (e.g., intracerebral delivery) have been successfully used to enhance drug transport to the CNS. The use of nanocarriers, such as liposomes and solid polymeric or lipid nanoparticles may be advantageous over the current strategies. These nanocarriers can not only mask the BBB limiting characteristics of the therapeutic drug molecule, but may also protect the drug from chemical/enzymatic degradation, and additionally provide the opportunity for sustained release characteristics. Reduction of toxicity to peripheral organs can also be achieved with these nanocarriers. This review article discusses the various barriers for drug delivery to the CNS and reviews the current state of nanocarriers for enhancing drug transport into the CNS.

ABSTRACTgroup, is a centrally acting analgesic with weak opioid agonist properties. Tramadol has been proved to be effective in both experimental and clinical pain without causing serious cardiovascular or respiratory side effects. 1 The half-life of the drug is about 5.5 hours and the usual oral dosage regimen is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400 mg/day.2 To reduce the frequency of administration and to improve patient compliance, a sustained-release formulation of tramadol is desirable. The drug is freely soluble in water and hence judicious selection of release retarding excipients is necessary to achieve a constant in vivo input rate of the drug. The most commonly used method of modulating the drug release is to include it in a matrix system.3 Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance. 4 The drug release for extended duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs with high water solubility, hydrophobic polymers (waxes) are suitable as matrixing agents for developing sustained-release dosage forms.5 Hydrophobic polymers provide several advantages, ranging from good stability at varying pH values and moisture levels to well-established safe applications.The effect of concentration of hydrophilic (hydroxypropyl methylcellulose [HPMC]) and hydrophobic polymers (hydrogenated castor oil [HCO], ethylcellulose) on the release rate of tramadol was studied. Hydrophilic matrix tablets were prepared by wet granulation technique, while hydrophobic (wax) matrix tablets were prepared by melt granulation technique and in vitro dissolution studies were performed using United States Pharmacopeia (USP) apparatus type II. Hydrophobic matrix tablets resulted in sustained in vitro drug release (>20 hours) as compared with hydrophilic matrix tablets (<14 hours). The presence of ethylcellulose in either of the matrix systems prolonged the release rate of the drug. Tablets prepared by combination of hydrophilic and hydrophobic polymers failed to prolong the drug release beyond 12 hours. The effect of ethylcellulose coating (Surelease) and the presence of lactose and HPMC in the coating composition on the drug release was also investigated. Hydrophobic matrix tablets prepared using HCO were found to be best suited for modulating the delivery of the highly watersoluble drug, tramadol hydrochloride. KEYWORDS: tramadol, hydrogenated vegetable oil, hydroxypropyl methylcellulose, ethylcellulose, melt granulationIn the present study, various matrix systems were designed and tested for controlled delivery of tramadol. The objectives of the study were (1) to investigate the performance of hydrophilic and hydrophobic matrix systems in controlling the release of this freely soluble drug, and (2) to inve...

Significant advances in the understanding of the genetic abnormalities that lead to the development, progression, and metastasis of neoplastic diseases has raised the promise of gene therapy as an approach to medical intervention. Most of the clinical protocols that have been approved in the United States for gene therapy have used the viral vectors because of the high efficiency of gene transfer. Conventional means of gene delivery using viral vectors, however, has undesirable side effects such as insertion of mutational viral gene into the host genome and development of replication competent viruses. Among nonviral gene delivery methods, polymeric nanoparticles are increasingly becoming popular as vectors of choice. The major limitation of these nanoparticles is poor transfection efficiency at the target site after systemic administration due to uptake by the cells of reticuloendothelial system (RES). In order to reduce the uptake by the cells of the RES and improve blood circulation time, these nanoparticles are coated with hydrophilic polymers such as poly(ethylene glycol) (PEG). This article reviews the use of such hydrophilic polymers employed for improving the circulation time of the nanocarriers. The mechanism of polymer coating and factors affecting the circulation time of these nanocarriers will be discussed. In addition to the long circulating property, modifications to improve the target specificity of the particles and the limitations of steric protection will be analyzed.Key words: Cancer; Gene Therapy; Non-Viral Vectors; and Long-Circulation. IntroductionAccording to the reports from the World Health Organization, global cancer rates are expected to increase by 50% to a total of 15 million by the year 2020 (1). The funding of the United States National Cancer Institute to more than 5000 investigators world wide for their research in cancer indicates the importance of eliminating the suffering and death due to cancer (2). The progress of research in the area of cancer requires a new paradigm in diagnosis and therapy of the disease.Although, chemotherapy has an important place in the clinical management of cancer, there are several limitations that require development of newer strategies for cancer therapy. Many of these drugs have narrow therapeutic indices resulting in high cytotoxicity to the surrounding healthy cells. Secondly, chemotherapeutic agents cannot be targeted to mutations affecting cell division, differentiation, and apoptosis. Gene therapy represents an interesting alternative where the protein of interest can be made locally near the disease site. The advantages of gene therapy include localized and sustained expression of genes in the target tissue, possibility of delivery of more than one transgene in the same vector, ability to treat drug resistant tumors, and low toxicity to the host. Cancer is associated with abnormalities in the sequence and expression of some critical genes, namely the proto-oncogenes (oncogenes) and the tumor suppressor genes. Protooncogenes are converted to...

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Nanoemulsion formulations were designed for enhancing the oral bioavailability of hydrophobic drugs. Paclitaxel was selected as a model hydrophobic drug, which is also a substrate for the P-glycoprotein efflux system. The oil-in-water (o/w) nanoemulsions were formulated with pine nut oil as the internal oil phase, egg lecithin as the primary emulsifier, and water as the external phase. Stearylamine and deoxycholic acid were used to impart positive and negative charge to the emulsions, respectively. Nanoemulsions were prepared by sonication method and characterized for particle size and surface charge. The control and nanoemulsion formulations with tritiated [3H]-paclitaxel were administered orally to female C57BL/6 mice and the distribution of the drug was examined. The formulated nanoemulsions had a particle size range of approximately 90-120 nm (laser diffraction method) and zeta potential values ranging from -56 mV to +34 mV. Following oral administration, a significantly higher concentration of paclitaxel was observed in the systemic circulation when administered in the nanoemulsion relative to control aqueous solution. The absorbed drug was found to be distributed in the liver, kidneys, and lungs. The results of this study suggest that nanoemulsions are promising novel formulations that can enhance the oral bioavailability of hydrophobic drugs, like paclitaxel.