Steve P. Rannard

Systematic tuning of pore morphologies and pore volumes in macroporous materials by freezing

Freezing and its combination with emulsion-templating are investigated to systematically tune pore morphologies and volumes in macroporous materials. Macroporous structures with controllable pore morphologies are formed under defined freezing conditions. Oil-in-water emulsions are processed to produce porous polymeric materials with a controlled proportion of ice-templated pores and emulsion-templated pores by systematically changing the volume ratio of the internal oil droplet phase to aqueous continuous phase in the emulsions. Pore morphology, bulk density, and pore volumes of these macroporous materials can thus be systematically tuned. Chemical crosslinking and sol–gel processing are further employed to produce porous polymeric and inorganic materials (silica, silica–alumina, and zirconia) with enhanced mechanical stability and hierarchical porosity.

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy.

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥1week, ≥1month or ≥6months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV

Background and ObjectivesAntiretrovirals are currently used for the treatment and prevention of HIV infection. However, poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying antiretroviral administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight antiretrovirals through physiologically based pharmacokinetic (PBPK) modelling.MethodsA whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulationsResultsThe predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control their release rate can be addressed.ConclusionsThese data may help inform the target product profiles for LA antiretroviral reformulation strategies.

Architecture-driven aqueous stability of hydrophobic, branched polymer nanoparticles prepared by rapid nanoprecipitation

The first nanoprecipitation study of hydrophobic branched vinyl polymers is presented with control across a wide range of particle diameters (approximately 60–800 nm) from control of degree of polymerisation and precipitation parameters. In contrast to linear polymers of identical primary chain length, the formation of stable nanoparticles in aqueous media appears to be architecture driven with a contribution from oligomeric chain-ends with measureable water-solubility. The aqueous nanoparticles dispersions are robust and stable to dilution, solvent addition, sonication and temperature. The addition of small amounts of NaCl led to a destabilisation indicating charge stabilisation is also a major contributor to stability.

One-pot synthesis of methacrylic acid–ethylene oxide branched block and graft copolymers

Despite the large volume of academic literature on the synthesis and physico-chemical characterization of block copolymers and their potential for application in a wide variety of products, relatively few of these materials have been commercialized. More often than not the main obstacle to this is the high cost of synthesis versus the extra value added to potential products. Devising more cost-effective routes to block copolymers therefore remains an important challenge to polymer chemists. Using conventional solution free radical polymerization we have now synthesized, each in one-pot, architecturally complex ‘branched diblock copolymers’ and compositionally related ‘grafted branched copolymers’, exploiting a generic branching synthetic methodology developed in our own laboratory. In each case blocks of poly(methacrylic acid) and poly(ethylene glycol) (PEG) are involved. The first group was obtained by copolymerization of methacrylic acid with a PEG dimethacrylate with branching favoured in competition with crosslinking by use of appropriate levels of free radical chain transfer agent. For the second series methacrylic acid has been copolymerized with a PEG monomethacrylate and ethylene glycol dimethacrylate, again with crosslinking inhibited by use of a chain transfer agent. Good yields of products are obtained and typically the polymerization mole feed compositions have been chosen to yield an even mass balance of poly(methacrylic acid) and PEG blocks in the copolymers, though this parameter is readily adjustable. The molecular composition of the products has been characterized by elemental microanalysis and 1H NMR spectroscopy, with the latter also combining with multi-angle light scattering size exclusion chromatographic (MALS/SEC) molar mass data to provide information on the branching architecture. The products are complex mixtures in terms of both architecture and molar mass, but the synthetic strategy is far simpler, more practical and more cost-effective than alternative routes to structurally more uniform analogues via multi-step living polymerization procedures are likely to be. The materials are therefore complementary to, rather than competitive with, these analogues. The present approach lends itself to efficient scale-up, and could make significant quantities of materials readily available for further physico-chemical characterization and applications evaluation.

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies

Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.

Facile synthesis of complex multi-component organic and organic–magnetic inorganic nanocomposite particles

A generic in situ method for producing triple component hydrophobic inorganic–organic nanocomposite particles, using a combination of modified emulsion templating and freeze-drying, is presented. Model nanocomposite particles have been developed bearing up to three hydrophobic ingredients chosen from polystyrene, oil red and 15–20 nm oleic acid-coated super-paramagnetic iron oxide (Fe3O4) nanoparticles. The technique avoids harsh conditions, in situ polymer synthesis and lengthy workup procedures, and results in high incorporation of magnetic particles (approximately 80% of triple-component nanocomposite particles contain magnetite) with retention of super-paramagnetism (>90% preservation). The nanocomposites have been characterised using dynamic light scattering, and studied under static and flow conditions in the presence of magnetic fields. Drug release was demonstrated using model nanocomposite particles bearing ibuprofen with differing hydrophobic polymer; polycaprolactone and poly(n-butyl methacrylate). Drug release varied with temperature, suggesting the synthetic technique could thus be adopted to develop drug carrier particles with tailored drug release properties.

Research Spotlight: Nanomedicines for HIV therapy

Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment.

Synthesis and thermal studies of aliphatic polyurethane dendrimers: a geometric approach to the Flory–Fox equation for dendrimer glass transition temperature

A new convergent synthesis for polyurethane dendrons to generation 4, and dendrimers to generation 3, is presented with control of surface functionality. The systematic synthesis of twenty-six new dendritic materials has led to a study of the factors affecting Tg using widely accepted approaches. The established understanding of dendritic polymerTg behaviour is that the Flory–Fox models, used for linear polymers, are unsuitable as the high number of chain ends and globular nature of dendrimers requires special consideration. In our review of the accepted understanding we have shown that the conventional Flory–Fox models predict Tg∞ accurately and generate identical values to the established modifications of the Flory–Fox equation that consider ‘dendrimer-relevant’ aspects such as the non-zero values of ne/M at infinite molecular weight. We also present a new approach using the geometric parameters of dendrimer mass evolution suggesting that the Flory–Fox equation is indeed appropriate for determination of dendrimerTg∞.

Flow cytometric analysis of the physical and protein-binding characteristics of solid drug nanoparticle suspensions

AIM Oral and intramuscular sustained-release antiretroviral solid drug nanoparticles (SDNs) are in development but there is limited understanding of whether nanoparticles or dissolved drug predominate systemically. MATERIALS & METHODS A flow cytometric method was developed to analyze SDNs in biological fluids such as plasma, including the putative formation of a protein corona. RESULTS SDNs were found to be stable in plasma and could be observed using the techniques developed here. In addition, transferrin, fibrinogen and albumin were found to be associated with SDNs upon incubation. CONCLUSION This methodology has enabled us to determine protein interactions of SDNs in solution without the requirement of separation from the matrix. This will enable further studies of their biological fate.