Current Drug Delivery (v.8, #2)

Dynamics of Dissolution and Diffusion-Controlled Drug Release Systems by Laurent Simon, Parimala Bolisetty, Maria N. Erazo (144-151).
Analytical expressions were derived to explain the influence of the dissolution/diffusion number (Di) on the time constant and steady-state flux when dispersed drugs are released from a finite matrix. A key novelty of this work is the introduction of a single time-constant that combined the analysis of both dissolution- and diffusion-based systems. Focus is placed on systems with a constant dissolution rate and diffusion coefficient. Solutions, based on the residue theorem, were in agreement with published results describing the transport of estradiol in a polymeric matrix. The experimental cumulative amount of drug released was 0.1 mg/cm2 in 100 hours compared to 0.084 mg/cm2 predicted by the theoretical model. The process time constant, estimated from the first eigenvalue (t0) and a more accurate statistical approach (teff), showed a consistent decrease with increasing Di values. For a dissolution/diffusion number of 0.21, t0 and teff were estimated at 58.44 and 73.02 hrs, respectively. With the presence of a skin layer, teff increased to 575.7 hrs. These results can be used to assess the relative impact of dissolution and diffusion on the time it takes drugs to attain a therapeutic level in the bloodstream.

Assessment of Short-Term Changes Induced by a Dermatophagoides pteronyssinus Extract on Asthmatic Patients. Randomised, Double-Blind, Placebo-Controlled Trial by Carmen Vidal, Ana I. Tabar, Javier Figueroa, Jose A. Navarro, Cesarea Sanchez, Agustin Orovitg, Margarita Armisen, Susana Echechipia, Alejandro Joral, Susana Lizarza, M Teresa Lizaso, Virginia Rodriguez, Fernando de la Torre (152-158).
Background: Once the optimal dose is reached, subcutaneous immunotherapy [SCIT] with mite extract is capable of reducing symptoms and the need for rescue medication. Objective: To assess the capacity of a subcutaneous extract of mites [D. pteronyssinus] to bring about a reduction in concomitant medication as well as in vivo and in vitro changes in just 2-3 months of treatment in patients with allergic asthma. Methods: A total of 45 patients with persistent mildmoderate allergic asthma due to sensitisation to D. pteronyssinus were included in a multi-centre, double-blind, placebocontrolled trial. Length of treatment was 4 months. After a period for adjusting medication in order to classify asthma severity appropriately, patients were commenced on treatment of 400 or 800 and #956;g/day of budesonide as concomitant medication. Results: After 4 months of treatment there were no significant changes in the budesonide dose between the active group and the placebo group. In the active group there was a significant difference between active and placebo group in sIgG4 [p=.0003], as well as a significant increase in the cutaneous tolerance index [2.81, CI 95and#x25;: 1.29 - 7.48, which was significant with a Confidence Interval of 95and#x25;]. These changes were not observed in the placebo group. Conclusion: After just 4 months of treatment, SCIT was capable of inducing in vivo and in vitro changes, but these changes were not reflected in improved clinical outcome within the first 4 months of therapy.

The objective of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH dependent solubility such as atenolol for extended periods of time by modulating solubility with organic acid. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Consequently, for maintaining the desired pH over the entire period of drug dissolution a suitable thickening and suspending agent can be incorporated. By optimizing the concentration of thickening agent, it is possible to extend the availability of pH modifier in the core to provide an osmotic driving force or solubilization over the entire delivery period, so that the desired profile can be achieved for an active agent that has lower solubility characteristics. Finally, it was observed that the release rate of atenolol was influenced by the concentration of citric acid, mannitol and hydroxypropyl methylcellulose (HPMC). Results of scanning electron microscopy studies showed the formation of pores in the membrane from where the drug release occurred. The optimal formulation was found to be able to deliver atenolol at the rate of approximate zero-order up to 24 h, independent of pH of release media and agitation rate.

Erythropoietin Encapsulation in Chitosan Nanoparticles and Kinetics of Drug Release by M. Bokharaei, A. Margaritis, A. Xenocostas, D. J. Freeman (164-171).
Recombinant human erythropoietin (rHu-EPO) is a glycoprotein, which is produced commercially from Chinese hamster ovary (CHO) cells. It is used for the therapy of renal anemia and chemotherapy-induced anemia in cancer patients. Recent evidence suggests that rHu-EPO exerts tissue protective effects via multiple mechanisms which include inhibition of apoptosis, promotion of angiogenesis and decreased inflammation. After intravenous (IV) injection, the blood concentration of rHu-EPO rapidly decreases due to proteolysis resulting in a relatively short half-life of 8.5 h, which necessitates regular dosing with intervals that do not exceed 7 days. It would be desirable to develop an encapsulated formulation providing controlled release of rHu-EPO to maintain therapeutic concentrations in plasma, and for potential tissue protective applications to maintain high local therapeutic concentrations in tissue while minimizing potential unwanted systemic effects such as polycythemia and platelet activation, both of which can predispose to intravascular thrombosis. Nanoparticle encapsulation of rHu-EPO can also allow for direct injection at sites of injury in specific tissues/ organs, again minimizing systemic exposure of the drug. In this paper, we report the production of biopolymer nanoparticles by ionotropic gelation of chitosan with tripolyphosphate (TPP). The nanoparticle size distribution in aqueous solution was determined and rates of rHu-EPO release from chitosan-TPP nanoparticles were measured in PBS at 37and#176;C. It was observed that almost 30and#x25; of the encapsulated rHu-EPO was released within the first 48 hours and thereafter a linear release profile was observed for up to 2 weeks. Total drug release over 15 days was 63and#x25; of the initial amount.

Newer Approaches for Optimal Bioavailability of Ocularly Delivered Drugs: Review by K. Kesavan, J. Balasubramaniam, S. Kant, P. N. Singh, J. K. Pandit (172-193).
Eye diseases can cause discomfort and anxiety in patients, with the ultimate fear of loss of vision and facial disfigurement. Many regions of the eye are relatively inaccessible to systemically administered drugs and, as a result, topical drug delivery remains the preferred route in most cases. Drugs may be delivered to treat the precorneal region for conjunctivitis and blepharitis, or to provide intraocular diseases such as glaucoma, uveitis, and cytomegalovirus retinitis. Most of the ophthalmic formulation strategies aim at maximizing ocular drug permeability through prolongation of the drug residence time in the cornea and conjunctival sac, as well as minimizing precorneal drug loss. The conventional topical ocular drug delivery systems show drawbacks such as increased precorneal elimination and high variability in efficacy. Attempts have been made to overcome these problems and enhance ocular bioavailability by the development of newer drug delivery systems. This review is concerned with classification, recent findings and applications and biocompatibility of newer drug delivery systems for the treatment of ocular diseases.

Paclitaxel Loaded Nanosponges: In-Vitro Characterization and Cytotoxicity Study on MCF-7 Cell Line Culture by Khalid A. Ansari, Satyen J. Torne, Pradeep Pradeep R. Vavia, Francesco Trotta, Roberta Cavalli (194-202).
Beta cyclodextrin (and#946;-CD) based nanosponges were synthesized and paclitaxel inclusion complex with nanosponges were prepared using techniques of inclusion complex formation. The paclitaxel nanosponge's complexes were evaluated for their release. The nanosponges complexes were also evaluated using DSC, FTIR, and NMR techniques for confirmation of inclusion complex formation between paclitaxel and nanosponges. Particle size and morphology of paclitaxel nanosponge's complex were estimated using SEM, TEM and dynamic light scattering techniques. The particle sizes were found out to be in range of 400 to 600 nm. Cytotoxic efficacy of paclitaxel nanosponge complex was determined against MCF-7 cells and paclitaxel nanosponge's complex was found to be cytotoxic and more effective against this cell line.

Microwave Assisted Synthesis and Evaluation of Modified Pea Starch as Tablet Superdisintegrant by Akhilesh V. Singh, Anudwipa Singh, Lila K. Nath (203-207).
In the present study, cross linked sodium carboxymethylated pea starch (SCPS) was synthesized and evaluated as tablet superdisintegrant in diclofenac sodium based tablets. SCPS was synthesized using native pea starch with monochloroacetic acid and NaOH in microwave radiation environment. Finally the dried product was cross-linked with phosphorous oxychloride, which produced granular highly swellable starch. SCPS with degree of substitution of 0.34 was formed and it was further evaluated as superdisintegrant in diclofenac sodium based tablets. Diclofenac sodium tablets were prepared by direct compression method with 2, 4, 6 and 8and#x25;w/w of SCPS as superdisintegrant and further comparatively evaluated for in vitro disintegration and dissolution study with Sodium starch glycolate containing tablets as reference. The results revealed that SCPS could be a promising superdisintegrant for immediate release tablets in concentration dependant manner.

Aerosol Delivery of Antimicrobial Agents During Mechanical Ventilation: Current Practice and Perspectives by Argyris Michalopoulos, Eugenios I. Metaxas, Matthew E. Falagas (208-212).
Critically ill patients, who develop ventilator-associated pneumonia during prolonged mechanical ventilation, often require antimicrobial agents administered through the endotracheal or the tracheotomy tube. The delivery of antibiotics via the respiratory tract has been established over the past years as an alternative route in order to deliver high concentrations of antimicrobial agents directly to the lungs and avoid systemic toxicity. Since the only formal indications for inhaled/aerosolized antimicrobial agents is for patients suffering from cystic fibrosis, consequently the majority of research and published studies concerns this group of patients. Newer devices and new antibiotic formulations are currently off-label used in ambulatory cystic fibrosis patients whereas similar data for the mechanically ventilated patients do not yet exist.

The purpose of this study was to investigate the effectiveness and mechanism(s) of percutaneous absorption of propranolol hydrochloride (PHCL) across rat and human cadaver skin using seven novel terpenes with reference to marker terpene 1,8-cineole. In-vitro skin permeation studies were carried out via rat and human skin models. The mechanism of skin permeation of PHCL by terpenes was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Amongst the new terpenes, 1,4-cineole was found to be most effective enhancer for diffusion of PHCL through rat skin (ER=3.07) and human cadaver skin (ER=2.42) as compared to control. FTIR spectra and DSC thermogram of skin treated with aforesaid terpenes indicated that permeation occurred due to the disruption of lipid bilayers. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes, the irritation was higher with the and#946;-citronellene and rose oxide. It was concluded that 1,4-cineole can be successfully used as potential permeation enhancer for PHCL. It enhanced the absorption of hydrophilic drug by extraction and disruption of lipid bilayers and keratin denaturation of stratum corneum.