High-density poly(ethylene) (HDPE) is an important class of polymer used extensively in plastic packaging as well as numerous other applications. HDPE has a structure that consists of crystalline (monoclinic and orthorhombic) and amorphous domains. Here, we exploit a range of approaches focusing on magic angle spinning (MAS) nuclear magnetic resonance (NMR) aimed at comparing the effect of the HDPE sample formulation (cutting, shaving and cryomilling), from the commercially available manufactured pellets, into these domains and their quantification. 13C cross polarisation (CP) experiments reveal that these formulated HDPEs are qualitatively different and 13C CP build-up curves and 13C direct excitation experiments enable the content of each domain to be obtained, pointing to an increase of monoclinic domain at the expense of the orthorhombic one upon increased processing. The crystallinity contents obtained compared, in some cases, favourably with those obtained by differential scanning calorimetry (DSC) data. These results provide evidence that the manner of preparation of HDPE pellets modifies the concentration of the various domains and suggest that care should be taken during processing.
Lipid nanoparticles have proved an attractive approach for drug delivery; however, the challenges of optimising formulation stability and increasing drug loading have limited progression. In this work, we investigate the role of unpegylated lipid surfactants (helper lipids) in nanoparticle formation and the effect of blending helper lipids with pegylated lipid surfactants on the formation and stability of lipid-based nanoparticles by nanoprecipitation. Furthermore, blends of unpegylated/pegylated lipid surfactants were examined for ability to accommodate higher drug loading formulations by means of a higher weight percentage (wt%) of drug relative to total mass of formulation components (i.e. drug, surfactants and lipids). Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. Our findings demonstrate that the addition of unpegylated lipid surfactant (Lipoid S100) to pegylated lipid surfactant (Brij S20) enhances stability, particularly at higher weight percentages of the core material. This blending approach enables drug loading capacities exceeding 10% in the lipid nanoparticles. Notably, Lipoid S100 exhibited nucleating properties that aided in the formation and stabilisation of the nanoparticles. Furthermore, we examined the incorporation of a model drug into the lipid nanoparticle formulations. Blending the model drug with the core material disrupted the crystallinity of the core, offering additional potential benefits in terms of drug release and stability. This comprehensive investigation provides valuable insights into the interplay between surfactant properties, core material composition, and nanoparticle behaviour. The study enhances our understanding of lipid materials and offers guidance for the design and optimisation of lipid nanoparticle formulations.
Circulating, soluble polymer-drug conjugates have been utilised for many years to aid the delivery of sensitive, poorly-soluble or cytotoxic drugs, prolong circulation times or minimise side effects. Long-acting therapeutics are increasing in their healthcare importance, with intramuscular and subcutaneous administration of liquid formulations being most common. Degradable implants also offer opportunities and the use of polymer-prodrug conjugates as implant materials has not been widely reported in this context. Here, the potential for polymer-prodrug conjugates of the water soluble nucleoside reverse transciption inhibitor emtricitabine (FTC) is studied. A novel diol monomer scaffold, allowing variation of prodrug substitution, has been used to form polyesters and polycarbonates by step-growth polymerisation. Materials have been screened for physical properties that enable implant formation, studied for drug release to provide mechanistic insights, and tunable prolonged release of FTC has been demonstrated over a period of at least two weeks under relevant physiological conditions.
Prodrugs , Emtricitabine , Nucleosides , Polymers , Water , DNA-Directed RNA Polymerases
Nanogels are candidates for biomedical applications, and core-shell nanogels offer the potential to tune thermoresponsive behaviour with the capacity for extensive degradation. These properties were achieved by the combination of a core of poly(N-isopropylmethacrylamide) and a shell of poly(N-isopropylacrylamide), both crosslinked with the degradable crosslinker N,N'-bis(acryloyl)cystamine. In this work, the degradation behaviour of these nanogels was characterised using asymmetric flow field flow fractionation coupled with multi-angle and dynamic light scattering. By monitoring the degradation products of the nanogels in real-time, it was possible to identify three distinct stages of degradation: nanogel swelling, nanogel fragmentation, and nanogel fragment degradation. The results indicate that the core-shell nanogels degrade slower than their non-core-shell counterparts, possibly due to a higher degree of self-crosslinking reactions occurring in the shell. The majority of the degradation products had molecule weights below 10 kDa, which suggests that they may be cleared through the kidneys. This study provides important insights into the design and characterisation of degradable nanogels for biomedical applications, highlighting the need for accurate characterisation techniques to measure the potential biological impact of nanogel degradation products.
The World Health Organisation (WHO) estimates 15 million babies worldwide are born preterm each year, with 1 million infant mortalities and long-term morbidity in survivors. Whilst the past 40 years have provided some understanding in the causes of preterm birth, along with development of a range of therapeutic options, notably prophylactic use of progesterone or uterine contraction suppressants (tocolytics), the number of preterm births continues to rise. Existing therapeutics used to control uterine contractions are restricted in their clinical use due to pharmacological drawbacks such as poor potency, transfer of drugs to the fetus across the placenta and maternal side effects from activity in other maternal systems. This review focuses on addressing the urgent need for the development of alternative therapeutic systems with improved efficacy and safety for the treatment of preterm birth. We discuss the application of nanomedicine as a viable opportunity to engineer pre-existing tocolytic agents and progestogens into nanoformulations, to improve their efficacy and address current drawbacks to their use. We review different nanomedicines including liposomes, lipid-based carriers, polymers and nanosuspensions highlighting where possible, where these technologies have already been exploited e.g. liposomes, and their significance in improving the properties of pre-existing therapeutic agents within the field of obstetrics. We also highlight where active pharmaceutical agents (APIs) with tocolytic properties have been used for other clinical indications and how these could inform the design of future therapeutics or be repurposed to diversify their application such as for use in preterm birth. Finally we outline and discuss the future challenges.
As the desire and popularity of a tanned appearance continues, the social effects of UV-free tanning are becoming more important. Dihydroxyacetone (DHA) has seen extensive use as the main tanning agent in sunless tanners. The DHA-induced tan is a result of brown melanoidins formed by a non-enzymatic Maillard reaction between DHA and amino acid species found in the stratum corneum. DHA, thereby, provides a safer route to a tanned appearance compared with exposure to ultraviolet radiation. However, DHA is a highly reactive molecule, posing a multitude of challenges for potential product formulations. With their increased use, the safety considerations of topically applied DHA tanners have been investigated. Many different vehicles have been used for topical delivery of DHA, and they are becoming increasingly multifunctional. This review provides a holistic overview of dihydroxyacetone sunless tanning products.
Dihydroxyacetone , Ultraviolet Rays , Humans , Dihydroxyacetone/pharmacology , Ultraviolet Rays/adverse effects , Epidermis , Amino Acids , Drug Compounding
Long-acting drug delivery is a growing area of interest as it overcomes many challenges related to patient adherence to therapy and the pill burden associated with chronic illness. Injectable formulations are becoming more common and drug-releasing implants also provide several opportunities. Highly water soluble drug compounds are poor candidates for long-acting delivery. Here, the water-soluble nucleoside reverse transcriptase inhibitor emtricitabine (FTC) has been used as a novel A-B monomer in step-growth polymerisation with chloroformate functional Cn monomers, to produce new poly(carbamate/carbonate) structures with varying architecture. The polymer prodrugs were all solid at ambient temperature and have been shown to release FTC when subjected to mixed gender human plasma. Vacuum compression moulding has been used to form solid rod implants without polymer degradation; the rods show FTC release over long periods in the presence of microsomes, establishing the basis of a polymer prodrug strategy for FTC delivery.
Anti-HIV Agents , HIV Infections , Prodrugs , DNA-Directed RNA Polymerases/therapeutic use , Emtricitabine/pharmacology , Emtricitabine/therapeutic use , HIV Infections/drug therapy , Humans , Nucleosides , Polymers/therapeutic use , Prodrugs/chemistry , Reverse Transcriptase Inhibitors/therapeutic use , Water
We report the synthesis of core-shell nanogels by sequential addition of thermoresponsive monomers; N-isopropylacrylamide (NIPAM) and N-isopropylmethacrylamide (NIPMAM). The aggregation behaviour of aqueous dispersions of these particles in the presence of salt can be tuned by varying the monomer ratio. The inclusion of degradable cross-linker bis(acryloyl)cystamine (BAC) allows the nanogels to degrade in the presence of reducing agent, with nanogels composed of a copolymer of the two monomers not showing the same high levels of degradation as the comparable core-shell particles. These levels of degradation were also seen with physiologically relevant reducing agent concentration at pH 7. Therefore, it is hoped that the aggregation of these nanogels will have applications in nanomedicine and beyond.
A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the log P of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and log P appeared to strongly influence rates of nucleation. Model drugs with high log P were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form uniform and stable lipid based nanoparticles of high drug loading- through manipulation of log P are discussed.
Anti-HIV Agents/chemistry , Lamivudine/chemistry , Liposomes/chemistry , Nanoparticles/chemistry , Drug Carriers/chemistry , Drug Delivery Systems , Drug Stability , Hydrophobic and Hydrophilic Interactions , Materials Testing , Models, Molecular , Molecular Structure , Particle Size
The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate.
Antiviral Agents , COVID-19 Drug Treatment , Niclosamide , SARS-CoV-2/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Humans , Injections, Intramuscular , Nanoparticles , Niclosamide/administration & dosage , Niclosamide/pharmacology
The capacity to control the dispersed or aggregated state of colloidal particles is particularly attractive for facilitating a diverse range of smart applications. For this reason, stimuli-responsive nanoparticles have garnered much attention in recent years. Colloidal systems that exhibit multi-stimuli-responsive behaviour are particularly interesting materials due to the greater spatial and temporal control they display in terms of dispersion/aggregation status; such behaviour can be exploited for implant formation, easy separation of a previously dispersed material or for the blocking of unwanted pores. This review will provide an overview of the recent publications regarding multi-stimuli-responsive microgels and hybrid core-shell nanoparticles. These polymer-based nanoparticles are highly sensitive to environmental conditions and can form aggregated clusters due to a loss of colloidal stability, triggered by temperature, pH and ionic strength stimuli. We aim to provide the reader with a discussion of the recent developments in this area, as well as an understanding of the fundamental concepts which underpin the responsive behaviour, and an exploration of their applications.
The SARS-CoV-2 pandemic has spread at an unprecedented rate, and repurposing opportunities have been intensively studied with only limited success to date. If successful, repurposing will allow interventions to become more rapidly available than development of new chemical entities. Niclosamide has been proposed as a candidate for repurposing for SARS-CoV-2 based upon the observation that it is amongst the most potent antiviral molecules evaluated in vitro . To investigate the pharmacokinetics of niclosamide, reliable, reproducible and sensitive bioanalytical assays are required. Here, a liquid chromatography tandem mass spectrometry assay is presented which was linear from 31.25-2000 ng/mL (high dynamic range) and 0.78-100 ng/mL (low dynamic range). Accuracy and precision ranged between 97.2% and 112.5%, 100.4% and 110.0%, respectively. The presented assay should have utility in preclinical evaluation of the exposure-response relationship and may be adapted for later evaluation of niclosamide in clinical trials.
Poly(N-isopropylacrylamide) (pNIPAM) nanogels are a highly researched type of colloidal material. In this work, we establish a versatile asymmetric-flow field-flow fractionation (AF4) method that can provide high resolution particle sizing and also structural information on nanogel samples from 65-310 nm in hydrodynamic diameter and so different chemical compositions. To achieve this online multi-angle light scattering and dynamic light scattering detectors were used to provide measurement of the radius of gyration (R g) and hydrodynamic radius (R h) respectively. Two different eluents and a range of cross-flows were evaluated in order to provide effective fractionation and high recovery for the different nanogel samples. We found that using 0.1 M NaNO3 as the eluent and an initial cross-flow of 1 mL min-1 provided optimal separation conditions for all samples tested. Using this method, we analysed two types of samples, pNIPAM nanogels prepared by free radical dispersion polymerisation with increasing diameters and analysed poly(acrylic acid)-b-pNIPAM crosslinked nanogels prepared by reversible addition-fragmentation chain transfer dispersion polymerisation. We could determine that the differently sized free radical nanogels possessed differing internal structures; shape factors (R g/R h) ranged from 0.58-0.73 and revealed that the smallest nanogel had a homogeneous internal crosslinking density, while the larger nanogels had a more densely crosslinked core compared to the shell. The poly(acrylic acid)-b-pNIPAM crosslinked nanogels displayed clear core-shell structures due to all the crosslinking being contained in the core of the nanogel.
Solid lipid nanoparticles (SLNs) have proved to be effective nanocarriers with many advantages over other non-lipid-based systems. The development of new SLN formulations is often hindered through poor drug loading capacity and time-consuming optimisation of lipid/stabiliser combinations. One challenge in the development of new SLN formulations is understanding the complex interactions between amphiphilic stabilisers and hydrophobic lipids; the nature of these interactions can significantly impact SLN properties, including the internal polarity within the nanoparticle core. Herein, we report the use of pyrene to probe the internal lipid microenvironment inside SLNs. We investigate the effect of using different poloxamer stabilisers on the internal polarity of SLNs formed using the common solid lipid, Compritol 888 ATO. We show that the polarity of the internal lipid environment is modified by the length of the poly(propylene oxide) (PPO) block of the poloxamer stabiliser, with longer PPO blocks producing SLNs with less polar lipid cores. Blending of stabilisers could also be used to tune the polarity of the core lipid environment, which may allow for adjusting the polarity of the lipid to assist the loading of different therapeutics.
Stimuli-responsive layer-by-layer (LbL) capsules are appealing drug carriers for oral drug delivery owing to their abilities to utilize environmental differences to trigger changes in particles properties. LbL capsules typically have micrometer diameter ranging between 1 and 5 µm. The opportunity to use LbL for the modification of particles in the nanorange may provide enhanced benefits and properties for drug delivery. In this work, we used multiple polyelectrolytes to prepare novel stimuli-responsive multi-layered nanocapsules with submicron diameters. A systematic study was conducted to investigate the influence of various experimental parameters on the formation of calcium carbonate nanoparticles (CaCO3) as nanocores. The resultant nanocores were then used for the assembly of LbL nanocapsules and the variables that influenced the diameter of capsules were investigated. Finally, novel stimuli-responsive multi-layered nanocapsules made of four polyelectrolytes including Eudragit L100, chitosan, sodium alginate, and poly-L-arginine were prepared and characterized. The stimuli-responsive multi-layered nanocapsules loaded with a model drug, curcumin, were assessed for drug release under pH conditions that mimic the gastrointestinal tract. These data demonstrate the potential for nanocapsules to be designed to protect the drug in the stomach and release it in the lower gastrointestinal tract.
Calcium Carbonate/chemistry , Nanocapsules/chemistry , Nanoparticles/chemistry , Administration, Oral , Alginates/chemistry , Capsules/chemistry , Chitosan/chemistry , Curcumin/chemistry , Drug Carriers/chemistry , Drug Delivery Systems/methods , Drug Liberation , Polyelectrolytes/chemistry , Polymers/chemistry
This work represents a detailed investigation into the phase and morphological behavior of synergistic dual-stimuli-responsive poly(N-isopropylacrylamide) nanogels, a material that is of considerable interest as a matrix for in situ forming implants. Nanogels were synthesized with four different diameters (65, 160, 310, and 450 nm) as monodispersed particles. These different samples were then prepared and characterized as both dilute (0.1 wt %) and concentrated dispersions (2-22 wt %). In the dilute form, all of the nanogels had the same response to the triggers of the physiological temperature and ionic strength. In water, the nanogels would deswell when heated above 32 °C, while they would aggregate if heated above this temperature at the physiological ionic strength. In the concentrated form, the nanogels exhibited a wide range of morphological changes, with liquid, swollen gel, shrunken gel, and aggregate structures all possible. The occurrence of these structures was dependent on many factors such as the temperature, ionic strength of the solvent, size and ζ-potential of the nanogel, and dispersion concentration. We explored these factors in detail with techniques such as visual studies, rheology, effective volume fraction, and shape factor measurement. The different-sized nanogels displayed differing phase and morphological behavior, but generally higher concentrations of the nanogels (>7 wt %) yielded gels in water with the transitions depending on the temperature. The smallest nanogel (65 nm diameter) exhibited the most unique behavior; it did not form a swollen gel at any concentration tested. Shape factor measurement for the nanogel samples showed that two of the larger three samples (160 and 310 nm) had core-shell structures with denser core cross-linking, while the smallest nanogel sample displayed a homogeneous cross-linked structure. We hypothesize that the smallest nanogels are able to undergo more extensive interpenetration compared to the larger nanogels, which meant that the smallest nanogel was not able to form a swollen gel. In the presence of salt at 12 wt %, all of the nanogels formed aggregates when heated above 35 °C due to the screening of the electrostatic stabilization by the salt. This work revealed unique behavior of the smallest nanogel with a homogeneous cross-linked structure; its phase and morphological behavior were unlike a particle dispersion, rather these were more similar to those of a branched polymer solution. In total, these findings can be used to provide information about the design of poly(N-isopropylacrylamide) nanogel dispersions for different applications where highly specific spatiotemporal control of morphology is required, for example, in the formation of in situ forming implants or for pore blocking behavior.
HIV is a global public health threat and requires life-long, daily oral dosing to effectively treat. This pill burden often results in poor adherence to the medications. An injectable in situ forming implant with tuneable drug release kinetics would allow patients to replace some of their daily pills with a single infrequent injection. In this work, we investigate how the size of poly(N-isopropylacrylamide) (polyNIPAm) nanogels influences the long-acting release behaviour of the HIV drug lopinavir from an in situ forming implant. Four sizes of polyNIPAm nanogels were prepared with mean diameters of 65, 160, 310 and 450 nm as characterised by dynamic light scattering. These nanogels all displayed synergistic dual stimuli responsive behaviour by aggregating only upon heating above 31 °C at physiological ionic strength. Mixing the nanogels with solid drug nanoparticles (SDNs) of lopinavir and exposing this concentrated dispersion to physiological temperature and ionic strength resulted in the in situ formation of nanocomposite implants. Three different loadings of the SDNs (33, 50 and 66% w/w) with each of the nanogels were prepared. The drug release behaviour and stability of these nanocomposite implants were then assessed in vitro over 360 hours. All samples displayed a single phase of drug release and application of the Ritger-Peppas equation indicated Fickian diffusion. Nanocomposites with the lowest loading of SDNs (33%) showed a linear relationship between nanogel diameter and the dissolution constant. These results show an attractive method for tuning the release of lopinavir from in situ loading implants with high drug loadings.
Anti-HIV Agents/chemistry , Lopinavir/chemistry , Nanogels/chemistry , Anti-HIV Agents/chemical synthesis , Drug Liberation , Humans , Lopinavir/chemical synthesis , Particle Size , Polymers/chemical synthesis , Polymers/chemistry , Surface Properties
The geometries and surface properties of nanocarriers greatly influence the interaction between nanomaterials and living cells. In this work we combine multiwalled carbon nanotubes (CNTs) with poly-ε-caprolactone (PCL) to produce non-spherical nanocomposites with high aspect ratios by using a facile emulsion solvent evaporation method. Particles were characterised by dynamic light scattering (DLS), scanning electron microscopy (SEM), atomic force microscopy (AFM) and asymmetric flow field flow fractionation (AF4). Different sizes and morphologies of nanoparticles were produced depending on the concentration of the sodium dodecyl sulphate (SDS), CNTs and PCL. Rod-like PCL-CNT nanostructures with low polydispersity were obtained with 1.5 mg mL-1 of SDS, 0.9 mg mL-1 of CNTs and 10 mg mL-1 PCL. AFM analysis revealed that the PCL and PCL-CNT nanocomposite had comparatively similar moduli of 770 and 560 MPa respectively, indicating that all the CNTs have been coated with at least 2 nm of PCL. Thermogravimetric analysis of the PCL-CNT nanocomposite indicated that they contained 9.6% CNTs by mass. The asymmetric flow field flow fractionation of the samples revealed that the PCL-CNT had larger hydrodynamic diameters than PCL alone. Finally, the drug loading properties of the nanocomposites were assessed using docetaxel as the active substance. The nanocomposites showed comparable entrapment efficiencies of docetaxel (89%) to the CNTs alone (95%) and the PCL nanoparticles alone (81%). This is a facile method for obtaining non-spherical nanocomposites that combines the properties of PCL and CNTs such as the high aspect ratio, modulus. The high drug entrapment efficiency of these nanocomposites may have promising applications in drug delivery.
Complicated cases of retinal detachment can be treated with silicone oil tamponades. There is the potential for silicone oil tamponades to have adjunctive drug releasing behaviour within the eye, however the lipophilic nature of silicone oil limits the number of drugs that are suitable, and drug release from the hydrophobic reservoir is uncontrolled. Here, a radiometric technique was developed to accurately measure drug solubility in silicone oil and measure release into culture media. All-trans retinoic acid (atRA), a lipophilic drug known to act as an anti-proliferative within the eye, was used throughout this work. Chain-end modification of polydimethylsiloxane with atRA produced a polydimethylsiloxane retinoate (PDMS-atRA), which was used as an additive to silicone oil to modify the solvent environment within the silicone oil and the distribution coefficient. Blends of PDMS-atRA and silicone oil containing different concentrations of free atRA were produced. The presence of PDMS-atRA in silicone oil had a positive effect on atRA solubility and the longevity of release in vitro. The drug release period was independent of atRA starting concentration and dependent on the PDMS-atRA concentration in the blend. A clinically relevant release period of atRA over 7 weeks from a silicone oil blend with PDMS-atRA was observed. © 2018 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 938-946.
