A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery

The aim of the present work was to obtain an ophthalmic delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the treatment of ocular diseases. For this, an in situ forming gel comprised of the combination of a thermosetting polymer, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO, poloxamer), with a mucoadhesive agent (chitosan) was developed. Different polymer ratios were evaluated by oscillatory rheology, texture and mucoadhesive profiles. Scintigraphy studies in humans were conduced to verify the retention time of the formulations developed. The results showed that chitosan improves the mechanical strength and texture properties of poloxamer formulations and also confers mucoadhesive properties in a concentration-dependent manner. After a 10-min instillation of the poloxamer/chitosan 16:1 formulation in human eyes, 50-60% of the gel was still in contact with the cornea surface, which represents a fourfold increased retention in comparison with a conventional solution. Therefore, the developed formulation presented adequate mechanical and sensorial properties and remained in contact with the eye surface for a prolonged time. In conclusion, the in situ forming gel comprised of poloxamer/chitosan is a promising tool for the topical treatment of ocular diseases. (C) 2010 Elsevier B.V. All rights reserved.

Rheological, mechanical and mucoadhesive properties of thermoresponsive, bioadhesive binary mixtures composed of poloxamer 407 and carbopol 974P designed as platforms for implantable drug delivery systems for use in the oral cavity

This study described the formulation and characterisation of the viscoelastic, mechanical and mucoadhesive properties of thermoresponsive, binary polymeric systems composed of poloxamer (P407) and poly(acrylic acid, C974P) that were designed for use as a drug delivery platform within the oral cavity. Monopolymeric and binary polymeric formulations were prepared containing 10, 15 and 20% (w/w) poloxamer (407) and 0.10-0.25% (w/w) poly(acrylic acid, 934P). The flow theological and viscoelastic properties of the formulations were determined using controlled stress and oscillatory rheometry, respectively, the latter as a function of temperature. The mechanical and mucoadhesive properties (namely the force required to break the bond between the formulation and a pre-hydrated mucin disc) were determined using compression and tensile analysis, respectively. Binary systems composed of 10% (w/w) P407 and C934P were elastoviscous, were easily deformed under stress and did not exhibit mucoadhesion. Formulations containing 15 or 20% (w/w) Pluronic P407 and C934P exhibited a sol-gel temperature T(sol/gel), were viscoelastic and offered high elasticity and resistance to deformation at 37 degrees C. Conversely these formulations were elastoviscous and easily deformed at temperatures below the sol-gel transition temperature. The sol-gel transition temperatures of systems containing 15% (w/w) P407 were unaffected by the presence of C934P; however, increasing the concentration of C934P decreased the T(sol/gel) in formulations containing 20%(w/w) P407. Rheological synergy between P407 and C934P at 37 degrees C was observed and was accredited to secondary interactions between these polymers, in addition to hydrophobic interactions between P407 micelles. Importantly, formulations composed of 20% (w/w) P407 and C934P exhibited pronounced mucoadhesive properties. The ease of administration (below the T(sol/gel)) in conjunction with the viscoelastic (notably high elasticity) and mucoadhesive properties (at body temperature) render the formulations composed of 20% (w/w) P407 and C934P as potentially useful platforms for mucoadhesive, controlled topical drug delivery within the oral cavity. (c) 2009 Published by Elsevier B.V.

A valuation of patients` willingness-to-pay for insulin delivery in diabetes

Objectives: The aim of this study was to determine the insulin-delivery system and the attributes of insulin therapy that best meet patients` preferences, and to estimate patients` willingness-to-pay (WTP) for them. Methods: This was a cross-sectional discrete choice experiment (DCE) study involving 378 Canadian patients with type 1 or type 2 diabetes. Patients were asked to choose between two hypothetical insulin treatment options made up of different combinations of the attribute levels. Regression coefficients derived using conditional logit models were used to calculate patients` WTP. Stratification of the sample was performed to evaluate WTP by predefined subgroups. Results: A total of 274 patients successfully completed the survey. Overall, patients were willing to pay the most for better blood glucose control followed by weight gain. Surprisingly, route of insulin administration was the least important attribute overall. Segmented models indicated that insulin naive diabetics were willing to pay significantly more for both oral and inhaled short-acting insulin compared with insulin users. Surprisingly, type 1 diabetics were willing to pay $C11.53 for subcutaneous short-acting insulin, while type 2 diabetics were willing to pay $C47.23 to avoid subcutaneous short-acting insulin (p < .05). These findings support the hypothesis of a psychological barrier to initiating insulin therapy, but once that this barrier has been overcome, they accommodate and accept injectable therapy as a treatment option. Conclusions: By understanding and addressing patients` preferences for insulin therapy, diabetes educators can use this information to find an optimal treatment approach for each individual patient, which may ultimately lead to improved control, through improved compliance, and better diabetes outcomes.

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound. (c) 2009 Elsevier B.V. All rights reserved.

Family orientated delivery of routine nursing care in hospital

Hospital nursing may be better deployed to acute clinical patient care. The recruitment of family assistance will facilitate this process in patients in hospital awaiting placement and without acute care issues.

Perceptions of mental health service delivery among staff and Indigenous consumers: it's still about communication

Objective: A needs analysis was undertaken to determine the quality and effectiveness of mental health services to Indigenous consumers within a health district of Southern Queensland. The study focussed on identifying gaps in the service provision for Indigenous consumers. Tools and methodologies were developed to achieve this. Method: Data were collected through the distribution of questionnaires to the target populations: district health service staff and Indigenous consumers. Questionnaires were developed through consultation with the community and the Steering Committee in order to achieve culturally appropriate wording. Of prime importance was the adaptation of questionnaire language so it would be fully understood by Indigenous consumers. Both questionnaires were designed to provide a balanced perspective of current mental health service needs for Indigenous people within the mental health service. Results: Results suggest that existing mental health services do not adequately meet the needs of Indigenous people. Conclusions: Recommendations arising from this study indicate a need for better communication and genuine partnerships between the mental health service and Indigenous people that reflect respect of cultural heritage and recognises the importance of including Indigenous people in the design and management of mental health services. Attention to the recommendations from this study will help ensure a culturally appropriate and effective mental health service for Indigenous consumers.

A Step-by-Step Approach to Transit Oriented Development Project Delivery

A major challenge in successfully implementing transit-oriented development (TOD) is having a robust process that ensures effective appraisal, initiation and delivery of multi-stakeholder TOD projects. A step-by step project development process can assist in the methodic design, evaluation, and initiation of TOD projects. Successful TOD requires attention to transit, mixed-use development and public space. Brisbane, Australia provides a case-study where recent planning policies and infrastructure documents have laid a foundation for TOD, but where barriers lie in precinct level planning and project implementation. In this context and perhaps in others, the research effort needs to shift toward identification of appropriate project processes and strategies. This paper presents the outcomes of research conducted to date. Drawing on the mainstream approach to project development and financial evaluation for property projects, key steps for potential use in successful delivery of TOD projects have been identified, including: establish the framework; location selection; precinct context review; preliminary precinct design; the initial financial viability study; the decision stage; establishment of project structure; land acquisition; development application; and project delivery. The appropriateness of this mainstream development and appraisal process will be tested through stakeholder research, and the proposed process will then be refined for adoption in TOD projects. It is suggested that the criteria for successful TOD should be broadened beyond financial concerns in order to deliver public sector support for project initiation.

Using household survey data to inform policy decisions regarding the delivery of evidence-based parenting interventions.

Background: This study used household survey data on the prevalence of child, parent and family variables to establish potential targets for a population-level intervention to strengthen parenting skills in the community. The goals of the intervention include decreasing child conduct problems, increasing parental self-efficacy, use of positive parenting strategies, decreasing coercive parenting and increasing help-seeking, social support and participation in positive parenting programmes. Methods: A total of 4010 parents with a child under the age of 12 years completed a statewide telephone survey on parenting. Results: One in three parents reported that their child had a behavioural or emotional problem in the previous 6 months. Furthermore, 9% of children aged 2–12 years meet criteria for oppositional defiant disorder. Parents who reported their child's behaviour to be difficult were more likely to perceive parenting as a negative experience (i.e. demanding, stressful and depressing). Parents with greatest difficulties were mothers without partners and who had low levels of confidence in their parenting roles. About 20% of parents reported being stressed and 5% reported being depressed in the 2 weeks prior to the survey. Parents with personal adjustment problems had lower levels of parenting confidence and their child was more difficult to manage. Only one in four parents had participated in a parent education programme. Conclusions: Implications for the setting of population-level goals and targets for strengthening parenting skills are discussed.

Delivery of multiple CD8 cytotoxic T cell epitopes by DNA vaccination

Development of CD8 alpha beta CTL epitope-based vaccines requires an effective strategy capable of co-delivering large numbers of CTL epitopes, Here we describe a DNA plasmid encoding a polyepitope or polytope protein, which contained multiple contiguous minimal murine CTL epitopes, Mice vaccinated with this plasmid made MHC-restricted CTL responses to each of the epitopes, and protective CTL were demonstrated in recombinant vaccinia virus, influenza virus, and tumor challenge models, CTL responses generated by polytope DNA plasmid vaccination lasted for 1 yr, could be enhanced by co-delivering a gene for granulocyte-macrophage CSF, and appeared to be induced in the absence of CD4 T cell-mediated help, The ability to deliver large numbers of CTL epitopes using relatively small polytope constructs and DNA vaccination technology should find application in the design of human epitope-based CTL vaccines, in particular in vaccines against EBV, HIV, and certain cancers.

Epidermal iontophoresis: I. Development of the ionic mobility-pore model

Purpose, An integrated ionic mobility-pore model for epidermal iontophoresis is developed from theoretical considerations using both the free volume and pore restriction forms of the model for a range of solute radii (r(j)) approaching the pore radii (r(p)) as well as approximation of the pore restriction form for r(j)/r(p) < 0.4. In this model, we defined the determinants for iontophoresis as solute size (defined by MV, MW or radius), solute mobility, solute shape, solute charge, the Debye layer thickness, total current applied, solute concentration, fraction ionized, presence of extraneous ions (defined by solvent conductivity), epidermal permselectivity, partitioning rates to account for interaction of unionized and ionized lipophilic solutes with the wall of the pore and electroosmosis. Methods, The ionic mobility-pore model was developed from theoretical considerations to include each of the determinants of iontophoretic transport. The model was then used to reexamine iontophoretic flux conductivity and iontophoretic flux-fraction ionized literature data on the determinants of iontophoretic flux. Results. The ionic mobility-pore model was found to be consistent with existing experimental data and determinants defining iontophoretic transport. However, the predicted effects of solute size on iontophoresis are more consistent with the pore-restriction than free volume form of the model. A reanalysis of iontophoretic flux-conductivity data confirmed the model's prediction that, in the absence of significant electroosmosis, the reciprocal of flux is linearly related to either donor or receptor solution conductivity. Significant interaction with the pore walls, as described by the model, accounted for the reported pH dependence of the iontophoretic transport for a range of ionizable solutes. Conclusions. The ionic mobility-pore iontophoretic model developed enables a range of determinants of iontophoresis to be described in a single unifying equation which recognises a range of determinants of iontophoretic flux.

Epidermal iontophoresis: II. Application of the ionic mobility-pore model to the transport of local anesthetics

Purpose, An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. Methods. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. Results. The logarithm of the iontophoretic permeability coefficient (log PCj,iont) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PCj,iont was best defined by ionic mobility (and its determinants: conductivity, pK(a) and MW) and MW. Conclusions. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pK(a)) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.

Targeting local tissues by transdermal application: Understanding drug physicochemical properties that best exploit protein binding and blood flow effects

The targeting of topically applied drug molecules into tissues below a site of application requires an understanding of the complex interrelationships between the drug, its formulation, the barrier properties of the skin, and the physiological processes occurring below the skin that are responsible for drug clearance from the site, tissue, and/or systemic distribution and eventual elimination. There is still a certain amount of controversy over the ability of topically applied drugs to penetrate into deeper tissues by diffusion or whether this occurs by redistribution in the systemic circulation. The major focus of our work in this area has been in determining how changes in drug structure and physicochemical properties, such as protein binding and lipophilicity, affect drug clearance into the local dermal microcirculation and lymphatics, as well as subsequent distribution into deeper tissues below an application site. The present study outlines our recent thinking on the drug molecule optimal physical attributes, in terms of plasma and tissue partitioning behaviour, that offer the greatest potential for deep tissue targeting. Drug Dev. Res. 46:309-315, 1999. (C) 1999 Wiley-Liss, Inc.

Papillomavirus virus-like particles for the delivery of multiple cytotoxic T cell epitopes

Chimeric papillomavirus (PV) virus-like particles (VLPs) based on the bovine papillomavirus type 1 (BPV-1) L1 protein were constructed by replacing the 23-carboxyl-terminal amino acids of the BPV1 major protein L1 with an artificial polytope minigene, containing known CTL epitopes of human PV16 E7 protein, HIV IIIB gp120 P18, Nef, and reverse transcriptase (RT) proteins, and an HPV16 E7 linear B epitope. The CTL epitopes were restricted by three different MHC class 1 alleles (H-2(b), H-2(d), HLA-A*0201). The chimeric L1 protein assembled into VLPs when expressed in SF-9 cells by recombinant baculovirus. After immunization of mice with polytope VLPs in the absence of adjuvant, serum antibodies were detected which reacted with both polytope VLPs and wild-type BPV1L1 VLPs, in addition to the HPV16E7 linear B cell epitope. CTL precursors specific for the HPV16 E7, HIV P18, and RT CTL epitopes were also detected in the spleen of immunized mice. Polytope VLPs can thus deliver multiple B and T epitopes as immunogens to the MHC class I and class II pathways, extending the utility of VLPs as self-adjuvanting immunogen delivery systems. (C) 2000 Academic Press.

Undergraduate student experience in dental service delivery in rural South Australia: An analysis of costs and benefits

Background, Rural experience for dental students can provide valuable clinical education, change attitudes to rural practice, and make a valuable contribution to clinical service provision. The aim of this paper is to assess the costs and benefits of service delivery by students through rural training programmes Methods: Groups of two students worked in the public dental clinics in adjacent rural centres where there had been long-term difficulties in recruiting staff. The costs and benefits of the programme were assessed by the impact on waiting lists, the total cost per patient of, a course of care and by the marginal cost of adding service provision by students to existing arrangements. Results: The total costs of emergency and complete treatment provided by students were greater than the costs of treatment provided by public-sector dentists but less than the costs of private providers treating public patients. However, the value of services were greater when care was provided by students or private providers and the marginal cost of students providing services was 50-70 per cent of the cost of care provided by public dentists. Conclusion: This assessment suggests that the service benefits achieved compliment the primary objective of influencing the attitude of students to rural practice.