Natalie J. Medlicott

Delivery systems for the administration of drugs to the periodontal pocket

Abstract A number of delivery systems have been investigated for administration of antibacterial agents in the treatment of plaque-initiated periodontal disease. These include prolonged release intrapocket devices which are inserted at diseased sites. An effective antibacterial concentration is maintained if drug lost by elimination processes is replaced. Bioassays or sensitive HPLC assays may be used to monitor drug concentrations in the gingival crevicular fluid and allow estimation of the duration of effective release. Non-degradable and degradable systems have been developed, and although improvements in clinical and microbiological parameters are reported with both these systems, advantages have been identified with the degradable systems. Importantly, depleted degradable devices do not require removal at the end of treatment, but repeated administration is generally required, as these systems mostly produce effective drug concentrations for short periods. To improve this method of drug administration the aims and optimal duration of treatment need to be further clarified so that development of delivery system can occur through modification of the devices release and degradation characteristics.

The importance of interfaces in protein drug delivery – why is protein adsorption of interest in pharmaceutical formulations?

Introduction: In the area of peptide and protein drug products, interfaces are present as part of the basic liquid formulation, when freeze-dried formulations are reconstituted and when particulate delivery systems are prepared. Proteins are known to interact with these interfaces, and the effects seen are often irreversible adsorption and structural changes. Areas covered: This review focuses on the ways in which peptides and proteins interact with surfaces and interfaces, and the effect these interactions have on the stability and safety of the active protein in pharmaceutical formulations. It illustrates, through examples, what can be determined by an adsorption study, and what can change when either the protein or the interfaces are modified. Last but not least, it addresses the value of these studies. The reader will gain an update on the basics of protein adsorption, with a focus on pharmaceutically relevant interfaces and recent advances in the field. Expert opinion: Protein adsorption is widely studied; however, a more unified approach is still needed, especially on the adsorption of pharmaceutically relevant proteins, modified proteins and surfaces.

Utility of interleukin-12 and interleukin-10 in comparison with other cytokines and acute-phase reactants in the diagnosis of neonatal sepsis.

We compared the test characteristics of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT), C-reactive protein (CRP), and full blood count (FBC) in the diagnosis of neonatal sepsis. This prospective cohort study in the Neonatal Intensive Care Unit of Dunedin hospital of patients between July 1, 2002 and February 28, 2007 included 117 neonates commenced on antibiotics for 164 episodes of suspected sepsis. Blood cultures, FBC, CRP, IL-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), TNF-alpha, and PCT were obtained at the time sepsis was first suspected and for the following 3 days. Receiver operator characteristics (ROC) plots and test characteristics were determined using culture-positive sepsis as the gold standard. At the time sepsis was first suspected, the most promising individual test was IL-12(p70) with an area under the curve (95% confidence interval [CI]) for the ROC of 0.74 (0.63 to 0.86), which (with a cutoff at 75 pg/mL) had a sensitivity (95% CI) of 28% (20 to 36%) and a specificity of 98% (96 to 100%). IL-10 had a sensitivity of 17% (10 to 23%) and a specificity of 99% (97 to 100%). IL-10 and IL-12(p70) are promising diagnostic tests that can be used to confirm sepsis in neonates.

Chlorhexidine release from poly(ε-caprolactone) films prepared by solvent evaporation

Abstract The effect of selected formulation variables on the release of chlorhexidine from poly(e-caprolactone) films was evaluated in vitro using a complete factorial experimental design. Repeated measures analysis of variance showed chlorhexidine type (diacetate or base), drug load (10, 20 or 30% w/w), chlorhexidine particle size ( or 63−125 μm ) and film side (upper or lower) significantly affected the percentage released over 10 and 30 days. Significant interactions were also observed between factors. Release from the upper side of films occurred more slowly than from the lower side of films for most formulations. This difference was particularly apparent for films containing chlorhexidine diacetate. The general release equation ( M t / M ∞ = kt n ) was fitted to the release data and constants estimated. The value of n, which indicates the mechanism of release, tended towards 0.5 for release at high drug loadings which may suggest release was predominantly diffusion-controlled from these films. Transecting sections of film, prepared with chlorhexidine diacetate μm (drug loading 20% w/w), and analysing the chlorhexidine content at varying distances from the film surfaces showed a gradient in chlorhexidine concentration through the film, with lower concentrations near the upper side and higher concentrations near the lower side.

Pulsatile release from subcutaneous implants

Pulsatile delivery of antigens and hormones from subcutaneous implants could have uses in the animal production and veterinary medicine. Development of single-shot vaccines which release both initial and booster antigen from a single administration and hormonal preparations that release in a similar manner to the natural secretion patterns are two areas with potential. Formulation approaches employed to produce subcutaneous implants with pulsatile release profiles are reviewed.

Casting solvent controlled release of chlorhexidine from ethylcellulose films prepared by solvent evaporation

Abstract Chlorhexidine release from ethylcellulose films cast from solvents of different dichloromethane/ethanol compositions was studied. Release rate was proportional to the square root of time. Increased ethanol content within the casting solvent significantly enhanced release rate. Release rate and cumulative mass released at different time periods (5, 10, 15 and 25 days) were proportional to the solubility parameter of the casting solvent.

Intravenous drug delivery in neonates: lessons learnt

Intravenous drug administration presents a series of challenges that relate to the pathophysiology of the neonate and intravenous infusion systems in neonates. These challenges arise from slow intravenous flow rates, small drug volume, dead space volume and limitations on the flush volume in neonates. While there is a reasonable understanding of newborn pharmacokinetics, an appreciation of the substantial delay and variability in the rate of drug delivery from the intravenous line is often lacking. This can lead to difficulties in accurately determining the pharmacokinetic and pharmacodynamic relationship of drugs in the smallest patients. The physical variables that affect the passage of drugs through neonatal lines need to be further explored in order to improve our understanding of their impact on the delivery of drugs by this route in neonates. Through careful investigation, the underlying causes of delayed drug delivery may be identified and administration protocols can then be modified to ensure predictable, appropriate drug input kinetics.

Local delivery of chlorhexidine using a tooth-bonded delivery system.

Films containing 20% w/w chlorhexidine base (particle size 63-125 microm) in poly(epsilon-caprolactone), MW 35,000-45,000, were prepared by solvent evaporation and sections attached to the mesio-lingual and mesio-buccal surfaces of the lower first molar in healthy volunteers. Saliva (<1.5 microl) was collected on Periopaper and chlorhexidine concentrations measured by HPLC were typically higher in the area immediately adjacent to the tooth-bonded film sections and lower at more distant sites. Analysis of variance of chlorhexidine concentrations, adjacent to the film sections, showed concentrations were significantly different on the buccal and lingual sides of the tooth and depended on the time of sampling (n=5, P<0.05).

Preliminary release studies of chlorhexidine (base and diacetate) from poly(ϵ-caprolactone) films prepared by solvent evaporation

Abstract Chlorhexidine release from poly(ϵ-caprolactone) films was zero-order after an initial period. Significant burst effects were observed with chlorhexidine base (5, 10% w/w) but not diacetate loaded films (10, 15, 20, 30% w/w). These differences may be due to the physicochemical state of chlorhexidine within the films.

Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates.

Objectives This study aimed to investigate intravenous infusions as used in the neonatal intensive care setting, to determine the effect of gentamicin dose (mg), gentamicin concentrations (mg/ml), flow rate (ml/h) and flush volume (ml) upon the length of infusion time.