Development of Robust Tablet Formulations with Enhanced Drug Dissolution Profiles from Centrifugally-Spun Micro-Fibrous Solid Dispersions of Itraconazole, a BCS Class II Drug.

Fibre-based oral drug delivery systems are an attractive approach to addressing low drug solubility, although clear strategies for incorporating such systems into viable dosage forms have not yet been demonstrated. The present study extends our previous work on drug-loaded sucrose microfibres produced by centrifugal melt spinning to examine systems with high drug loading and investigates their incorporation into realistic tablet formulations. Itraconazole, a model BCS Class II hydrophobic drug, was incorporated into sucrose microfibres at 10, 20, 30, and 50% w/w. Microfibres were exposed to high relative humidity conditions (25 °C/75% RH) for 30 days to deliberately induce sucrose recrystallisation and collapse of the fibrous structure into powdery particles. The collapsed particles were successfully processed into pharmaceutically acceptable tablets using a dry mixing and direct compression approach. The dissolution advantage of the fresh microfibres was maintained and even enhanced after humidity treatment for drug loadings up to 30% w/w and, importantly, retained after compression into tablets. Variations in excipient content and compression force allowed manipulation of the disintegration rate and drug content of the tablets. This then permitted control of the rate of supersaturation generation, allowing the optimisation of the formulation in terms of its dissolution profile. In conclusion, the microfibre-tablet approach has been shown to be a viable method for formulating poorly soluble BCS Class II drugs with improved dissolution performance.

In vitro and in vivo biological assessment of dual drug-loaded coaxial nanofibers for the treatment of corneal abrasion.

The treatment of corneal abrasion currently involves the topical administration of antibiotics, with moxifloxacin HCl (0.5% w/v) eye drops being one of the most widely used treatments. Our previous work (Tawfik et al., 2020) involved the development of coaxial poly-lactic-co-glycolic acid (PLGA) and polyvinylpyrrolidone (PVP) nanofibers loaded with the antibiotic moxifloxacin HCl and the anti-scarring agent pirfenidone in the core (PVP) and shell (PLGA) respectively, with a view to the system comprising an ocular insert for the combination therapy of corneal abrasion. In this study, we examine the antimicrobial, anti-scarring and pharmacokinetic properties of the fibers alongside consideration of their toxicity and propensity for irritation. Minimum inhibitory concentration and zone of inhibition studies against S. aureus and P. aeruginosa were performed, while fibroblast cell viability and α-smooth muscle actin (α-SMA, a biomarker for scar formation) were measured using MTT and Western Blot assays, respectively. Pharmacokinetic studies and efficacy against infection were performed using a rabbit model, while ocular irritancy was assessed using the Draize test. The studies demonstrated that the antimicrobial activity of the moxifloxacin HCl was preserved following encapsulation into the nanofibers, while the downregulation of α-SMA was demonstrated using concentrations below the IC20 values (concentration required to decrease corneal fibroblast viability by no more than 20%). The pharmacokinetic study showed retention and sustained release of the moxifloxacin HCl over a 24-hour period, in contrast to equivalent eye drops which required four times daily dosing. Evidence of low level (according to the MMTS scale) irritation was detected for the nanofiber systems. Overall, the study has demonstrated that the dual drug-loaded nanofiber system shows potential for once daily dosing as an ocular insert for the treatment of corneal abrasion.

A Potential Alternative Orodispersible Formulation to Prednisolone Sodium Phosphate Orally Disintegrating Tablets.

The orally disintegrating tablet (ODT) has shown vast potential as an alternative oral dosage form to conventional tablets wherein they can disintegrate rapidly (≤30 s) upon contact with saliva fluid and should have an acceptable mouthfeel as long as their weight doesn't exceed 500 mg. However, owing to the bitterness of several active ingredients, there is a need to find a suitable alternative to ODTs that maintains their features and can be taste-masked more simply and inexpensively. Therefore, electrospun nanofibers and solvent-cast oral dispersible films (ODFs) are used in this study as potential OD formulations for prednisolone sodium phosphate (PSP) that is commercially available as ODTs. The encapsulation efficiency (EE%) of the ODFs was higher (≈100%) compared to the nanofibers (≈87%), while the disintegration time was considerably faster for the electrospun nanofibers (≈30 s) than the solvent-cast ODFs (≈700 s). Hence, accelerated release rate of PSP from the nanofibers was obtained, due to their higher surface area and characteristic surface morphology that permitted higher wettability and thus, faster erosion. Taste-assessment study using the electronic-tongue quantified the bitterness threshold of the drug and its aversiveness concentration (2.79 mM). Therefore, a taste-masking strategy would be useful when further formulating PSP as an OD formulation.

Development and Evaluation of Feline Tailored Amlodipine Besylate Mini-Tablets Using L-lysine as a Candidate Flavouring Agent.

Felines may find orally administered medicines unpalatable, thus presenting a problem in the treatment of chronic conditions such as hypertension, a commonly diagnosed condition in felines requiring daily administration of medication. A pertinent example is amlodipine besylate, formulations of which are known to be poorly tolerated by cats. There is therefore a need to develop feline-specific delivery approaches that are both simple to administer and mask the taste of the drug, thereby enhancing the owner's commitment to treatment and the associated therapeutic outcome for the companion animal. In addition, it is helpful to develop accessible and reproducible means of assessing taste for pre-clinical selection, hence the use of recently developed taste biosensor systems for veterinary applications is an area of interest. This study focuses on developing feline-specific amlodipine besylate formulations by improving the taste using a suitable flavouring agent while reducing dosage form size to a 2 mm diameter mini-tablet. The choice of L-lysine as a flavouring agent was based on the dietary and taste preference of cats. The impact of L-lysine on the taste perception of the formulation was evaluated using a biosensor system (E-tongue) fitted with sensors sensitive to bitter tastes. The results showed L-lysine successfully masked bitterness, while the drug release studies suggest that it has no impact on drug dissolution. In addition, tableting parameters such as tablet mass uniformity, content uniformity, tablet diameter, thickness and hardness were all satisfactory. The present study suggests that amlodipine besylate mini-tablets containing L-lysine could improve the palatability and in turn support product acceptability and ease of administration. These data could have an impact on orally administered medicines for cats and other veterinary species through product differentiation and competitive advantage in the companion animal market sector. The study also outlines the use of the electronic tongue as a tool for formulation selection in the veterinary field.

Dual drug-loaded coaxial nanofibers for the treatment of corneal abrasion.

Corneal abrasion is a scratch wound on the surface of the anterior segment of the eye, which can predispose a patient to corneal infection and scarring, particularly if the cut penetrates to the deep corneal layers. Here we investigate a novel approach to co-administer an anti-scarring agent and an antibiotic, both being incorporated into one dosage form so as to accelerate wound closure and to treat any associated infection. More specifically, we have used electrospun fibers as a means of incorporating the two drugs into distinct compartments via coaxial electrospinning. Samples were characterised using a range of imaging, spectroscopic and thermal methods, while an HPLC assay has been developed to allow measurement of the concentration of both drug components in both the initial fibers and on release. Fibers loaded with pirfenidone in the hydrophobic polymer, PLGA, as the outer layer and moxifloxacin in the hydrophilic polymer PVP as the inner layer were successfully prepared, with smooth and non-porous surfaces and a mean diameter of circa 630 nm. TEM image demonstrated clear distinctive layers (a core and a shell), suggesting the successful preparation of the drug-loaded coaxial fibers, supported by HPLC entrapment studies, while fluorescence microscopy confirmed the presence of the moxifloxacin within the fibers. The fibers were capable of extending the release of both drugs, hence raising the possibility of a single daily dose of the drug-loaded coaxial fibers for the treatment of corneal abrasion.

Design and Characterization of Cyclosporine A-Loaded Nanofibers for Enhanced Drug Dissolution.

Despite widespread use as an immunosuppressant, the therapeutic efficacy of the undecapeptide cyclosporine A (CyA) is compromised when given by the oral route because of the innate hydrophobicity of the drug molecule, potentially leading to poor aqueous solubility and bioavailability. The aim of this study was to develop and characterize nanofibers based on the water-miscible polymer polyvinylpyrrolidone (PVP), incorporating CyA preloaded into polymeric surfactants so as to promote micelle formation on hydration; therefore, this approach represents the novel combination of three dissolution enhancement methodologies, namely solid dispersion technology, micellar systems, and nanofibers with enhanced surface area. The preparation of the nanofibers was performed in two steps. First, mixed micelles composed of the water-soluble vitamin E derivative d-α-tocopheryl poly(ethylene glycol) 1000 succinate and the amphiphilic triblock polymer Pluronic F127 (Poloxamer 407) were prepared. The micelles were characterized in terms of size, surface charge, drug loading, and encapsulation efficiency using transmission electron microscopy, dynamic light scattering, Fourier-transform infrared spectroscopy, high-performance liquid chromatography, and scanning electron and atomic force microscopy analysis. Nanofibers composed of PVP and the drug-loaded surfactant system were then prepared via electrospinning, with accompanying thermal, spectroscopic, and surface topological analysis. Dissolution studies indicated an extremely rapid dissolution profile for the fibers compared to the drug alone, while wettability studies also indicated a marked decrease in contact angle compared to the drug alone. Overall, the new approach appears to offer a viable means for considerably improving the dissolution of the hydrophobic peptide CyA, with associated implications for improved oral bioavailability.

In vitro drug release from acetylated high amylose starch-zein films for oral colon-specific drug delivery.

This study describes the preparation of free films of zein with and without acetylated high amylose maize starch (HAS) and their corresponding coated tablets as a novel approach to colonic drug delivery. We hypothesise that the embedding of a digestible starch component within the inert zein would allow the film to remain intact until the large intestine is reached. Free films of zein alone and starch/zein were prepared and characterized. SEM and AFM images of film surface showed that films were morphologically inhomogeneous, particularly at lower HAS/Zein ratios; however, nanothermal analysis data suggested that these differences in appearance within the same film are not compositional differences. Moreover, FT-IR could detect no molecular interaction between the two polymers. Paracetamol tablets were coated with HAS/Zein aqueous based coatings of different compositions to a TWG of 20%. Drug release from zein alone and 1:5 HAS/Zein coated tablets under upper gastrointestinal conditions (pH 1.2, pH 6.8 with pepsin and pancreatin included) was very similar (for example approximately 12% and 14% of the drug was released, respectively, after 6 h in a sequential in vitro test), suggesting that release in this region is limited and is not influenced by the presence of HAS in the ratio to zein under study. Studies using an in vitro colon model showed that under simulated colonic conditions, the drug release was significantly (p < 0.05) more rapid from 1:5 HAS/Zein, compared to the zein alone coating formulation. These data therefore support the potential use of zein-starch mixed films for colonic targeting purposes.

Plant-expressed Hepatitis B core antigen virus-like particles: Characterization and investigation of their stability in simulated and pig gastro-intestinal fluids.

Virus-like particles (VLPs) are potential oral vaccine candidates, as their highly compact structure may allow them to withstand the harsh conditions of the gastro-intestinal (GI) environment. Hepatitis B core antigen (HBcAg) is an immunogenic protein that assembles into 30 or 34nm diameter VLPs. Here, the stabilities of both the HBcAg polypeptide itself and the three-dimensional structure of the VLPs upon exposure to in vitro and ex vivo simulated gastric and intestinal fluids were investigated. Plant-expressed HBcAg VLPs were efficiently purified by sucrose density gradient and characterized. The purified VLPs did not show major chemical or physical instability upon exposure to the low pH conditions typically found in the stomach; however, they completely agglomerated upon acidification and subsequent pH neutralization. The HBcAg polypeptide was highly digested upon exposure to pepsin in simulated gastric fluids. HBcAg appeared more stable in both simulated and ex vivo intestinal fluids, where despite a partial digestion of the HBcAg polypeptide, the VLPs maintained their most immunogenic epitopes and their particulate conformation. These results suggest that HBcAg VLPs are likely to be unstable in gastric fluids, yet if the gastric instability could be bypassed, they could maintain their particulate structure and immunogenicity in intestinal fluids.

Microfibrous Solid Dispersions of Poorly Water-Soluble Drugs Produced via Centrifugal Spinning: Unexpected Dissolution Behavior on Recrystallization.

Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ), and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53, and 75% RH) at 25 °C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state, and dissolution performance of microfibers. While all samples were stable at 11% RH, at 33% RH the ITZ-sucrose system showed greater resistance against devitrification compared to the OLZ- and PRX-sucrose systems. For all three samples, the freshly prepared microfibers showed enhanced dissolution and supersaturation compared to the drug alone and physical mixes; surprisingly, the dissolution advantage was largely maintained or even enhanced (in the case of ITZ) following the moisture-induced recrystallization under 75% RH. Therefore, this study suggests that the moisture-induced recrystallization process may result in considerable dissolution enhancement compared to the drug alone, while overcoming the physical stability risks associated with the amorphous state.

Development of photothermal FTIR microspectroscopy as a novel means of spatially identifying amorphous and crystalline salbutamol sulfate on composite surfaces.

Photothermal Fourier transform infrared (FTIR) microspectroscopy (PTMS), involving the combination of FTIR spectroscopy with atomic force microscopy, has been used to examine compacts of amorphous and crystalline salbutamol sulfate in order to assess the ability of the technique to distinguish between different physical forms in a multicomponent material. Samples of amorphous and crystalline material were assessed using modulated temperature differential scanning calorimetry (DSC), atomic force microscopy, microthermal analysis, and conventional FTIR. Mixed compacts were then prepared such that verification of the location of the forms present was possible via topography and localized thermal analysis. PTMS studies were then performed on selected interrogation points, with spectra obtained which were largely intermediate between those corresponding to the two individual forms. Calculation of the thermal diffusivity indicated a resolution for the technique corresponding to a hemisphere of a major diameter in the region of 40 µm, which is large in relation to the particle sizes involved. However, distinction into amorphous, crystalline, and indeterminate categories was possible using chemometric analysis (hierarchical cluster analysis and principal component analysis). Good agreement was found between the identification methods for the mixed systems. The study has therefore shown the potential, as well as identifying the limitations, of using PTMS as a means of spatially identifying components in complex materials.

Development of fully amorphous dispersions of a low T(g) drug via co-spray drying with hydrophilic polymers.

The aim of the study was to prepare molecular dispersions of a physically highly unstable amorphous drug, paracetamol (acetaminophen with a T(g) of ca. 25°C) via co-spray drying with a variety of polymers. Solid dispersions at a range of drug loadings (10-90%w/w) using hydroxypropyl methylcellulose/acetate succinate (HPMC/HPMC AS), polyvinylpyrrolidone (PVP) and copovidone were produced and characterised by modulated temperature differential scanning calorimetry (MTDSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). PVP-based polymers showed a greater tendency than the HPMC-based group to generate temperature-stable dispersions. In particular, copovidone (Plasdone® S-630) was found to be the most effective of the polymers studied and could formulate molecular dispersions at drug loadings up to and including 40%w/w. However, no evidence for direct drug-polymer interactions was found for such systems as a possible stabilising mechanism. The expected relationship of a higher T(g) of the polymer leading to greater stabilisation was not observed, while there was an inverse relationship between viscosity grade and amorphous phase generation. The study has therefore shown that temperature-stable amorphous dispersions of a low T(g) drug may be prepared by co-spray drying, particularly using PVP-based polymers.

An investigation into water interactions with amorphous and milled salbutamol sulphate: the development of predictive models for uptake and recrystallization.

An investigation into the effect of water uptake on the glass transition of spray dried and milled salbutamol sulphate has been performed, with a particular view to exploring how the water uptake, T(g) value and recrystallization behaviour correlate. Samples of milled and spray dried drug were stored under controlled humidity conditions and the T(g) measured as a function of time. The T(g) was measured using modulated temperature differential scanning calorimetry (MTDSC) while the water content was measured using thermogravimetric analysis (TGA). A correlation was found between time of storage, water content and T(g) in that the samples showed time dependent equilibration with the storage environment (either gaining or losing water depending on the RH). The relationship between water content and stability, based on the concept of T(g) lowering, was modelled using the semi-empirical approach of Royall et al. (1999) as well as a derivation of the Kwei equation which allowed the interaction between the water and substrate to be accounted for. A method for predicting stability based on two simple DSC runs is proposed. In addition, we discuss the observation of a double glass transition for the spray dried samples.

Characterization and quantification of amorphous material in milled and spray-dried salbutamol sulfate: a comparison of thermal, spectroscopic, and water vapor sorption approaches.

A study has been undertaken using a range of established and novel approaches to examine the effects of milling on the structure and crystallization behavior of salbutamol sulfate. A combination of modulated temperature differential scanning calorimetry, attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffraction, and gravimetric vapor sorption analysis have been employed, with a particular view to examining the validity of using spray-dried material as a comparator. Although the expected increase in amorphization with milling time was observed, several unexpected observations were made including an apparently anomalous relationship between glass transition temperature and water content; this was used as the basis for the development of a novel method of quantifying amorphous content. Reasonable agreement was found between the data obtained from the spectroscopic and thermal methods, particularly those latter approaches that do not rely on recrystallization for quantification. The activation energy for the onset process was determined and found to be similar for all materials studied. The study has indicated that when using spray-dried material as a standard, the associated limitations must be appreciated, particularly in terms of the assumption of comparability of the recrystallization process between materials that is embedded in many quantification techniques.

The effect of composition and gastric conditions on the self-emulsification process of ibuprofen-loaded self-emulsifying drug delivery systems: a microscopic and dynamic gastric model study.

PURPOSE: To investigate the physical processes involved in the emulsification of self-emulsifying drug delivery systems (SEDDSs) and the use of the Dynamic Gastric Model (DGM) as a characterisation tool. METHODS: SEDDSs based on soybean oil, Tween 80, Span 80 and ibuprofen were prepared and their equilibrium phase diagrams established. The emulsification behaviour in a range of media was studied using polarised light microscopy and particle sizing. The behaviour of the SEDDSs in the DGM and conventional testing equipment was assessed. RESULTS: A range of liquid crystalline mesophases was observed, enhanced in the presence of the drug. Polarised light microscopy showed different emulsification processes in the presence and absence of the drug, which was also manifest in different droplet sizes. The droplet size distribution varied between the DGM and the USP II dissolution apparatus. CONCLUSIONS: The model SEDDS displays complex liquid crystalline behaviour which may be intimately involved in the emulsification process, which in turn may alter particle size on emulsification, although there remains a question as to the in vivo significance of this effect. Furthermore, we demonstrate that the DGM represents a very promising new method of assessing the biological fate of SEDDSs.

Zein-iodine complex studied by FTIR spectroscopy and dielectric and dynamic rheometry in films and precipitates.

In the present study the effect of iodine on properties of zein films and zein precipitates obtained after hydrophobic aggregation was evaluated. Zein films were cast with and without glycerol (as plasticizer) after incorporation of iodine at different levels (2-8%, zein wt basis). Zein films were characterized by secondary structure (determined by infrared spectroscopy) and dielectric and mechanical properties. The rheological properties of zein precipitates as a function of frequency and temperature were evaluated using a dynamic rheometer. Inclusion of iodine changed the secondary structure of zein films and decreased their tensile strength as well as strain at failure. In aggregates, changes in G' (elastic modulus) and G'' (viscous modulus) during heating were affected by the presence of iodine due to the inhibition of aggregation. The water-holding capacity of precipitates precipitated in the presence of iodine was higher than that of those without iodine.

Plasticization of zein: a thermomechanical, FTIR, and dielectric study.

Zein, the main seed storage protein of maize, has been widely studied as a possible source of material for the production of biodegradable plastic films. Plasticization of zein is critical to make functional films. While there have been a number of publications which report the behavior of systems with a wide variety of plasticizers, there have been few which attempt to examine the interactions of protein and plasticizer at the molecular level. In this paper, we report on the plasticizing effects of water, glycerol, and 2-mercaptoethanol, which were examined by a combination of spectroscopy (FTIR and dielectric) and thermomechanical methods. The results suggest that both water and glycerol are adsorbed onto the protein and form hydrogen bonds with the amide groups. The plasticizer then builds up in patches on the protein surface. 2-Mercaptoethanol only exhibited a weak plasticizing effect due probably to disulfide bond breaking.

A study on maize proteins as a potential new tablet excipient.

This investigation has examined the use of zein proteins from maize as the major component in oral controlled-release tablets, such formulations often being required to improve patient compliance. Tablets containing ground zein proteins, calcium hydrogen orthophosphate, polyvinyl pyrrolidone, theophylline and magnesium stearate were produced by wet granulation and compression on a single station tablet press and were compared to directly compressed tablets based on zein proteins, calcium hydrogen orthophosphate and theophylline. Non invasive techniques such as Fourier Transform infrared spectroscopy and Fourier Transform Raman spectroscopy were employed to investigate any changes in the secondary structure of zein proteins during tablet production. Random coils, alpha helices and beta sheets predominated and their relative content remained unaffected during grinding, wet granulation and compression, indicating that formulations based on zeins will be robust, i.e. insensitive to minor changes in the production conditions. Drug release from the tablets was studied using a standard pharmacopoeial dissolution test. Dissolution profiles in water, 0.1M HCl (pH=1) and phosphate buffer (pH=6.8) show that only a limited amount of theophylline was released after 4.5h, suggesting that zein proteins could act as a potential vehicle for oral controlled drug release. Analysis of the theophylline release profiles using the Peppas and Sahlin model reveals that diffusion and polymer relaxation occurred in acidic (pH=1) and buffered (pH=6.8) conditions for wet granulated tablets, whereas diffusion was predominant in directly compressed tablets. In conclusion, the present study has shown that zeins can be successfully used as a pharmaceutical excipient, and in particular as a matrix in monolithic controlled release tablets.

The role of space charge formation in the generation of thermally stimulated current (TSC) spectroscopy data for a model amorphous drug system.

Thermally stimulated current (TSC) spectroscopy is attracting increasing attention as a means of materials characterization, particularly in terms of measuring slow relaxation processes in solid samples. However, wider use of the technique within the pharmaceutical field has been inhibited by difficulties associated with the interpretation of TSC data, particularly in terms of deconvoluting dipolar relaxation processes from charge distribution phenomena. Here, we present evidence that space charge and electrode contact effects may play a significant role in the generation of peaks that have thus far proved difficult to interpret. We also introduce the use of a stabilization temperature in order to control the space charge magnitude. We have studied amorphous indometacin as a model drug compound and have varied the measurement parameters (stabilization and polarization temperatures), interpreting the changes in spectral composition in terms of charge redistribution processes. More specifically, we suggested that charge drift and diffusion processes, charge injection from the electrodes and high activation energy charge redistribution processes may all contribute to the appearance of shoulders and 'spurious' peaks. We present recommendations for eliminating or reducing these effects that may allow more confident interpretation of TSC data.

A laser imaging and neutron reflection investigation into the monolayer behaviour of fatty acids used for taste masking microspheres.

Fatty acid microspheres have been used for taste masking purposes whereby the drug is preferentially released in the lower gastrointestinal tract, although the mechanisms involved are poorly understood. In this study, we use a combination of surface pressure measurements, Brewster angle microscopy (BAM) and neutron reflectivity measurements to study the phase miscibility and escaping tendency from mixed stearic and palmitic acid films with a view to relating this to drug dissolution behaviour. It was noted that mixed systems showed considerably greater film interaction and instability than those composed of the pure lipid, especially in alkaline media. BAM studies were able to identify a range of phase separated structures for both the pure and mixed systems. Neutron reflectivity studies indicated a marked selective dissolution of palmitic acid into the subphase as a function of time and allowed quantification of the rate of dissolution of this species. It is concluded that the fatty acids are interacting within the monolayer and in addition the palmitic acid is escaping the mixed monolayers and dissolving into the alkali subphase. These findings have strong relevance for understanding the mechanism of drug release from the associated microspheres.