A Novel Chitosan Nanosponge as a Vehicle for Transepidermal Drug Delivery

Transepidermal drug delivery achieves high drug concentrations at the action site and ensures continuous drug delivery and better patient compliance with fewer adverse effects. However, drug delivery through topical application is still limited in terms of drug penetration. Chitosan is a promising enhancer to overcome this constraint, as it can enhance drug diffusion by opening the tight junctions of the stratum corneum. Therefore, here, we developed a novel chitosan nanosponge (CNS) with an optimal ratio and molecular weight of chitosan to improve drug penetration through skin. To prepare the CNS, two types of chitosan (3 and 10 kDa) were each conjugated with poloxamer 407 using para-nitrophenyl chloroformate, and the products were mixed with poloxamer 407 at ratios of 5:5, 8:2, and 10:0. The resulting mixtures were molded to produce flexible soft nanosponges by simple nanoprecipitation. The CNSs were highly stable in biological buffer for four weeks and showed no toxicity in human dermal fibroblasts. The CNSs increased drug permeability through human cadaver skin in a Franz-type diffusion cell, with substantially higher permeability with 3 kDa chitosan at a ratio of 8:2. This suggests the applicability of the novel CNS as a promising carrier for efficient transepidermal drug delivery.

Lidocaine Hydrochloride Nanoparticles Preparation using Multiple Emulsions and its Physicochemical Evaluation

Lidocaine is a primary local anesthesia that blocks the ionic fluxes required for the beginning and operation of impulses in the neuronal membrane. The benefits of local anesthetics, such as enhancing patient acceptance, prohibiting systemic toxicity and delivering continuous drug delivery, make them the attracting field for pharmaceutical researchers. The nanoparticles were prepared by solvent evaporation W1/O/W2 emulsion method and in the ratios of 1 to 1, 1 to 2 and 1 to 3 drug to polymer. The production yield, loading efficiency, particle size, poly dispersity index and zeta potential of selected formulation were 84.30%, 80.60%, 192[Formula: see text]nm, 0.18[Formula: see text]mV and [Formula: see text][Formula: see text]mV, respectively. DSC and FTIR studies showed that no chemical interactions between drug and polymer Formulations showed an initial burst release, which is a reason for the good capacity of the polymer to maintain the drug in it and lead to a primary slow release.

EXTH-26. SECONDARY STRUCTURE ANALYSIS OF THE EGFR PRE-mRNA TRANSCRIPT TO IDENTIFY TARGETABLE REGIONS AND OPTIMIZE RNA THERAPY

Individuals diagnosed with glioblastoma multiforme (GBM) have a short life expectancy of 12–15 months. Current strategies are often limited by the blood-brain barrier. This project is to develop therapies to bypass challenges to effective and continuous drug delivery to the brain, targeting cancer-driving genes. Epidermal growth factor receptor (EGFR) is dysregulated in 57% of all GBM. Our approach uses an adeno-associated virus gene transfer vector encoding RNA therapeutics targeting critical elements of the EGFR pre-mRNA transcript. The ‘pre-mRNA structurome’ can be used to uncover and determine the accessibility of targetable regions. Our approach has the potential to deliver one single dose of gene therapy directly to the GBM tumor environment and block the production of EGFR and activate the expression of a stable therapeutic isoform of EGFR. To advance our therapeutic strategy, we have analyzed the EGFR secondary structure using selective 2’ hydroxyl acylation and primer extension followed by mutational profiling (SHAPE-MaP). SHAPE-MaP reactivity profiles were generated revealing the structure of splicing and cryptic polyadenylation signal (PAS) elements within the targeted region. We identified enhancer binding motifs surrounding the 5’ splice site and hidden elements of the cryptic PAS. Based on these structural profiles, we generated RNA therapies to unravel the hidden PAS to activate expression of the short therapeutic isoform.

P57 Continuous drug delivery is significantly affected by relative height changes between patient and syringe driver

AimsSyringe drivers are the principle method of giving continuous infusions of important drugs to patients. Many of these drugs are critical for the maintenance of normal physiology. Anecdotal evidence abounds of severe patient instability on movement of syringe drivers during infusion. Our objective was to define the variation in drug delivery seen in three different syringe drivers, with changes in relative height between the syringe driver and the end of the giving set.MethodsThree syringe drivers (Alaris CC (Becton Dickinson), Perfusor Space (B Braun), and Synamed μSP6000 (Arcomed)) were analysed for reliability of flow at 0.5, 1, 2, and 5 ml/hr. A small air bubble was introduced into the giving set, and the progression of this was documented before and after a vertical movement of the syringe driver by 25 or 50 cm upwards or downwards relative to the delivery port.ResultsFor all pumps, delivery was interrupted on movement of the pumps downwards, and a bolus was given with movement of the pump upwards. Delivery halted at lower pump speeds for longer than higher pump speeds. The maximum delivery interruption was 11.8 minutes. Boluses given on moving the pump up were calculated as the equivalent number of minutes needed to deliver the bolus volume at steady state. The maximum bolus given was equivalent to 15.8 minutes of delivery. We were unable to eliminate the effects seen by very slow, steady movement of the pumps up or down. Static height differences made no difference to delivery.ConclusionsSyringe drivers should not be moved vertically in relation to the patient. Critical drug delivery is interrupted for up to 12 minutes with relative downward movements, and significant boluses of drugs are given with relative upward movements. As far as possible, elimination of relative height movements is advised, and extreme caution is necessary if any movements are unavoidable.

A New Technique and Device for Controlled and Continuous Drug Delivery into the Brain – A Proof of Concept Study

BackgroundDrug delivery into the brain has been a challenge for the past 100 years because of the blood brain barrier. The existing non-invasive techniques cannot provide controlled and continuous drug delivery into the brain and the invasive techniques make the brain prone to infection from external agents. Hence a new technique which can provide controlled and continuous drug delivery without the need for any surgical intervention in the brain holds immense potential.ObjectiveThe objective of this study is to deliver drugs into the brain using a novel oral and maxillofacial technique and device.MethodDrug delivery into the brain from the oral and maxillofacial region was tested using a novel technique and device in an in vivo rabbit model and an ex vivo goat head model. A control animal and an experimental animal were used in each study. Drugs which do not cross the blood brain barrier normally were tested. Dopamine was delivered in vivo from the maxillo-facial region. Anti-glial fibrillary acidic protein antibody was delivered ex vivo from the oral region. Samples were collected from different sites including the brain and the optic nerve.ResultsThe in vivo model showed a significant increase of dopamine at the pons (51.89%), midbrain (27%), medulla (48.5%) and cortex (72.637%). On including samples from other regions in the t-test, the increase was not statistically significant (p=0.538), suggestive of a central feedback mechanism for brain and peripheral dopamine. A decrease in plasma dopamine during drug delivery further supported a central control for dopamine. In the ex vivo model, a statistically significant (p=0.047) delivery of antibodies occurred at multiple sites including pons (86.7%), cortex (256.5%), and the optic nerve (128.8%).ConclusionThis technique and device can deliver drugs into the brain without detectable increase in systemic circulation. Therefore it may be used for delivering drugs in Parkinson’s disease, Alzheimer’s disease, Pain management, Brain tumors especially pontine tumors, infections like neuro-AIDS, Basal meningitis etc. Retinal drug delivery may also be possible.

Sedatives and anti-anxiety agents in critical illness

Sedative and anti-anxiety agents are administered to many mechanically-ventilated intensive care unit (ICU) patients. While commonly considered supportive care, suboptimal administration of sedatives has been linked to longer duration of mechanical ventilation and longer ICU length of stay. The use of a structured multidisciplinary approach can help improve outcomes. The level of consciousness, as well as the presence and severity of agitation should be routinely evaluated using a validated sedation–agitation scale. The approach to delivery of sedation should be based upon specific goals, particularly mechanical ventilation, while maintaining the lightest possible level of sedation. Selection should be based upon clinical circumstances and patient characteristics, however, when continuous infusion sedation is required, experts suggest using non-benzodiazepine agents. A variety of strategies for sedation management have been demonstrated to be effective in clinical trials including use of protocols, targeting light sedation, preference of analgesics for initial therapy, use of intermittent, rather than continuous drug delivery when possible, and daily interruption of sedation. Finally, light sedation should be linked to performance of spontaneous breathing trials, as well as early mobilization.