Current Drug Delivery (v.7, #5)

Thermodynamics of Drug Nanoencapsulation: Case Study of Phenytoin- Poly (D, L-lactide) Nanocarrier by Nisha Vijay, James B. Murowchick, Bi-Botti C. Youan (343-354).
In order to rationalize the nanoencapsulation process, a thermodynamic analysis allowed to predict the limit of a model drug (phenytoin, PHT) loading into poly (d, l-lactic acid) nanocarrier (PLA NC) prepared by solvent displacement method. The NC were characterized for size, morphology, thermal behavior and crystallography by dynamic light scattering, electron microscopies, differential scanning calorimetry, and powder X-ray diffraction, respectively. The drug loading, encapsulation efficiency (EE) and in vitro drug release profile were determined using high performance liquid chromatography. There was a logarithmic correlation between the partial molar free energy change based on the molecular descriptors and the drug / polymer weight (D/P) ratio predicting an equilibrium state at ratio=0.29. This was consistent with experimental data as PHT appeared to be loaded either in crystalline or molecular/amorphous state within the PLA matrix with an average EE coefficient of 91.5and#x25;. Overall, the smallest PHT NC had a mean diameter of 231 nm and was produced at the limiting D/P ratio of 0.33, using PHT: 18mg, PLA: 60mg and surfactant: 0.3and#x25; w/v. The drug release occurred by diffusion following Higuchi model within 24 hours. These data suggested that thermodynamic analysis allows elucidating PHT encapsulation within PLA NC and may be useful in the rationale design of other macromolecular basednanocarriers.

The emerging and#x201C;anti-austerityand#x201D; anti-cancer therapeutic strategy targets the ability of certain cancer cell lines, particularly pancreatic cancer, to survive nutrient deprivation. While biochemical pathways for the tolerance to nutrient deprivation are still not well understood, a growing number of inhibitors of this process are being discovered. A number of natural products have been isolated, structurally characterized and evaluated as inhibitors of austerity, thereby providing valuable initial structure-activity relationship data.

A Timely Review of State-of-the-Art Chronopharmaceuticals Synchronized with Biological Rhythms by Seshni Sewlall, Viness Pillay, Michael P. Danckwerts, Yahya E. Choonara, Valence M.K. Ndesendo, Lisa C. du Toit (370-388).
Extensive research into circadian rhythms and their influence on biological systems has given rise to the science of chronobiology and subsequently chronotherapy, the science of delivering drugs in synchrony with biological rhythms. The field of chronotherapeutics paves the way for advances and complexities in current drug delivery technology. The ultimate goal of current chronopharmaceutical research strives to design ideal chronotherapeutic drug delivery systems that respond to such therapeutic needs. Considering the fact that physiological events such as heart rate, blood pressure, plasma concentration of hormones, plasma proteins and enzymes display constancy over time, drug delivery systems with constant release profiles have thus been favored. However, due to circadian rhythms, the conventional paradigm of constant drug delivery may not be what is needed. Instead, precisely timed drug delivery systems are required in order to correlate drug delivery with circadian rhythms to provide maximum therapeutic efficacy for chronotherapeutic diseases when most needed. The aim of this review paper is to outline the concepts in designing chronopharmaceuticals from a clinical viewpoint of major chronotherapeutic diseases such as asthma, allergic rhinitis, cardiovascular disorders, rheumatoid arthritis and cancer as well as relatively minor niche areas of interest such as in glaucoma, diabetes, immunity, pain, gastric ulcers, epilepsy and even HIV/AIDS that would require chronotherapy. In addition this review paper attempts to concisely assimilate and explicate the role of circadian rhythms in these various disease states and provide a focused overview of the current state-of-the-art in designing strategies for chronopharmaceutical formulations employed for treating chronotherapeutic diseases.

Current Approaches for Drug Delivery to Central Nervous System by Sharif Hossain, Toshihiro Akaike, Ezharul Hoque Chowdhury (389-397).
Brain, the center of the nervous system in all vertebrate, plays the most vital role in every function of human body. However, many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. In spite of the major advances in neuroscience, many potential therapeutics are still unable to reach the central nervous system (CNS) due to the blood - brain barrier (BBB) which is formed by the tight junctions within the capillary endothelium of the vertebrate brain .This results in the capillary wall behaving as a continuous lipid bilayer and preventing the passage of polar and lipid insoluble substances. Several approaches for delivering drugs to the CNS have been developed to enhance the capacity of therapeutic molecules to cross the BBB by modifying the drug itself, or by coupling it to a vector for receptor-mediated, carrier mediated or adsorption-mediated transcytosis. The current challenge is to develop drug delivery systems that ensure the safe and effective passage of drugs across the BBB. This review focuses on the strategies and approaches developed to enhance drug delivery to the CNS.

From the literature we can draw conclusions regarding the local use of minocycline in periodontal diseases. This review article attempts to evaluate the role of local delivery of minocycline HCl in the management of periodontal diseases. The efficacies of several local delivery devices of minocycline like minocycline films, strips, gels/ointment, microspheres and nanoparticles are discussed. The functional characteristics of local delivery devices of minocycline, their effectiveness as monotherapy, and comparison with scaling and root planning (SRP) are discussed in detail. Methods for the analysis of minocycline in various biological fluids, clinical trials and patents relevant to the local use of minocycline HCl in dental diseases have also been addressed in the article, conceptualizing the fact that direct application of minocycline into the diseased periodontal sulcus is an attractive treatment approach.

Effect of Polyethylene Glycols on the Trans-Ungual Delivery of Terbinafine by Anroop B. Nair, Bireswar Chakraborty, S. Narasimha Murthy (407-414).
Topical nail drug delivery could be improved by identifying potent chemical penetration enhancers. The purpose of this study was to assess the effect of polyethylene glycols (PEGs) on the trans-ungual delivery of terbinafine. In vitro permeation studies were carried out by passive and iontophoresis (0.5 mA/cm2) processes for a period of 1 h using gel formulations containing different molecular weight PEGs (30and#x25;w/w). The release of drug from the loaded nail plates, and the possible mechanisms for the enhanced delivery were studied. Passive delivery using formulation with low molecular weight PEGs (200 and 400 MW) indicated moderate enhancement in the permeation and drug load in the nail plate, compared to the control formulation. However, the effect of low molecular weight PEGs was predominant during iontophoresis process with greater amount of terbinafine being permeated (and#x223C;35 and#956;g/cm2) and loaded into the nail plate (and#x223C;2.7 and#956;g/mg). However, little or no effect on drug delivery was observed with high molecular weight PEGs (1000-3350 MW) in passive and iontophoresis processes. Release of drug from the nail plates loaded by iontophoresis using low molecular weight PEG (400 MW) exhibited sustain effect which continued over a period of 72 days. The enhancement in drug permeation by low molecular weight PEGs is likely due to their ability to lead to greater water uptake and swelling of nail. This study concluded that the low molecular weight PEGs are indeed a promising trans-ungual permeation enhancer.

Combined Patch Containing Salicylic Acid and Nicotinamide: Role of Drug Interaction by Cristina Padula, Chiara Ferretti, Sara Nicoli, Patrizia Santi (415-420).
The aim of the present study was to formulate a combined patch containing salicylic (SA) acid and nicotinamide (NA), useful for the treatment of mild acne, and to verify their mutual effect on drug permeation and skin retention. The performance of the patch was tested in vitro in permeation experiments using pig ear skin as barrier. To better understand the data obtained from the film, permeation from solutions and isopropyl myristate/water partition coefficient were also determined. The results obtained in the present work suggest a mutual influence of NA and SA on their permeation across the skin from an innovative transdermal film. The partition coefficient obtained when the two molecules were simultaneously present was typically lower than the respective value obtained with NA and SA alone.

Drug Eluting Coronary Artery Stents by Rajashree Hirlekar, Mayank Patel, Sunilkumar Jain, Vilasrao Kadam (421-427).
Atherosclerosis is the primary cause of coronary heart disease, which is characterized by a narrowing (stenosis) of the arteries that supply blood to tissues of the heart. Over the past decade, the use of and#x201C;Bare metallic stentsand#x201D; during Percutaneous Transluminal Coronary Angioplasty (PTCA) has become a common practice for treating the coronary arterial stenosis. However, the restenosis is common problem in patients receiving stents. Recently, Drug-Eluting Stents (DES) with synthetic polymer coatings which act as drug reservoirs and elute drugs over a period of several weeks or months have emerged to tackle restenosis. The polymer coatings on these stents contain various drugs like immunosuppressive drugs, anti-neoplastic drugs, anti-inflammatory drugs, migration inhibitor drugs and enhanced healing drugs that inhibit thrombus formation, inflammation or cellular proliferation which in turn prevent restenosis. Different methods like dip coating, dip spin coating, ultrasonic spray coating and ink-jet coating help to coat stent uniformly. Drug from the stent can be released by diffusion, dissolution or ion exchange mechanism. There are some disadvantages of the polymer coated stents and hence they are being superseded by completely bioabsorbable stents. Such stents are heading for clinical trials and may hit the market soon. This review gives a glimpse over DES and the future prospects of DES.

Kinetics of Vascular Targeted Monoclonal Antibody by Stephen J. Kennel, Ying Huang, Wen- Bin Zeng, Alan Stuckey, Jonathan Wall (428-435).
Purpose: There is growing interest in delivery of drugs and radioisotopes with carriers designed to target molecular receptors in the vascular space. In contrast to targets outside of blood vessels, vascular receptors are easily accessed and tracer binding is not significantly impacted by the size of the targeted drug carrier. Although it is accepted that vascular targeting is very efficient, the kinetics of target binding in the vascular space immediately after injection has not been evaluated. MAb 201B accumulation in mouse lung, by virtue of its binding to thrombomodulin on lung endothelium, has been used as a model for imaging and vascular targeting. Procedures: MAb 201B was radioiodinated with either 125I comparing two different methods of radioiodination to assess label stability. MAb accumulation and retention were monitored after iv injection in normal BALB/c mice by standard biodistribution experiments, SPECT/CT. MAb radiolabeled with positron emitting 124I was evaluated by dynamic microPET. Results: The data show that lung uptake and kinetics of loss (t1/2and#x223C;40 hrs) of 125I MAb 201B was similar with two different radio-iodination methods. Loss of radioiodine was detected in sample radiolabeled using the chloramine T method, but only at later time points (24hrs). For very short time evaluations the more efficient chloramine T method was adopted for PET studies with 124I. Lung uptake of 124I MAb 201B occurred within seconds of injection as observed in dynamic microPET analysis with little 124I MAb ever detected in the peripheral circulation. In contrast, distribution kinetics of control 124I MAb 14 or 124I MAb 201B that had been diluted with excess cold MAb demonstrated equilibration throughout the vascular space. CONCLUSION: Accumulation of MAb targeted to epitopes in the vascular space occurs very rapidly, is highly specific and very efficient. Drug delivery with vascular targeting agents can accommodate fast acting therapeutic agents including short half lived radioisotopes

Evaluation of Assam Bora Rice Starch as Plasma Volume Expander by Polymer Analysis by Ashokanshu Bhattacharya, Sohail Akhter, Sheikh Shahnawaz, Abdul Wadood Siddiqui, Mohammad Zaki Ahmad (436-441).
Water soluble polysaccharides are currently finding increasing use as a basis material for plasma volume expander. In clinical setting it is desirable to have a precise knowledge of steric and chemical structure, since these affect the pharmacokinetics and pharmacology of plasma volume expander. Branch component of starch amylopectin is very similar in structure to glycogen, the reserve polysaccharide of animal and therefore is liable to be compatible with body tissue. The knowledge of weight average molecular mass, degree of branching, osmotic pressure and coil dimension are essential, since low molecular mass do not have desirable effect and large molar mass have undesirable effect. Assam Bora rice starch was characterized by polymer analysis for use as plasma volume expander. Characterization involves the determination of FTIR spectra, degree of branching by H1 NMR, osmotic pressure by internal measurement technique, establishment of Mark-Houwink relationship and determination of Molecular weight – viscosity relationship.

Botulinum A Toxin Intravesical Injections for Painful Bladder Syndrome: Impact Upon Pain, Psychological Functioning and Quality of Life by Antonella Giannantoni, Roberta Cagini, Michele Del Zingaro, Silvia Proietti, Roberto Quartesan, Massimo Porena, Massimiliano Piselli (442-446).
Introduction. To assess the impact of intravesically injected botulinum A toxin (BoNT/A) upon bladder pain, urological complaints, symptoms of anxiety and depression, and Quality of Life (QoL) in patients with painful bladder symptoms (PBS) refractory to conventional treatment. Patients and Methods. In this prospective study 14 patients received one injection of BoNT/A (200 U diluted in 20 ml 0.9and#x25; NaCl), under cystoscopic guidance. At pre- and 3 months post- treatment all patients underwent an urological assessment (voiding diary, urodynamics), a pain quantification on a visual analog scale (VAS), an evaluation with the 14-item Hamilton Anxiety Rating Scale (HAM-A) to assess symptoms of psychic and somatic anxiety, an evaluation with the Hamilton Depression Rating Scale (HAM-D) to assess depression, and the 36-item Medical Outcomes Study Short Form (SF-36) to assess QoL. Results. At pre-treatment all 14 patients had increased daytime and nighttime urinary frequency and high VAS scores. Nine patients had pathological HAM-A scores and all had pathological HAM-D scores. At the 3-month follow-up 10/14 patients reported a subjective improvement in pain. Mean VAS score, mean daytime and nighttime urinary frequency decreased significantly (p andlt; 0.01, andlt; 0.01 and andlt; 0.01, respectively). All domains in SF-36 and HAM-A significantly improved (p andlt; 0.01). All domains, except weight and sleep disorders, significantly improved in HAM-D, particularly somatoform symptoms (p andlt; 0.01), cognitive performance (p andlt; 0.01), and circadian variations (p andlt; 0.01). Conclusion. In patients with refractory PBS with symptoms of anxiety, depression and poor QoL, BoNT/A intravesical treatment reduced bladder pain, improved psychological functioning, and well-being.

Ovalbumin (OVA) is often used as a model antigen, and its biodistribution is important for the induction of immunization, especially oral immunization. In this study, an allergic substance-detecting kit, Egg Protein ELISA kit, was applied to the investigation of the biodistribution of fluorescein isothiocyanate-labeled ovalbumin (FITC-OVA). After FITC-OVA solution and its double liposomes were administered into the intestinal loop with one Peyer's patch, the biodistribution of FITC-OVA was examined with the Egg Protein ELISA kit. Each calibration was performed by fitting a quadratic curve to the observed ELISA response points. The ELISA response was almost the same between OVA and FITC-OVA. Similar ELISA response curves were obtained in Peyer's patch (PP) homogenate, spleen (SP) homogenate and plasma (PL). The concentration of FITC-OVA could be determined at 4 – 64 ng/ml for aqueous solution and SP homogenate and at 1 – 64 ng/ml for PP homogenate and PL. Thus, it was suggested that the ELISA kit should be useful for measurement of OVA biodistribution in an oral immunization study. After the administration of FITC-OVA solution and its double liposomes into the intestinal loop, the biodistribution of OVA-FITC in PP, SP and PL was investigated. The distributed amount was the greatest in PP. At the early time, the distributed amount in PP, SP and PL tended to be greater with FITC-OVA solution than the double liposomes. FITC-OVA was retained longer in PP with the double liposomes than FITC-OVA solution. The present results indicated that OVA could transfer well to PP and systemic circulation even with the solution dosage form in the loop method, probably because it was not exposed to harsh conditions such as a gastric fluid. Namely, it implied that the protection from gastric pH and enzyme by the double liposomes, which had been reported before, would be importantly associated with the promotion of immune induction. In addition, the double liposomes could retain OVA longer in PP, which might cause the enhancement of oral immunization.