Drug Delivery Letters - Volume 4, Issue 1, 2014

Advances in strategies for treating a wide variety of diseases require an efficient delivery of the active compounds into the cytosol of target cells. One of the challenges for the efficient intracellular delivery of therapeutic biomolecules after their cell internalization by endocytosis is to manipulate or circumvent the non-productive trafficking from endosomes to lysosomes, where degradation may occur. Because the nanocarriers generally cannot directly cross the lipid bilayer of the endosomes, the pH targeting approach, which can lead to as elective disruption of the endosomal membrane, is regarded as a promising strategy to promote a specific triggered release of active biomolecules. The combination of the endosomal acidity with the endosomolytic capability of the nanocarrier can increase the intracellular delivery of many drugs, genes and proteins, which, therefore, might enhance their therapeutic efficacy and, in specific cases, overcome the multidrug resistance of many bacterial and tumor cells. Different approaches have been taken to develop pHsensitive drug delivery devices, including the incorporation of pH-responsive polymers, peptides, surfactants and fusogenic lipids. This review focuses on the recent progress in pH-sensitive nanocarriers and their performance as nanoscale strategies for the intracellular drug, gene and protein delivery, with emphasis on their specificity to the acidic environment of the endosomal compartments.

Administration of drugs is often associated with basic problems such as toxicity, instability and improper biodistribution. Encapsulation of the drug in a suitable carrier such as liposomes is one of the well recognized methods that protects the drug from the body milieu to improve stability, safety and targeting efficiency of the drug towards the target site. However, while encapsulation provides a favorable biodistribution, low toxicity and improved stability of drugs, delivery carriers should be capable of releasing encapsulated material at the appropriate site to exert their activity. Effective intracellular drug delivery is desired for many therapeutic agents those having specific molecular targets in the cytoplasm, nucleus, or other subcellular compartments of a cell such as mitochondria. Several nanocarriers that are designed to release drugs at desired sites have been developed so far. Among these, exhaustive research has established liposomes as an effective triggerable drug carrier. This mini review covers various aspects of triggering modalities examined to date such as temperature, pH, enzymes and light using liposomes.

Milnacipran hydrochloride (MIL) is a selective serotonin and norepinephrine dual reuptake inhibitor used for the treatment of depression and fibromyalgia. The aim of present work was to carry out comparative pharmacokinetics evaluation of in-house developed oral controlled release (CR) and marketed immediate release (IR) tablet formulation of MIL. Three prototype CR formulations (i) MIL with HPMC 100K, single hydrophilic polymeric matrix tablet [MSH], (ii) MIL with HPMC 100K and sodium CMC, binary hydrophilic polymeric matrix tablet [MBH] and (iii) MIL with hydrophilic and hydrophobic wax polymeric matrix tablets using HPMC 100K and paraffin wax [MHW] were formulated. One optimized formulation from each prototype formulation was selected for in-vivo study in rabbits. In-vivo plasma concentration data were obtained from 6 healthy male New Zealand albino rabbits after administration of IR and CR tablets of MIL. Plasma samples were analyzed by in-house developed RP-HPLC method. Remarkable differences in plasma drug profile were observed between IR and CR formulations, expressed by lower Cmax, delayed Tmax and extended MRT values for CR tablets. The mean Cmax and Tmax values from CR tablets were found to be 480.28 ± 31.27 to 586.53 ± 15.24 ng/mL and 8 to 10 h respectively whereas for IR formulation these were 1075.25± 50.38 ng/mL and 1 h respectively. The MRT was found twice in CR formulation than IR formulation. Level A in-vitro and in-vivo correlation was also established for developed CR formulations with correlation coefficient 0.896 to 0.930, which indicates a fair correlation between in-vitro release and in-vivo absorption of MIL from dosage form.

During the past 20 years, advances in drug formulations and innovative routes of administration have been made. The understanding of drug transport across tissues has increased. The administration of drug by transmucosal routes offers the advantage of being a relatively painless administration and has the potential for greater flexibility in a variety of clinical situations. The transmucosal route includes oral, nasal, vaginal, and urethral and presents a challenge in the field of novel drug delivery technology. The oral transmucosal delivery, especially the buccal and sublingual routes have been explored successfully for a number of drugs in the last few decades with novel approaches emerging continuously. The transmucosal membranes are relatively permeable, have a rich blood flow and hence allow the rapid uptake of a drug into systemic circulation to avoid first pass metabolism. This route of drug delivery offers a number of benefits over other drug delivery approaches and allows drugs to circumvent some of the body’s natural defense mechanisms like first pass metabolism, harsh stomach environment etc. Several approaches have been used like drug delivery through the nasal route by using sprays, pumps and gels while the mucoadhesive, quick dissolve tablets and solid lozenge formulations are for the oral mucosal route. Also, vaginal or urethral routes can be explored using mucoadhesive suppositories, in-situ gel and foam etc. The purpose of this review is to compile the basic approach studies by different research groups in the last few years.

Colorectal cancer being a life style disease, number of cases is increasing day by day. Oral drug delivery to treat colonic diseases encounters many problems like drug stability in the harsh environment of the upper GI tract, low percentage of drug remained in the dosage form to be released in the colon, heavy dilution of the drug released in the colon fluid etc. Hence novel strategies for colon targeting has attracted significant attention during the past 20 years in providing several therapeutic advantages particularly for drugs that are sensitive to acidic condition and to intestinal enzymes. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis while site specific release strategy is needed for local action for conditions involving colonic pathologies, such as ulcerative colitis, colorectal cancer, Crohn's disease and colon cancer. This article is focused on different polymeric materials particularly of natural origin that are considered to design different types of colon delivery systems and their comparative efficacies are discussed.

Oral fast dissolving films have carved a niche in the pharmaceutical industry and are giving a competitive edge as compared to other dosage forms as an innovative drug delivery. Pfizer introduced Listerine melt in mouth pocket packs to overcome the limitations of other dosage forms. Since then a large number of pharmaceutical industries are casting light upon this drug delivery with attributing to its major contribution in the market share by gaining wide consumer acceptance over a large population. Modification of a tablet dosage form to avoid the risk of dysphasia, elimination of water, easy portability and choking in pediatrics and geriatrics, by formulating fast disintegrating films ensures quick release of the drug within negligible time and has proven to be an effective treatment particularly during nausea, parkinson’s disease and other emergency conditions. Presently, oral films have gained entry to the market as breath freshener, anti-histamines, vitamin supplements, anti-emetics and pain relieving drugs. Fast dissolving films have the potential to deliver a drug systemically via buccal, sublingual or palatal delivery. Sublingual films are superior over the buccal films due to relatively thin area of the sublingual region which provides rapid onset of action, since the drug enters the bloodstream directly via the veins attached to the sublingual gland and eliminates first pass metabolism. Further, addition of bioadhesive polymers along with superdisintegrants provides faster disintegration ensuring rapid release of the drug during emergency conditions. Thus sublingual films proved to be a promising and effective drug delivery.

Novel drug delivery systems (NDDS) delivered the active molecules to the target site in a defined manner for produce the desired effects without disturbing the delicate bio-environment. Among many available colloidal drug delivery systems, Liposomes (a class based on phospholipids) have attracted more attention than other systems due to many meritorious features such as excellent chemical & biological stability, good solubilisation power, promote intracellular delivery of bio-active molecules, reduce the uptake of macrophages and encapsulate both hydrophilic as well as lipophillic drug molecule. In this review article, I try to give some basic knowledge about these carrier systems in tabular form, which is more understandable concept as compared to simple text form.

In research and development (R & D) sector, scientific and technical developments are ready for the expansion of oral drug delivery systems. The medicated chewing gum (MCG) takes accumulative approval as a drug delivery system in pharmaceutical as well as clinical fields. It offers advantages both for (a) local treatment and (b) systemic effect after absorption through the buccal, sublingual mucosal and from the gastrointestinal tract as comparison to conventional oral mucosal and oral dosage forms. It mainly consists of active substances and a gum core, which is mainly composed of an insoluble gum base, sweetener, antioxidants, softeners and flavouring agents. Today improved technologies have made it possible to develop and manufacture MCG with predefined properties. A large number of marketed formulations are available for prevention of caries, xerostomia alleviation, and vitamin/ mineral supplementation etc. In this review article, we discussed the unique characteristics and their applications of MCG formulation in different fields to control and treat the disease by sustained release of drug/ bioactive molecules. Finally, in upcoming years, we may realize that the MCG formulation place preference to other delivery systems to distribute the drugs locally.

The objective of the present study is to elaborate a new approach for drug loading into electrospun nanofibers through active loading based on non-solvent evaporation technique. The polymeric nanofibers were achieved by electrospinning method using PCL, PVA and a blend of sodium alginate & PVA as polymeric constituents. Different methods such as passive & active (solvent and non-solvent evaporation methods) techniques were used to prepare drug loaded nanofibers. The resulting nanofibers were characterized for morphology, drug loading, in-vitro release and degree of swelling. Different kinetic models were applied to the in-vitro release profile of different polymeric nanofibers. The prepared nanofibers were found to be uniform, non-beaded and non-woven with fiber diameter ranging from 200-450nm. Entrapment efficiency of metronidazole was increased by 30% when non-solvent evaporation method was used. Moreover the n value obtained from the Peppas model varied between 0.8-0.9 which was further confirmed that the mechanism of drug release was anomalous diffusion which refers to combination of both diffusion and erosion mechanism. The impetus for this development was that the non-solvent evaporation technique can be successfully used for drug loading to polymeric nanofibers.