Current Drug Delivery - Volume 6, Issue 3, 2009

Elastic vesicles have been developed and evaluated as novel topical and transdermal delivery systems. They are similar to conventional liposomes but with the incorporation of an edge activator in the lipid bilayer structure to provide elasticity. Elastic vesicles are applied non-occluded to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been investigated as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. Following topical application, structural changes in the stratum corneum have been identified and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been identified in the deeper viable tissues. Their method of transporting their drug payload into and through the skin has been investigated but remains an area of contention. This review provides an overview of the development of elastic vesicles for delivery into and via the skin.

The standard treatment for patients with bladder cancer is surgical transurethral resection (TUR). Intravesical chemotherapy and immunotherapy are widely used after TUR to prevent recurrence and progression of superficial disease. There are many drug therapies for bladder cancer via intravesical instillation. This review describes the drugs which are approved or currently tested for treating bladder cancers. Some new chemotherapies and immunotherapies under investigation are also introduced. Vehicles to carry or encapsulate intravesical drugs are introduced in this review. Enhancement approaches to promote drug absorption or prolong residence times such as nano-sized particles, thermo-chemotherapy, and electromotive drug administration are also discussed. This review summarizes the information regarding intravesical therapy and its enhancement techniques. Recent developments of these drugs and their carriers for in vivo or clinical use are presented.

The objective of the present study was to develop sustained release formulation of Diltiazem hydrochloride (DH) using biodegradable polymers. For this purpose microcapsules embedded Diltiazem hydrochloride were prepared using chitosan alone and also by incorporating some co polymers like methyl cellulose(MC), sodium carboxy methyl cellulose (SCMC) and poly vinyl pyrollidone (PVP) by employing complex emulsion method of microencapsulation. Glutaraldehyde saturated toluene solution is used as cross linking agent. Microcapsules were prepared in various core : coat ratios to know the effect of polymer and co polymers on drug release. Overall eight formulations were prepared and evaluated for flow behaviour, sieve analysis, drug entrapment efficiency, in vitro dissolution studies, stability studies, including scanning electron microscopy. 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 depended on core: coat ratio and nature of the polymers. FTIR analysis revealed chemical integrity between diltiazem hydrochloride (DH), chitosan and between the copolymers. Among the three copolymers used methyl cellulose retarded the drug release more than the other two, 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 using various mathematical models. In vivo result analysis of pharmacokinetic parameters revealed that t max of reference and test formulations were the same. From the study it was concluded that, sustained release Diltiazem hydro chloride microcapsules could be achieved with success using chitosan alone and also in combination with other biodegradable polymers.

The present study was aimed at developing and evaluating polymeric beads with sustained drug release and prolonged gastric residence. The polymeric beads were prepared by solvent evaporation technique using Cellulose acetate (CA) as matrix former for model drug Ibuprofen (IBF) in 1% aqueous polyvinyl alcohol (PVA) solution as external phase. Effects of various formulation variables like drug-polymer ratio, external phase viscosity, external phase volume, solvent ratio and processing variables like stirring speed, temperature of external phase, stirring time, and drying temperature on properties of beads were accessed. Drug polymer ratio was optimized to maximize the percent yield and drug content. Beads were characterized for shape, size, percent buoyancy, entrapment efficiency, floating time and in-vitro drug release. The scanning electron micrographs show a porous nature of beads thereby enabling them to float. When used alone, CA though formed good beads, drug entrapment efficiency was very low. To increase the drug entrapment, CA was partially substituted with Ethyl cellulose EC (up to 20%) to modulate drug entrapment efficiency and optimize the bead properties including drug release. Beads formed with higher viscous solution either formed agglomerates or dumbbell shaped structures. The optimized batches have uniform size distribution, remained buoyant for more than 18 hours and sustained the drug release up to 10 hours with diffusion through matrix being the main drug releasing mechanism.

Objectives: Success of selective drug therapies depends on the drug's depot time in the target to treat. Depot time is currently being prolonged, using drug-eluting beads or microspheres for selective internal radiation therapy. The purpose of this study was to establish a model for investigating the depot time of particles injected into tumors in relation to tumor vascularization and particle size. Materials and Methods: An animal model with two different vascularized tumors (Walker Carcinoma 256 (hypervascularized) and Yoshida Sarcoma (hypovascularized)) was used. The tumors were implanted into the hind leg of Wistar rats. When the tumors reached 10-15mm, rhenium radiolabeled particles of 25μm and 0.3μm were percutaneously injected into the tumors: large particles (Re-188 microspheres) in 10 hypo- and 10 hypervascularized tumors and small particles (Re- 186 sulfid colloid) in 4 hypo- and 16 hypervascularized tumors with the co-injection of the vasoconstrictor, adrenalin (0.01 mg), into 8 hypervascularized tumors. Tumor activity was measured with a gamma camera at 10 min, 1h, 3h, 6h, 14h and 48h p.i. In addition, activity in the lung, liver, spleen, kidneys, and lymph nodes was measured at 48 h p.i. Measurements were adjusted for decay times and then compared. Results: Drainage of the injected particles is bi-phasic, characterized by a fast wash-out. At 10 min p.i., intratumoral activity decreases to 70% of the initially injected activity. This is followed by a slow decline at 48 h p.i in which intratumoral activity decreases to at least 60% of the initially injected activity. Slow decline is independent of particle size and vascularization, whereas fast leakage depends on both. Co-injecting adrenalin significantly reduced the wash-out of the small particles. Radiolabeled microspheres accumulated mainly in the lungs, smaller colloids in the liver. Conclusions: Particle stay time, biodistribution, and stability can be easily monitored as shown in this animal model. The hematogeneous wash-out can be reduced, using larger particles and vasoconstrictors. Prolonged retention is independent of vascularization and particle size and appears to be sufficient for therapy.

The blood brain barrier protects the brain from harmful substances in the blood stream and has stopped the development of many powerful and interesting drugs candidates for central nervous system due to the low poor distribution and by efflux mechanisms. Many different approaches have been developed in order to overcome this barrier and the drug gain access to the brain. The polymeric nanoparticles are efficient colloidal systems that have been investigated to the brain drug delivery. This review will focus on the current strategies for brain drug delivery emphasizing the properties and characteristics of polymeric nanoparticles for this purpose.

Novel techniques for drug delivery have been investigated in human medicine in recent years. The transdermal route of drug delivery has attracted researchers due to many biomedical advantages associated with it. However, excellent impervious nature of skin is the greatest challenge that has to be overcome for successfully delivering drug molecules to the systemic circulation by this route. One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) that can reversibly compromise the skin's barrier function and consequently allow the entry of otherwise poorly penetrating molecules into the membrane and through to the systemic circulation. A large number of fatty acids have been used as permeation enhancers. They have proven to be effective and safe sorption promoters. This present review includes the classification, feasibility and application of fatty acids as sorption promoters for improved delivery of drug through skin.

Inadequate skin permeability is the main challenge encountered in the transdermal drug delivery and to solve this crisis physical and chemical enhancement techniques are being developed. The aim of the present investigation was to study the combined effect of two such techniques, iontophoresis and esterification, on the transdermal delivery of atenolol. A series of ester prodrugs of atenolol were synthesized, characterized and studied for physicochemical properties and stability. In vitro permeation studies were carried out for atenolol and prodrugs at different donor concentrations (5, 10, and 20 mM) by passive process and iontophoresis (0.5 mA/cm²). Evaluation of the physicochemical parameters showed significant increase in lipophilicity and slight reduction in pK value in the ester prodrugs compared to parent drug. Stability studies revealed higher stability at pH 4 than pH 6. Prodrugs significantly enhanced the transdermal flux of atenolol in passive process while in iontophoresis the enhancement ranged from 1.4 to 2.7 fold compared to atenolol. In the prodrug series, permeation rate increased with increase in the length of alkyl side chain up to the addition of 5 carbon units, but thereafter no specific pattern was recorded in both passive and iontophoretic process. The steady state flux was highest in atenolol valerate (1.48 μmol/cm² h), which shows the promise of meeting the desired permeation rate (3.0- 31.0 μmol/ h) for maintenance of the therapeutic level in a 70 kg human.

Bilayered tablets of Divalproex sodium for once-a-day administration were prepared using a hydrophilic and hydrophobic polymer as release retarding agents. This technology was found to be more effective than a simple matrix tablet with a mixture of the above polymers in order to retard the drug release for a period of 24 h. The drug release profile was strongly dependent on the presence of wicking agent, pathlength of hydrophobic layer, and hardness of tablet. f1 value of 6.92 and f2 value of 76.72 indicated similarity between the release profiles of batch BT3 and reference tablet (Depakote ® ER) with the target release of over 55% within 12 h and over 85% within 18 h. Mathematical modeling using Korsmeyer-Peppas equation indicated that the release followed a combination of diffusion and erosion mechanism.

Polymeric microspheres containing diphtheria and tetanus toxoids were prepared without protein stabilizers. A vaccine containing 2 Lf(tetanus) and 0.4 Lf(diphtheria) was injected either in BALB/c mice or in guinea-pigs. As control, a group received the alum-adsorbed unencapsulated toxoids. In mice, on day 44 one group and control received a booster and at day 111 the other group received the same booster dose. Before de booster, all groups had very low neutralizing antibodies, as determined by Toxin binding inhibition assay. One week after booster all groups had high antibody titers, especially those immunized with microencapsulated vaccine, which were at least 5 times higher than those immunized with alum vaccine for both antigens. Besides, guinea pigs receiving lower dose had antibodies titers as high as 60 UI/mL, and 30 times higher than those immunized with alum vaccine. Therefore by using an encapsulated vaccine without any kind of protein stabilizer we were able to induce in vivo protective responses irrespective of observed in vitro protein degradation by HPLC. Manipulating the vaccination schedule at the same time to the toxoids encapsulation does not only increase the antibody titers but also their specificity.

The present study was aimed to prepare and evaluate buccoadhesive films of miconazole nitrate (MCZ). The films based on chitosan were prepared by solvent casting method using L9 orthogonal array design to release the drug above its minimum inhibitory concentration (MIC) for a prolonged period of time so as to reduce its frequency of administration. As per the experimental design, guar gum, HPMC K15M and HEC were added at three different levels to control the drug release. Films showed smooth, uniform and non-sticky surface with good flexibility and folding endurance. Thickness and weight-variation data showed no significant difference among the batches, indicating that the polymeric blend possessed a good film forming ability and its desired properties could easily be achieved by varying the composition of the casting solution. Films composed of chitosan with guar gum appeared to be tougher; comparatively more bioadhesive in vitro, resided to an appropriate time interval and swelled at a more reasonable rate than those containing HPMC and HEC, suggesting the superiority of guar gum over other polymers. In vitro drug release studies conducted on all batches and microbiological studies done on the statistically optimized formulation demonstrated that the films had ability to sustain the drug concentration above its MIC for 6 hrs, despite the incorporation of a smaller dose (2.5 mg/cm² of the film). Films, except CF2 and CF3, followed Fickian diffusion of release mechanism. FT-IR spectra revealed no interactions between the drug and polymers.

The effect of obstructive jaundice on the distribution and elimination of propofol was studied in 15 patients with obstructive jaundice (total serum bilirubin, TBL ® 17.1μmol.l^-1) and in 15 control patients (TBL < 17.1μmol.l^-1). Following an i.v. bolus dose of propofol (2-2.5 mg.kg^-1) multiple arterial samples were obtained at timed intervals for 4 h and blood concentrations of propofol were measured by high pressure liquid chromatography. Compartmental analysis of propofol concentrations revealed a three-compartment model with elimination from a central compartment in all patients. Pharmacokinelic parameters: volumes of distribution at steady state (V^SS), volumes of distribution at equilibrium (Vr), volumes of the central compartment (V) and total body clearance (Cl) were similar in patients with obstructive jaundice (mean 12.3 (SD 6.0) litre.kg^-1, 32.99(21.42 ) litre.kg-1, 0.241(0.131) litre.kg-1, and 28.8(8.2) ml.min-1.kg^-1 respectively) compared with contro1 group (11.9 (5.4) litre.kg^-1, 28.30(13.70) litre.kg-1, 0.297(0.112) litre.kg-1, and 33.9(7.6) ml.min-1.kg^-1 respectively) (P>0.05). Half-times of the three phases ( T1/2 ^α,T1/2 ^β,T1/2 ^γ) were also similar between both groups.We conclude that in patients with obstructive jaundice the pharmacokinetics of propofol are similar to those of patients without obstructive jaundice.