Drug Delivery Letters - Volume 2, Issue 1, 2012

The first issue of Drug Delivery Letters for 2012 contains exciting articles with a focus on preclinical research in drug delivery. The effect of various formulation parameters are reported on the properties of hydrogel wound dressings Jadhav et al., and on plasmid DNA/membrane interaction during in vitro gene electrotransfer Escoffre et al., Formulation studies show the tableting properties of assam bora rice starch Ahmad et al., and preparation and evaluation of a vancomycin microemulsion for ocular drug delivery Nair et al., the multidimensional role of inulin as a symbiotic drug carrier, and synergistic adjuvant for the colonic delivery of 5-fluorouracyl are reported Sinha and Honey. Woodruff-Pak et al., report on the treatment of Alzheimer’s disease by immunotherapy. Treatment of intractable focal neocortical epilepsy is presented by Ludvig. The protection of bee venom proteins from microencapsulation-induced damage is reported by da Trindale et al., While Parejiya introduces a platform technology for the controlled oral delivery of highly water soluble drugs, and Rekha reports on the influence of ultrasound on transdermal drug delivery. These articles present strong, multidisciplinary research, and report on diverse and exciting aspects of drug delivery. I wish you all pleasant reading of these exciting results in the drug delivery filed.

Starches are used as fillers, binders, and disintegrating agents in the tablet formulation due to their suitable physicochemical as well as mechanical properties. In the present investigation, a study has been done on the compaction properties of Assam Bora rice starch, and their physicochemical properties are evaluated. Assam Bora rice starch exhibit good flow properties. The influences of physical and geometrical properties of starch were evaluated with regard to their compression properties. Further compaction properties of the Assam Bora rice starch were evaluated by density measurement, Heckel and Kawakita equation. The result obtained shows that Assam Bora rice starch deforms mainly by plastic deformation. From the study it has been concluded that Assam Bora rice starch would be more useful in minimizing the problems of lamination and capping especially on high speed tableting machine with short dwelling time for the plastic deformation of material, on the other hand it would be more useful when high tensile strength of tablet is desirable.

The work presented in this manuscript was undertaken to evaluate the effect of various formulation parameters on the essential properties of hydrogel wound dressings. PVA and PVP based hydrogel dressing systems were prepared by irradiation cross-linking and freeze thawing method. Prepared hydrogels were characterized for swelling index, water vapor transmission rate (WVTR), mechanical strength, gel fraction and in-vitro drug release. Hydrogel dressings prepared by irradiation method showed better physico-mechanical properties like swelling index, WVTR, and transparency as compared to hydrogels prepared by freeze thaw method, except the mechanical strength, which was less in case of hydrogels, prepared using irradiation method. An increase in concentration of PVP resulted in increase in tensile strength and swelling index, and decrease in gel fraction of hydrogel due to higher degree of cross linking. Overall, addition of PVP improves physico-mechanical properties of hydrogel as compared to Plain PVA containing hydrogels. An increase in irradiation dose increases tensile strength, but decreases equilibrium swelling of hydrogels. Gel fraction also increases with increase in irradiation dose up of 50 to 60 kGy, however further increase in irradiation dose decreases gel fraction of hydrogel, as polymer degradation process exceeds cross linking process. Finally, the drug release studies were performed using silver sulfadiazine (AgSD) as a model drug in hydrogel prepared by freeze-thaw method and drug release was found to be zero-order suggesting constant drug availability on the hydrogel applied wound, which is highly desirable.

To investigate immunotherapy in non-rodent model of Alzheimer’s disease (AD), 14 rabbits were fed a cholesterol/ copper regimen for 10 weeks (“hypercholesterolemic” or “AD model rabbits”), and 4 rabbits were fed normally (“control rabbits”). Six or 8 weeks after diet initiation, 10 hypercholesterolemic and 4 control rabbits were injected with conjugated Aβ1-42-peptide mixed with Freund’s complete adjuvant and boosted every two weeks with 4 additional doses in Freund’s incomplete adjuvant. Serum antibody titers were measured using an Aβ1-42-specific ELISA from blood. Brain Aβ was analyzed with immunohistochemistry. Anti-Aβ antibodies doubled from approximately 2.6 to 5.2 ng/ml. Even with this relatively low increase in anti-Aβ antibodies, there was a significant reduction in intracellular brain Aβ. Pathology is present in AD model rabbits by 4 weeks after diet initiation. Future studies of immunotherapy should begin earlier in disease progression that is comparable to preclinical AD in humans for greater reduction of brain Aβ.

Electropermeabilization is one of the non-viral methods successfully used to transfer genes into living cells invitro and in-vivo. Although this method shows promises in the field of gene therapy, very little is known about the basic processes supporting plasmid DNA transfer. In contrast to small molecules that have direct access to the cytoplasm, plasmid DNA forms a long-lasting complex with the permeabilized membrane. The present letter reports the semi-quantitative analysis of the effect of electric pulse intensity on plasmid DNA/membrane interaction at the single-cell level using fluorescence microscopy. The raising of electric field intensity induces an increase in the cellular perimeter of plasmid DNA/membrane interaction and in the total number of plasmid DNA complexes. The increase in the perimeter of plasmid DNA/membrane interaction is in good agreement with the theoretical perimeter of membrane permeabilization. This theory easily explains the quantitative increase in plasmid DNA and gives explanations for the success of electro-mediated gene delivery.

The main objective of the present investigation was to develop and evaluate the potential of microemulsion (ME) for the ocular delivery of Vanocomycin (VM). The solubility of VM in oils and surfactants were checked to identify components of the micro emulsion. The ternary phase diagrams were plotted to identify the area of ME existence. The prepared ME’s were characterized for pH value, refractive index, viscosity, stability, and surface morphology by SEM analysis, zetapotential, FTIR, in vitro diffusion studies. These microemulsions resulted favorable features for ocular use. They show acceptable physico-chemical behavior, especially pH value, refractive index and viscosity. A prolonged VM release from the microemulsions was shown in in-vitro experiments. VM -ME is promising for ocular drug delivery for the treatment of topical eye diseases as the sol to gel transition increases viscosity which enhances the ocular retention while retaining the therapeutic efficiency.

The present study was aimed towards development of porosity controlled osmotic pump as a platform technology for delivering highly water soluble drugs using Milnacipran HCl as a model drug. Theoretical zero order drug release profile (5 mg/hr) was targeted to achieve for fulfilling desired plasma concentration up to 24 hrs. Novel ethyl cellulose based coating system, Aquarius EKX 19102 SRX-2, was employed in the development of osmotic pump. Influences of media pH, agitation intensity and osmotic pressure on drug release rate were investigated. Statistical approaches including mean dissolution time, dissolution efficiency, similarity factor and SeDeM diagram were applied to translate dissolution profile in to a single value. The Aquarius EKX 19102 SRX-2 coating system at 7% weight gain exhibited zero order drug release. Scanning electron microscopy confirmed the microporous structure of the film. The results obtained from stability study, Fourier Transform Infra Red spectra and Differential Scanning Calorimetry study of optimized formulation confirmed stable characteristics. This platform technology was further validated using Diltiazem HCl and satisfactory results were obtained. FORTRAN language based software was applied to assess drug release kinetics and it was found to be zero order.

The effect of ultrasound energy on transdermal permeation of Losartan Potassium (LP) across albino rat skin was studied in vitro. Experiments were performed using therapeutic ultrasound (1MHz) at different intensities (0.5 and 2.5 W/cm2) for 10 and 30 minutes in continuous and pulsed (1:1) modes. Ultrasound variables used in present investigation were selected on the basis of 23 full factorial design. The flux observed from passive transdermal permeation was found to be 12.52 ± 3.32 μg/cm2/h. Significant enhancement in LP flux was observed when higher intensity (2.5 W/cm2) was applied for 30 min in pulsed and continuous mode. Sonophoresis (2.5 W/cm2) for 30 min in continuous mode resulted in greater LP transport (142.00 ± 13.93 μg/cm2/h). However, sonophoresis applied for 0.5 W/cm2 (30 min.) and 2.5 W/cm2 (30 min.) in pulsed mode resulted in net LP transport of 60.55 ± 9.04 and 104.60 ± 15.29 μg/cm2/h, respectively. There was ∼8.3-fold (2.5 W/cm2, 30 min) enhancement in transcutaneous steady-state flux values in pulsed mode and ∼11.3-fold (2.5 W/cm2, 30 min) enhancement in continuous mode as compared to control. The results were substantiated by histopathological studies and factorial design results. Given the promising results, it was concluded that the sonophoresis is a promising technique for transdermal delivery of LP and has the potential to be predictable.

PLGA (poly-lactide-co-glycolide) microspheres have more than 30 years of use in drug delivery, but there are some limitations related to protein stability during the process of microencapsulation. During the W1/O phase (in the W1/O/W2 microencapsulation process), hydrophobic interfaces are expanded where interfacial adsorption occurs followed by protein unfolding and aggregation. These problems have limited their usage as vaccine carriers. The Hoffmeister series ions were added to BV (bee venom) proteins to obtain their stability during microencapsulation. A correlation was established between the salts used in aqueous solutions and changes in BV solubility and conformations. The BV α-helical content was stable without protein aggregation or hydrophobic exposition, and a small change at the S-S dihedral angles. BV aggregation was avoided by 20 % in the presence of 40 mM MgCl2, (chaotropic salt) with preserved biological activity. The aim of this work was achieved, which was to obtain the maximum BV stability and can be considered a biotechnological breakthrough because a simple solution like salt addition avoided heterologous proteins usage to reach protein stability.

Natural polysaccharides are being extensively manipulated for the colon drug delivery systems. Nowadays, therapeutic compositions are being investigated that can effectively play a versatile role. The present investigation is aimed to design a colon specific microbially triggered system using biodegradable co-polymer mixtures. The prime focus of the study was to design and evaluate a swelling dependent delayed release system for a colonic delivery of anticancer agent 5-Fluorouracil (5-FU) and further to determine the effects of carboxypolymer (Carbopol®71G-NF) on release behavior of 5-FU from a matrix tablet system containing different amounts of inulin (a biodegradable oligofructose) aiding in enzymatic degradation by colonic microflora. Mixed film coating with a blend of Ethylcellulose: Eudragit®S-100 (2:1) at coat weight levels of 2%w/w, 4%w/w and 6.0%w/w was carried out respectively, which further retarded the drug release in the initial hours of the in-vitro dissolution profile. Swelling studies were also carried out on uncoated matrix tablet batches. The releases studies with or without rat caecal contents were performed on optimized batches and the samples were analyzed by a validated RP-HPLC method. In-vitro rat caecal study results revealed that complete drug release would occur from the tablets in the human colonic microenvironment. The study revealed an effective site specific delivery of a hydrophilic chemotherapeutic agent, 5-FU to the colon for the treatment of various local as well as systemic pathologies.

The Subdural Pharmacotherapy Device (SPD) is an experimental medical implant for the treatment of intractable focal neocortical epilepsy. The device performs spatially and temporally controlled administration of seizurepreventing drugs into the subarachnoid space overlaying the neocortical seizure focus or foci. This is accomplished with the use of a multifunction subdural strip, through which the device periodically (a) delivers drugs to achieve local treatment without systemic side-effects, (b) receives electrophysiological feedback on this local treatment so that neither ineffective nor toxic drug administration can take place, and (c) removes local cerebrospinal fluid (CSF) containing tissue reaction cells and proteins to maintain adequate transmeningeal drug diffusion into the seizure focus for long periods. The present drug-of-choice that emerged for this device is muscimol, a potent GABAA receptor agonist. Experimental data obtained in freely-behaving nonhuman primates implanted with the muscimol-delivering SPD showed that this treatment can fully prevent focal neocortical seizures for many months without tolerance. Neurological symptoms or behavioral abnormalities did not develop during SPD-use, for at least a year. Based on all accumulated data, the muscimol-delivering SPD seems to have clinical potential. The present device needs to be adapted to human use, and its safety and antiepileptic efficacy need to be confirmed in further studies. Should this effort succeed, it may well lead to a new therapeutic option for at least a subgroup of the approximately 150,000 US patients who suffer from otherwise untreatable focal neocortical epilepsy.