Current Drug Delivery - Volume 7, Issue 2, 2010

The objective of the present study was to develop sustained release microcapsules of verapamil hydrochloride (VH) using biodegradable polymers. For this purpose microcapsules embedded verapamil hydrochloride were prepared using sodium alginate alone and also by incorporating some co polymers like methyl cellulose(MC), sodium carboxy methyl cellulose (SCMC), poly vinyl pyrrollidone (PVP) and xanthan gum by employing complex emulsion method of microencapsulation. Microcapsules were prepared in various core: coat ratios to know the effect of polymer and co polymers on drug release. Overall ten formulations were prepared and evaluated for flow behavior, sieve analysis, drug entrapment efficiency, in vitro dissolution studies, stability studies, including scanning electron microscopy and DSC. The resulting microcapsules were discrete, large, spherical and also free flowing. The drug content in all the batches of microcapsules was found to be uniform. The release was dependeut on core: coat ratio and nature of the polymers. FTIR analysis revealed chemical integrity between Verapamil hydrochloride (VH), sodium alginate and between the copolymers. Among the four copolymers used methyl cellulose retarded the drug release more than the other three, hence the same formulation was subjected for in vivo studies. The drug release from the microcapsules was found to be following non fickian diffusion. Mechanism of drug release was diffusion controlled first order kinetics. Drug diffusion co efficient and correlation co-efficient were also assessed by using various mathematical models. In vivo result analysis of pharmacokinetic parameters revealed that t max of reference and test formulations were almost same. From the study it was concluded that, sustained release Verapamil hydro chloride microcapsules could be achieved with success using sodium alginate alone and also in combination with other biodegradable polymers.

5-Fluorouracil (5-FU) is currently used for treatment of oral squamous cell carcinoma (OSCC). 5-FU is given by i.v. although the systemic administration is associated with severe toxic effects and no topical formulations of 5-FU for buccal drug delivery have been reported. In this study we would report the development of buccal tablets suitable for direct application of low-doses of 5-FU on cancer lesions. The topical administration could be effective on tumor area while systemic undesired side effects are avoided. Preliminarily, the limited tendency of 5-FU to cross the buccal tissue was established using reconstituted human oral epithelium (RHOE, in vitro) and porcine buccal mucosa (ex vivo) as mucosal models. The values of steady-state flux and permeability coefficient suggested the scarce aptitude of 5-FU to reach the systemic circulation. Matrix buccal tablets, were designed for 5-FU local delivery, developed and prepared. Release tests showed a highly reproducible Higuchian drug discharge. After tablet administration on buccal tissue specimens, the occurrence of histomorphological effects of 5-FU was highlighted. Apoptotic events were registered in all samples treated while only negligible amounts of 5-FU permeated the buccal membrane and reached the simulated plasma. The results suggest that loaded matrix tablets containing 5% of 5-FU could be a useful means in topical treatment of OSCC.

The nasal route as a site of vaccine delivery for both local and systemic effect is currently of considerable interest. The administration of vaccines to mucosal surfaces such as the nasopharynx associated lymphoid tissues confers many advantages since the nasal mucosa is a primary site through which most inhaled antigens are encountered. However, the success of intranasally delivered mucosal vaccines is limited by lack of effective vaccine formulations or delivery systems suitable for use in humans. This review provides a brief overview of the mucosal immune system at the nasal surface, enhancement techniques for induction of mucosal immune response after intranasal administration of particulate systems and an explanation of the inherent properties of polyacrylate polymer-based particulate systems that may facilitate mucosal immune responses.

The stratum corneum (SC) is a primary rate limiting barrier to permeation of drug molecules through the skin. Small molecular weight lipophilic drugs that are effective at low doses can be effectively delivered by passive transdermal delivery. The SC does not permit passage of polar/hydrophilic and macromolecules. Passive and physical penetration enhancements strategies are used to overcome this barrier property of the SC. Passive penetration enhancement techniques include use of supersaturated solutions and penetration enhancers. In general, the drug delivery potential of chemical modalities is limited. Therefore, physical permeation enhancement techniques gained a lot of focus in the recent past. Physical penetration enhancement techniques include iontophoresis, electroporation and sonophoresis. Electroporation utilizes high voltage pulses that are applied for a very short time to permeabilize the skin to facilitate transport of macromolecules and hydrophilic compounds. Several drugs have been administered via this system successfully. This review presents an overview of in-vitro and in-vivo studies demonstrating therapeutic benefits offered by electroporation assisted permeation. Factors affecting electroporation, synergism between electroporation and other penetration enhancing strategies are also discussed.

Cholecystokinin, produced in the proximal small intestine, is a short acting satiating peptide hormone. CCK-10, before and after mono-iodination, was previously coupled to 10kDa polyethylene glycol (PEG). The formed conjugates PEG10kDa-CCK-10 and PEG10kDa-[127I]-CCK-10 show after i.p. administration to rats a sustained food intake reduction during 8h in comparison to 2h for free CCK-10. The present study examined the blood pharmacokinetics of this pharmacological interesting molecule by means of PEG10kDa-[123I]-CCK-10 following intravenous, intraperitoneal, intramuscular and nasal administration and the biodistribution after i.p. administration. HPLC analysis with radiometric detection allowed the differentiation between inorganic iodide and the intact tracer in blood. Blood kinetics after i.v. injection was fitted to a bi-exponential with a distribution half-life of 15 min and with an elimination half-life of 8 hours for intact PEG10kDa-[123I]-CCK-10. The biodistribution studies showed a higher accumulation of the tracer for all administration routes in organs expressing CCK receptors localized in the gastrointestinal tract such as pancreas, duodenum and small intestine. No indication of blood brain barrier crossing for the conjugate could be observed independently of the administration route. Main clearance was via the urinary pathway.

The colon specific polymeric conjugates of celecoxib were prepared with dextran of different molecular weight Mr ∼40 000, 70 000, and 100 000 (CSD-40, CSD-70 and CSD-100). Succinic acid was used as linker between the drug and dextran. The prepared conjugates were characterized by UV, IR, 1H NMR and HPLC. The maximum degree of substitution 3.9±0.20 %was found with the dextran CSD-100 conjugate. The percent release of drug obtained by in-vitro hydrolysis studies, was found to be 24.37± 0.6, 23.0 ± 0.5 and 20.13± 0.8 in simulated colonic fluid (SCF) pH 6.8 while 17.90 ± 0.4, 16.8± 0.75 and 15.47 ± 0.5 in simulated intestinal fluid (SIF) pH 7.4 for CSD-40, CSD-70 and CSD-100, respectively, in both medium. The drug release from the conjugates was observed for 24 h in 3% w/v rat caecal content and found to be 41.77 ± 1.2, 39.03 ± 1.0 and 35.26 ± 1.09 for CSD-40, CSD-70 and CSD-100 conjugates, respectively. The half life of conjugates was determined and was found to be short in 3% w/v rat caecal content. No amount of drug was released in simulated gastric fluid pH 1.2 and stomach homogenate in 2 h. The amount of drug released from small intestine homogenate was 3.4± 0.1 percent in 12 h for the CSD-40. The above result suggests that dextran could be used as a macromolecular carrier for colon specific drug delivery of celecoxib.

In the past years, alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. In conventional/current therapy oral tablet, capsule and injectable formulations are used for anti-cancer drugs delivery. These formulations associated with problems like severe toxic side effects on healthy organs, difficulties in clinical administration, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site specific controlled drug delivery systems. Novel drug delivery systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and targeting the drug to the disease tissue leading to better therapeutic effect with minimum side effects. In this review, we have explored the literature related to recent development in delivery of anti-cancer drugs identify problems in present conventional chemotherapy and detailed newer approaches and future development in the delivery of anti-cancer drugs.

Water soluble polysaccharides are the most effective oncotic agents, which are used for the treatment of intravascular volume deficiency. Nowadays, they are used as basic material for plasma volume expander. Plasma volume expander based on starch has lower tendency to remain in any major organ of body in comparison to other plasma volume expander. Branched component of starch amylopectin is very similar in structure to glycogen, the reserve polysaccharides of animal; for all this reason starch is compatible with body tissues. Physicochemical properties of raw starch and amylopectin, isolated from Assam Bora rice were characterized for using it as plasma volume expander. Characterization involves the determination of ash value, weight average molecular mass, viscosity and resistance towards enzymatic (amylase) hydrolysis. Amylose content was almost negligible. The X-ray diffraction pattern of Assam Bora rice starch was typically A type. High degree of crystallinity of Assam Bora rice starch reflect its resistance towards enzymatic hydrolysis, which is of therapeutic advantage for using it as a plasma volume expander.

Nanotechnology is a novel but rapidly advancing domain of Therapeutics. Nanoscale-diameter particles such as liposomes and dendrimers may be conscribed for the effective and safe administration of several drugs. The main advantages of nanosystem-mediated drug delivery are the following; i) sufficient absorption, ii) delayed metabolism and excretion, iii) longer half-life, iv) ability to cross several anatomical barriers, v) enhanced accumulation in specific targettissues (e.g. malignant tumors), vi) lower toxicity of the drug. During the last years there is a growing interest around the potential contribution of Nanotechnology in the development of Nuclear Medicine and vice versa. Radioactive agents called radiopharmaceuticals are already used in several medical procedures. Exploiting their ability to accumulate selectively on specific organ-targets, radiopharmaceuticals serve in diagnostic applications, such as scintiscan, PET scan and in therapy of several diseases (e.g. thyroid cancer). The use of nanosystems may further ameliorate the properties of radiopharmaceuticals regarding their targeting ability and their unique pharmacokinetic properties. On the other hand radionuclides may serve in experimental studies for the pharmacological evaluation of nanosystems. Nevertheless further research is required in order to confirm the effectiveness and safety of nanosystem-mediated radiopharmaceutical applications.

The aim of these studies was to compare the effect of liposome composition on physico-chemical characteristics and transfection efficacy of cationic liposomes both in vitro and in vivo. Comparison between 4 popularly used cationic lipids, showed 3β-N-(dimethylaminoethyl)carbamate (DC-Chol) to promote the highest transfect levels in cells in vitro with levels being at least 6 times higher than those of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA). 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and dimethyldioctadecylammonium (DDA) and approximately twice as efficient as dipalmitoyl-trimethylammonium-propane (DPTAP). To establish the role of the helper lipid, DC-Chol liposomes were formulated in combination with either 1,2-dioleoyl-sn-glycero-3- phosphatidylethanolamine (DOPE) or cholesterol (Chol) (1:1 molar ratio) with and without the addition of phosphatidyl choline. The choice of helper lipid incorporated within the bilayer was found to influence the formation of complexes, their resultant structure and their transfection efficiency in vitro, with SUV-DNA complexes containing optimum levels of DOPE giving higher transfection than those containing cholesterol. The inclusion of PC within the formulation also reduced transfection efficiency in vitro. However, when administered in vivo, SUV-DNA complexes composed of PC:Chol:DC-Chol at a molar ratio of 16:8:4 μmole/ml were the most effective at inducing splenocyte proliferation upon exposure to antigen in comparison to control spleens. These results demonstrate that there is no in vitro/in vivo correlation between the transfection efficacy of these liposome formulations and in vitro transfection in the above cell model cannot be taken as a reliable indicator for in vivo efficacy of DNA vaccines.