Unravelling the interactions between small molecules and liposomal bilayers via molecular dynamics and thermodynamic modelling.

Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.

Photosensitiser-incorporated microparticles for photodynamic inactivation of bacteria.

Antimicrobial resistance is an ever-growing global concern, making the development of alternative antimicrobial agents and techniques an urgent priority to protect public health. Antimicrobial photodynamic therapy (aPDT) is one such promising alternative, which harnesses the cytotoxic action of reactive oxygen species (ROS) generated upon irradiation of photosensitisers (PSs) with visible light to destroy microorganisms. In this study we report a convenient and facile method to produce highly photoactive antimicrobial microparticles, exhibiting minimal PS leaching, and examine the effect of particle size on antimicrobial activity. A ball milling technique produced a range of sizes of anionic p(HEMA-co-MAA) microparticles, providing large surface areas available for electrostatic attachment of the cationic PS, Toluidine Blue O (TBO). The TBO-incorporated microparticles showed a size-dependent effect on antimicrobial activity, with a decrease in microparticle size resulting in an increase in the bacterial reductions achieved when irradiated with red light. The >6 log10Pseudomonas aeruginosa and Staphylococcus aureus reductions (>99.9999%) achieved within 30 and 60 min, respectively, by TBO-incorporated >90 µm microparticles were attributed to the cytotoxic action of the ROS generated by TBO molecules bound to the microparticles, with no PS leaching from these particles detected over this timeframe. TBO-incorporated microparticles capable of significantly reducing the bioburden of solutions with short durations of low intensity red light irradiation and minimal leaching present an attractive platform for various antimicrobial applications.

High drug loading nanosized amorphous solid dispersion (NASD) with enhanced in vitro solubility and permeability: Benchmarking conventional ASD.

Through liquid-liquid phase separation (LLPS), it is possible to generate drug-rich nanoparticles during the dissolution of conventional amorphous solid dispersions (ASDs). These self-generated nanoparticles may improve the oral absorption of poorly water-soluble drugs by enhancing the drug's apparent solubility and effective membrane permeability. However, due to the high concentration threshold required for LLPS, conventional ASDs that can consistently generate drug-rich nanoparticles during dissolution are rare. More importantly, the quality of these meta-stable drug-rich nanoparticles is hard to control during dissolution, leading to inconsistency in formulation performances. This work has described a continuous twin-screw extrusion process capable of producing nanosized ASD (NASD) formulations that can offer better solubility and permeability enhancements over conventional ASD formulations. Two polymeric carriers, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), with a model hydrophobic drug celecoxib (BCS II), were formulated into both ASD and NASD formulations. Compared to the conventional ASD formulation, the prefabricated NASD (sizes ranging between 40 and 200 nm) embedded within a polyol matrix can be rapidly dispersed into a nanoparticle suspension in the presence of aqueous media. The resulting NASDs achieved drug loadings up to 80 % w/w and a maximum of 98 % encapsulation efficiency. Because of the TSE platform's high drug-loading capacity and high scalability, the developed method may be useful for continuously producing personalized nanomedicines.

Exploiting hydrogen bonding to enhance lidocaine loading and stability in a poly ethylene-co-vinyl acetate carrier matrix.

Sustained release of lidocaine from poly ethylene-co-vinyl acetate (EVA) implants can significantly improve pain management outcomes; however, poor drug loading is a major limitation. Recently, myristic acid was found to improve drug loading in EVA by inhibiting the crystallization of lidocaine. Here, lidocaine's interaction with myristic acid was studied by differential scanning calorimetry. Spectra of lidocaine-myristic acid mixtures were analysed using two-dimensional correlation (2DCOS) maps. Furthermore, spectroscopic analysis of EVA matrices containing lidocaine, alone and in combination with myristic acid, was also performed and drug release was evaluated in vitro. A eutectic was obtained on combining lidocaine and myristic acid at the molar ratio of 1:1 due to loss of myristic acid's dimeric conformation resulting in hydrogen bonding of its COOH group with lidocaine's amide I moieties. In EVA, hydrogen bonding between adjacent lidocaine molecules caused crystallization above a threshold concentration and could be inhibited by incorporation of myristic acid by eutectic formation. By altering the molecular confirmation and solid state properties of lidocaine in EVA, myristic acid reduces lidocaine crystallization, increases drug loading and influences drug release kinetics. Exploiting these interactions and promoting further hydrogen bonding through the addition of specific excipients presents a viable strategy to enhance and stabilise drug loading in polymer matrices for various applications.

Investigation into the role of the polymer in enhancing microwave-induced in situ amorphization.

Microwave-induced in situ amorphization is an emerging technology to tackle the persistent stability issue of amorphous solid dispersions (ASDs) during manufacture and storage. The aim of this study was to introduce new effective polymeric carriers with diverse properties to microwave-induced in situ amorphization and to better understand their functions in relation to the final dissolution performance of microwaved tablets. Tablets composed of indomethacin (IND) and different polymers were compacted, stored at 75% relative humidity for at least 1 week and microwaved at 1000 W to induce amorphization. A series of polymers, polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios displaying varyingproperties in functional groupratio, hygroscopicity, molecular weight (Mw), and glass transition temperature (Tg) of the polymer were used as model carriers. The results suggested that more than 90% of IND was amorphized after 20 mins microwaving in all 20% (w/w) drug loaded tablets except for IND:PVAc tablets presenting approx. 36% residual crystallinity. Among them, tablets composed of PVP/VA I-335 and PVP K30 achieved complete in situ amorphization upon microwaving. Further analysis indicated that the influencing factors, polymer Mw and Tg of moisture-plasticized polymer, played a major role in microwave-induced in situ amorphization. In in vitro dissolution study, ASDs containing PVP/VA I-535 with moderate hydrophilicity and 0.96 ± 1.92% IND residual crystallinity showed the most rapid and complete drug release among all formulations, presenting the most promising dissolution performance. Further study on the chemical stability of such formulation showed a statistically insignificant decrease of drug content after pre-conditioning and microwaving (P = 0.288 > 0.05).

The optimization of process analytical technology for the inline quantification of multiple drugs in fixed dose combinations during continuous processing.

Complications associated with uncontrolled hypertension are considered the major cause of premature death worldwide. Fixed-dose combinations (FDCs) offer an alternative approach to polypharmacy with the aim to improve patient compliance. Process Analytical Technology (PAT) is gaining momentum as a non-invasive, predictive tool to control the quality of drugs during continuous processing. PAT offers real-time quality control that can be built into the production line. However, the vast majority of studies reported in the literature have focused on quantifying a single drug during continuous processing. The aim of this study was to develop non-destructive, predictive inline PAT tools allowing for the simultaneous quantification of two antihypertensive drugs, Hydrochlorothiazide (HCTZ) and Ramipril (RMP), during the continuous manufacture of FDCs. A calibration set composed of HCTZ and RMP at concentration ranges of 6.5 to 40 and 2.5-15 (% w/w), respectively, were manufactured using hot melt extrusion. The extrudates were analysed during the process using inline Raman spectroscopy. Optimum wavenumber regions were observed at 200-400 and 630-730 cm-1 for HCTZ, and 980-1100 cm-1 for RMP using principal component analysis. Partial least squares (PLS) regression was performed to establish the predictive calibration models. The PLS developed models showed excellent linearity (R2 = 0.986 and 0.974), selectivity (PC1 = 98.6% and 91.9%) and accuracy (RMSEcv = 1.586 and 0.645%) for HCTZ and RMP, respectively. Additionally, RMSEP values were reported as 1.237 and 1.007% for HCTZ and RMP, respectively, depicting good predictability for drug content in the validation set. The output of this study demonstrated that utilisation of the full potential of chemometrics, Raman spectroscopy can be used for the simultaneous inline quantification of multiple drugs in complex formulations. This facilitates the in-process quality control of FDCs and other multicomponent systems during continuous pharmaceutical production.

A non-opioid analgesic implant for sustained post-operative intraperitoneal delivery of lidocaine, characterized using an ovine model.

Appropriate management of post-operative pain is an ongoing challenge in surgical practice. At present, systemic opioid administration is routinely used for analgesia in the post-operative setting. However, due to significant adverse effects and potential for misuse, there is a perceived need for the development of alternative, opioid-sparing treatment modalities. Continuous infusion of local anesthetic into the peritoneum after major abdominal surgery reduces pain and opioid consumption, and enhances recovery from surgery. Here we describe a non-opioid, poly(ethylene-co-vinyl-acetate) intraperitoneal implant for the sustained delivery of local anesthetic following major abdominal surgery. A radio-opaque core had the required mechanical strength to facilitate placement and removal procedures. This core was enclosed by an outer shell containing an evenly dispersed local anesthetic, lidocaine. Sustained release of lidocaine was observed in an ovine model over days and the movement modelled between peritoneal fluid and circulating plasma. While desirably high levels of lidocaine were achieved in the peritoneal space these were several orders of magnitude higher than blood levels, which remained well below toxic levels. A pharmacokinetic model is presented that incorporates in vitro release data to describe lidocaine concentrations in both peritoneal and plasma compartments, predicting similar release to that suggested by lidocaine concentrations remaining in the device after 3 and 7 days in situ. Histological analysis revealed similar inflammatory responses following implantation of the co-extruded implant and a commercially used silicone drain after three days. This non-opioid analgesic implant provides sustained release of lidocaine in an ovine model and is suitable for moving onto first in human trials.

A statistical determination of the contribution of viscoelasticity of aqueous carbohydrate polymer networks to drug release.

In this study the relationship between the viscoelasticity/mechanical properties of metronidazole-containing aqueous polymer networks composed of HEC and PVP and drug release was statistically modelled. The networks were characterised using oscillatory analysis and drug release was performed using dissolution analysis (pH 7.4). Statistical modelling of the rheological properties and their relationship with drug release was performed using Analysis of Variance, Multivariate Analysis of Variance and stepwise regression. Modelling of drug release was performed using both the Korsmeyer-Peppas and Peppas-Sahlin models to understand the mechanism of drug release and the contributions of network swelling/erosion and diffusion on drug release. HEC and PVP were shown to significantly enhance the rheological properties of the networks. Furthermore, rheological synergy was observed whenever PVP was added to HEC and was due to non-covalent bond formation between these polymers. The magnitude of this synergy increased as functions of increasing concentrations of each polymer. Drug release was dependent on the concentration of HEC and independent of the presence of PVP. The release of metronidazole from networks composed of HEC 3% w/w and PVP (1-5% w/w) was controlled by network swelling/erosion whereas for the networks containing PVP and 5% and 10% w/w HEC, the dominant mechanism of drug release was diffusion. Limited correlation was observed between network rheological properties and drug release. It is suggested that this is due to dissociation of the HEC-PVP interactions and dissolution of PVP during drug release, resulting in a network structure whose properties are dominated by those of HEC. This is the first study that has statistically examined the role of binary polymer network viscoelasticity on drug release. Based on the findings of this study, caution should be shown when formulating aqueous networks with enhanced rheological properties as these effects may not necessarily contribute to other primary determinants of device performance, notably drug release.

Maintain Your Brain: Protocol of a 3-Year Randomized Controlled Trial of a Personalized Multi-Modal Digital Health Intervention to Prevent Cognitive Decline Among Community Dwelling 55 to 77 Year Olds.

BACKGROUND: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort. METHODS: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute's 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial. DISCUSSION: MYB will be the largest internet-based trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use.

Investigation of Methylene Blue Release from Functional Polymeric Systems Using Dielectric Analysis.

BACKGROUND: Methylene blue (MB) is a photosensitizer used in photodynamic therapy (PDT) to treat colorectal cancer tumors and leishmaniasis infection. The clinical efficacy of PDT using MB is dependent on the physicochemical characteristics of the formulation. Bioadhesive thermoresponsive systems containing poloxamer 407 and Carbopol 934P have been proposed as platforms for PDT. However, the effect of MB on the physicochemical properties of these platforms is not fully understood, particularly in light of the MB availability. OBJECTIVE: The aim of this study was to investigate the dielectric characteristics of functional polymeric systems containing MB and their influence on mucoadhesion and drug release. METHODS: Binary polymeric systems containing different concentrations of poloxamer 407, Carbopol 934P and MB were evaluated as dielectric and mucoadhesive properties, as well as in vitro drug release profile. RESULTS: MB, temperature and polymeric composition influenced the physicochemical properties of the systems. The presence of MB altered the supramolecular structure of the preparations. The mucoadhesive properties of systems were influenced by MB presence and the formulation with the lowest amount of MB displayed faster release. CONCLUSION: The lower MB concentration in the systems displayed better results in terms of ionic mobility and drug release, and is indicative of a suitable clinical performance.

Strontium-containing, carbohydrate-based polymer networks as tooth-adherent systems for the treatment of dentine hypersensitivity.

This study describes the design/physicochemical properties of strontium-containing, mucoadhesive carbohydrate polymeric platforms, designed as treatments for dentine hypersensitivity. Interactive networks were composed of strontium chloride (10% w/w), one of two base polymers (sodium carboxymethylcellulose, NaCMC or hydroxyethylcellulose, HEC), polycarbophil (PC) and, when required, polyvinylpyrrolidone (PVP). The physicochemical properties were characterised using oscillatory and flow rheometry, texture profile analysis, mucoadhesion analysis and, additionally, the strontium release properties were examined. All platforms exhibited pseudoplastic flow. Increasing polymer concentrations increased network viscoelasticity, consistency, hardness, compressibility, gel strength, adhesiveness, mucoadhesion and, retarded strontium release. Principally zero-order strontium release was observed from all platforms. Incorporation of strontium reduced the network elasticity, consistency, hardness, compressibility, gel strength and mucoadhesion; HEC-based platforms being affected to a greater extent than NaCMC platforms. NaCMC-based platforms containing 10% strontium chloride, PVP (3% w/w) and PC (3% w/w) potentially displayed the correct balance of physicochemical properties for the treatment of dentine sensitivity.

Design of binary polymeric platforms containing É©-carrageenan and hydroxypropylcellulose for use in cataract surgery.

This study describes the design and characterisation of the rheological and mechanical properties of binary polymeric systems composed of 2-Hydroxypropylcellulose and É©-carrageenan, designed as ophthalmic viscoelastic devices (OVDs). Platforms were characterised using dilute solution, flow and oscillatory rheometry and texture profile analysis. Rheological synergy between the two polymers was observed both in the dilute and gel states. All platforms exhibited pseudoplastic flow. Increasing polymer concentrations significantly decreased the loss tangent and rate index yet increased the storage and loss moduli, consistency, gel hardness, compressibility and adhesiveness, the latter being related to the in-vivo retention properties of the platforms. Binary polymeric platforms exhibited unique physicochemical properties, properties that could not be engineered using mono-polymeric platforms. Using characterisation methods that provide information relevant to their clinical performance, low-cost binary platforms (3% hydroxypropylcellulose and either 1% or 2% É©-carrageenan) were identified that exhibited rheological, textural and viscoelastic properties advantageous for use as OVDs.

Comparative Study of Different Methods for the Prediction of Drug-Polymer Solubility.

In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.

Novel supercritical carbon dioxide impregnation technique for the production of amorphous solid drug dispersions: a comparison to hot melt extrusion.

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

Universal Internet-based prevention for alcohol and cannabis use reduces truancy, psychological distress and moral disengagement: a cluster randomised controlled trial.

AIMS: A universal Internet-based preventive intervention has been shown to reduce alcohol and cannabis use. The aim of this study was to examine if this program could also reduce risk-factors associated with substance use in adolescents. METHOD: A cluster randomised controlled trial was conducted in Sydney, Australia in 2007-2008 to assess the effectiveness of the Internet-based Climate Schools: Alcohol and Cannabis course. The evidence-based course, aimed at reducing alcohol and cannabis use, consists of two sets of six lessons delivered approximately six months apart. A total of 764 students (mean 13.1years) from 10 secondary schools were randomly allocated to receive the preventive intervention (n=397, five schools), or their usual health classes (n=367, five schools) over the year. Participants were assessed at baseline, immediately post, and six and twelve months following the intervention on their levels of truancy, psychological distress and moral disengagement. RESULTS: Compared to the control group, students in the intervention group showed significant reductions in truancy, psychological distress and moral disengagement up to twelve months following completion of the intervention. CONCLUSIONS: These intervention effects indicate that Internet-based preventive interventions designed to prevent alcohol and cannabis use can concurrently reduce risk-factors associated with substance use in adolescents. CLINICAL TRIALS REGISTRATION: Australian Clinical Trials Registry ACTRN: 012607000312448.

The 10-item Kessler psychological distress scale (K10) as a screening instrument in older individuals.

OBJECTIVE: To provide population-based Kessler Psychological Distress Scale (K10) normative data for older adults and cut scores for screening. PARTICIPANTS: Adults age ≥65 years who participated in either the 1997 or 2007 Australian National Surveys of Mental Health and Well-being (N = 3,697). MEASUREMENTS: The proportion of respondents who reported psychological distress, and the correspondence of K10 scores with diagnosis of mental disorder, disability, and service use. RESULTS: Scores on the K10 corresponded well with rates of mental disorder. Higher K10 scores were associated with increased levels of internalizing disorder, comorbidity, functional disability, and service use. Receiver operating characteristic curve analysis revealed an area under the curve score of 0.86, suggesting good predictive power. For screening purposes, a cut score of 15 was found to be associated with the best balance between sensitivity (0.77) and specificity (0.78). Similar levels of predictive power were observed across various subgroups of the population. Score ranges for groups who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition affective or anxiety disorder showed that for those age 65-75, a score of 20 or greater and a score of 17 or greater for those older than 75 years warrant heightened clinical interest. CONCLUSIONS: The K10 exhibits sensitivity to internalizing disorders as they occur across the lifespan and can be used with confidence when assessing psychological distress in old-age community dwellers. The significant association between higher K10 scores and disability suggests that the presence of psychological distress, regardless of diagnostic status, requires clinician attention.

Health anxiety in Australia: prevalence, comorbidity, disability and service use.

BACKGROUND: Health anxiety is associated with high distress, disability and increased health service utilisation. However, there are relatively few epidemiological studies examining the extent of health anxiety or the associated sociodemographic and health risk factors in the general population. AIMS: To provide epidemiological data on health anxiety in the Australian population. METHOD: Lifetime and current prevalence estimates, associations between comorbid disorders, psychological distress, impairment, disability and mental health service utilisation were generated using the Australian 2007 National Survey of Mental Health and Wellbeing. RESULTS: Health anxiety affects approximately 5.7% of the Australian population across the lifespan and 3.4% met criteria for health anxiety at the time of the interview. Age, employment status, smoking status and comorbid physical conditions were significantly related to health anxiety symptoms. Health anxiety was associated with significantly more distress, impairment, disability and health service utilisation than that found in respondents without health anxiety. CONCLUSIONS: Health anxiety is non-trivial; it affects a significant proportion of the population and further research and clinical investigation of health anxiety is required.

Understanding the performance of melt-extruded poly(ethylene oxide)-bicalutamide solid dispersions: characterisation of microstructural properties using thermal, spectroscopic and drug release methods.

In this article, we have prepared hot-melt-extruded solid dispersions of bicalutamide (BL) using poly(ethylene oxide) (PEO) as a matrix platform. Prior to preparation, miscibility of PEO and BL was assessed using differential scanning calorimetry (DSC). The onset of BL melting was significantly depressed in the presence of PEO, and using Flory-Huggins (FH) theory, we identified a negative value of -3.4, confirming miscibility. Additionally, using FH lattice theory, we estimated the Gibbs free energy of mixing which was shown to be negative, passing through a minimum at a polymer fraction of 0.55. Using these data, solid dispersions at drug-to-polymer ratios of 1:10, 2:10 and 3:10 were prepared via hot-melt extrusion. Using a combination of DSC, powder X-ray diffractometry and scanning electron microscopy, amorphous dispersions of BL were confirmed at the lower two drug loadings. At the 3:10 BL to PEO ratio, crystalline BL was detected. The percent crystallinity of PEO was reduced by approximately 10% in all formulations following extrusion. The increased amorphous content within PEO following extrusion accommodated amorphous BL at drug to polymer loadings up to 2:10; however, the increased amorphous domains with PEO following extrusion were not sufficient to fully accommodate BL at drug-to-polymer ratios of 3:10.

Development of novel oral formulations prepared via hot melt extrusion for targeted delivery of photosensitizer to the colon.

Colon-residing bacteria, such as vancomycin-resistant Enterococcus faecalis and Bacteroides fragilis, can cause a range of serious clinical infections. Photodynamic antimicrobial chemotherapy (PACT) may be a novel treatment option for these multidrug resistant organisms. The aim of this study was to formulate a Eudragit®-based drug delivery system, via hot melt extrusion (HME), for targeting colonic release of photosensitizer. The susceptibility of E. faecalis and B. fragilis to PACT mediated by methylene blue (MB), meso-tetra(N-methyl-4-pyridyl)porphine tetra-tosylate (TMP), or 5-aminolevulinic acid hexyl-ester (h-ALA) was determined, with tetrachlorodecaoxide (TCDO), an oxygen-releasing compound, added in some studies. Results show that, for MB, an average of 30% of the total drug load was released over a 6-h period. For TMP and h-ALA, these values were 50% and 16% respectively. No drug was released in the acidic media. Levels of E. faecalis and B. fragilis were reduced by up to 4.67 and 7.73 logs, respectively, on PACT exposure under anaerobic conditions, with increased kill associated with TCDO. With these formulations, photosensitizer release could potentially be targeted to the colon, and colon-residing pathogens killed by PACT. TCDO could be used in vivo to generate oxygen, which could significantly impact on the success of PACT in the clinic.