Development of a physiologically-based pharmacokinetic model of the rat central nervous system

Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

Self-assembly-driven electrospinning:the transition from fibers to intact beaded morphologies

Polymer beads have attracted considerable interest for use in catalysis, drug delivery, and photo­nics due to their particular shape and surface morphology. Electrospinning, typically used for producing nanofibers, can also be used to fabricate polymer beads if the solution has a sufficiently low concentration. In this work, a novel approach for producing more uniform, intact beads is presented by electrospinning self-assembled block copolymer (BCP) solutions. This approach allows a relatively high polymer concentration to be used, yet with a low degree of entanglement between polymer chains due to microphase separation of the BCP in a selective solvent system. Herein, to demonstrate the technology, a well-studied polystyrene-poly(ethylene butylene)–polystyrene triblock copolymer is dissolved in a co-solvent system. The effect of solvent composition on the characteristics of the fibers and beads is intensively studied, and the mechanism of this fiber-to-bead is found to be dependent on microphase separation of the BCP.

Excipients in medicines for children:scientific and regulatory paradigms

There is an ongoing debate over the use of pharmaceutical excipients in medicines for children, triggered by the increased number of formulations suitable for this target patient population. Pharmaceutical excipients can be regarded as essential / necessary enablers in formulation development. These are materials other than the 'active pharmaceutical ingredient' which are added to the formulation to achieve a specific function1. This may include aiding in the processing or manufacture of the drug delivery system such as lubricants or flow aids, controlling the release of the active ingredient to achieve modified release, enhance patient acceptability by improving taste of medicines or to develop easily swallowed dosage forms.

Poly(glycerol adipate-co-ω-pentadecalactone) spray-dried microparticles as sustained release carriers for pulmonary delivery

Purpose: The aim of this work was to optimize biodegradable polyester poly(glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL, microparticles as sustained release (SR) carriers for pulmonary drug delivery. Methods: Microparticles were produced by spray drying directly from double emulsion with and without dispersibility enhancers (L-arginine and L-leucine) (0.5-1.5%w/w) using sodium fluorescein (SF) as a model hydrophilic drug. Results: Spray-dried microparticles without dispersibility enhancers exhibited aggregated powders leading to low fine particle fraction (%FPF) (28.79±3.24), fine particle dose (FPD) (14.42±1.57 μg), with a mass median aerodynamic diameter (MMAD) 2.86±0.24 μm. However, L-leucine was significantly superior in enhancing the aerosolization performance ( L-arginine:%FPF 27.61±4.49-26.57±1.85; FPD 12.40±0.99-19.54±0.16 μg and MMAD 2.18±0.35-2. 98±0.25 μm, L-leucine:%FPF 36.90±3.6-43.38±5. 6; FPD 18.66±2.90-21.58±2.46 μg and MMAD 2.55±0.03-3. 68±0.12 μm). Incorporating L-leucine (1.5%w/w) reduced the burst release (24.04±3.87%) of SF compared to unmodified formulations (41.87±2.46%), with both undergoing a square root of time (Higuchi's pattern) dependent release. Comparing the toxicity profiles of PGA-co-PDL with L-leucine (1.5%w/w) (5 mg/ml) and poly(lactide-co-glycolide), (5 mg/ml) spray-dried microparticles in human bronchial epithelial 16HBE14o-cell lines, resulted in cell viability of 85.57±5.44 and 60.66±6.75%, respectively, after 72 h treatment. Conclusion:The above data suggest that PGA-co-PDL may be a useful polymer for preparing SR microparticle carriers, together with dispersibility enhancers, for pulmonary delivery. © Springer Science+Business Media, LLC 2011.

Designing liposomal adjuvants for the next generation of vaccines

Liposomes not only offer the ability to enhance drug delivery, but can effectively act as vaccine delivery systems and adjuvants. Their flexibility in size, charge, bilayer rigidity and composition allow for targeted antigen delivery via a range of administration routes. In the development of liposomal adjuvants, the type of immune response promoted has been linked to their physico-chemical characteristics, with the size and charge of the liposomal particles impacting on liposome biodistribution, exposure in the lymph nodes and recruitment of the innate immune system. The addition of immunostimulatory agents can further potentiate their immunogenic properties. Here, we outline the attributes that should be considered in the design and manufacture of liposomal adjuvants for the delivery of sub-unit and nucleic acid based vaccines.

Development of photosensitive liposomes for the controlled release of drugs

The facility to controlled triggered release from a “cage” system remains a key requirement for novel drug delivery. Earlier studies have shown that Bis-Azo PC based photosensitive liposomes are beneficial for drug delivery. Thus, the aim of this project was to develop photosensitive liposomes that can be used for the controlled release of drugs through UV irradiation, particularly therapeutic agents for the treatment of psoriasis. Bis-Azo PC was successfully synthesized and incorporated into a range of liposomal formulations, and these liposomes were applied for the controlled release of BSA-FITC. Bis-Azo PC sensitized liposomes were prepared via interdigitation fusion method. IFV containing optimum cholesterol amount in terms of protein loading, stability and photo-trigger release of protein was investigated. Further studies investigated the stability and triggered release of the HMT from IFV. Finally, permeation behavior of HMT and HMT-entrapped IFV through rat skin was examined using Franz cell. Results from protein study indicated that the stable entrapment of the model protein was feasible as shown through fluorescence spectroscopy and maximum of 84% protein release from IFV after 12 min of UV irradiation. Moreover, stability studies indicated that IFV were more stable at 4 0C as compared to 25 0C. Hence, DPPC:Chol:Bis-Azo PC (16:2:1) based IFV was chosen for the controlled release of HMT and these studies exhibited that photo-trigger release and stability data of HMT-entrapped IFV are in line with the protein results. Franz cell work inferred that HMT-entrapped IFV attributed to slower skin permeation as compared to HMT. CLSM also demonstrated that HMT can be used as a fluorescent label for the in vitro skin study. Overall, the work highlighted in this thesis has given useful insight into the potentials of Bis-Azo PC based IFV as a promising carrier for the treatment of psoriasis.

Microfluidics based manufacture of liposomes simultaneously entrapping hydrophilic and lipophilic drugs

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually, and in combination, using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ∼90 to 300 nm. In terms of drug loading, microfluidics production promoted high loading within ∼100 nm vesicles for both the water soluble drug (20–25% of initial amount added) and the bilayer embedded drug (40–42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug.