A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm2 to 2.85±0.36N/mm2 upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets

[sup]1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations

Quantitative analysis using proton NMR (1H qNMR) has been employed in various areas such as pharmaceutical analysis (e.g., dissolution study), vaccines, natural products analysis, metabolites, and macrolide antibiotics in agriculture industry. However, it is not routinely used in the quantification of saccharides in dry powder inhaler (DPI) formulations. The aim of this study was to develop a 1H NMR method for the quantification of saccharides employed in DPI formulations. Dry powders as DPI carriers were prepared by spray drying (SD) and spray freeze drying (SFD) using three saccharides: namely D-mannitol, D-sorbitol and D-(+)-sucrose. The calibration curves constructed for all three saccharides demonstrated linearity with R2 value of 1. The 1H qNMR method produced accurate (relative error %: 0.184-3.697) and precise data with high repeatability (RSD %: 0.517-3.126) within the calibration curve concentration range. The 1H qNMR method also demonstrated significant sensitivity with low values of limit of detection (0.058 mM for D-mannitol, 0.045 mM for D-(+)-sucrose, and 0.056 mM for D-sorbitol) and limit of quantitation (0.175 mM for D-mannitol, 0.135 mM for D-(+)-sucrose, and 0.168 mM for D-sorbitol). Pulmonary deposition via impaction experiments of the three saccharides was quantified using the developed method. It was found that SFD D-mannitol (68.99%) and SFD D-(+)-sucrose (66.62%) exhibited better delivered dose (total saccharide deposition in throat and all impactor stages) than SD D-mannitol (49.03%) and SD D-(+)-sucrose (57.70%) (p< 0.05). The developed 1H qNMR methodology can be routinely used as an analytical method to assess pulmonary deposition in impaction experiments of saccharides employed as carriers in DPI formulations

Assembling surfactants-mucoadhesive polymer nanomicelles (ASMP-nano) for ocular delivery of cyclosporine-A

The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer seems promising since a limited number of commercial products containing CyA have been recently approved. The scope of this investigation was the design of Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano), based on a binary system of two surfactants in combination with hyaluronic acid, and their biopharmaceutical evaluation. The optimisation of the ASMP-Nano in term of the amount of surfactants, CyA-loading and size determined the selection of the clear and stable Nano1HAB-CyA formulation containing 0.105% w/w CyA loaded-nanomicelles with a size of 14.41 nm. The nanostructured system had a protective effect towards epithelial corneal cells with a cell viability of more than 80%. It interacted with cellular barriers favouring the uptake and the accumulation of CyA into the cells as evidenced by fluorescent probe distribution, by hindering CyA permeation through reconstituted corneal epithelial tissue. In pharmacokinetics study on rabbits, the nanomicellar carrier prolonged the CyA retention time in the precorneal area mainly in presence of hyaluronic acid (HA), a mucoadhesive polymer

On the biocompatibility and teat retention of in situ gelling intramammary formulations : cattle mastitis prevention and treatment

Treatment and prevention of cattle mastitis remains a formidable challenge due to the anatomical and physiological constraints of the cow udder. In this study, we investigated polymeric excipients and solvents that can form, (when combined) novel, non-toxic and biocompatible in situ gelling formulations in the mammary gland of bovine cattle. We also report on a new approach to screen intramammary formulations using fresh excised cow teats. Fourteen hydrophilic polymers and six solvents were evaluated for in vitro cytotoxicity and biocompatibility towards cultured bovine mammary epithelial cells (MAC-T), microscopic and macroscopic examination upon contact with excised cow teats. No significant cytotoxicity (p > 0.05) was observed with polyethylene oxides, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate and xanthan gum. Polycarbophil and carbopol polymers showed significantly higher cytotoxicity (p p < 0.05). In situ gelling formulations comprising hydroxypropyl methylcellulose or carboxymethyl cellulose and solvents in specific ratios were biocompatible at higher concentrations with MAC-T cells compared to alginates. All investigated formulations could undergo in situ sol-to-gel phase transformation, forming non-toxic gels with good biocompatibility in excised cow teats hence, showing potential for use as intramammary carriers for sustained drug delivery

Prediction of corneal permeability using artificial neural networks

The purpose of this study was to develop a simple model for prediction of corneal permeability of structurally different drugs as a function of calculated molecular descriptors using artificial neural networks. A set of 45 compounds with experimentally derived values of corneal permeability (log C) was used to develop, test and validate a predictive model. Each compound was encoded with 1194 calculated molecular structure descriptors. A genetic algorithm was used to select a subset of descriptors that best describe corneal permeability coefficient log C and a supervised network with radial basis transfer function (RBF) was used to correlate calculated molecular descriptors with experimentally derived measures of corneal permeability. The best model, with 4 input descriptors and 12 hidden neurones was chosen, and the significance of the selected descriptors to corneal permeability was examined. Strong correlation of predicted with experimentally derived log C values (correlation coefficient greater than 0.87 and 0.83 respectively) was obtained for the training and testing data sets. The developed model could be useful for the rapid prediction of the corneal permeability of candidate drugs based on molecular structure alone as it does not require experimentally derived data

Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 2: precorneal retention and in vivo pharmacodynamic study

In situ gelling systems are viscous polymer-based solutions that exhibit a sol-to-gel phase transition upon change in a physicochemical parameter such as ionic strength, temperature or pH, therefore prolonging the formulations' residence time on the ocular surface. Ion-activated in situ gelling systems, that are able to crosslink with the cations in the tear fluid, have previously been evaluated in terms of their rheological, textural and in vitro release characteristics. The present study describes the ocular irritancy, precorneal retention time and in vivo release characteristics of the same formulations. It was shown that all tested polymer systems were non-irritant. Precorneal retention studies revealed a biphasic rapid release for the solution with less than 40% radioactivity left on the ocular surface after 15 min, while formulations based on gellan gum, xanthan gum and carrageenan seemed to drain at an almost constant rate with more than 80% radioactivity remaining. This was in agreement with the in vivo miotic studies, which demonstrated that the area under the curve and the miotic response at 120 min after administration for gellan gum, xanthan gum and carrageenan formulations of pilocarpine were increased by 2.5-fold compared to an aqueous solution, which demonstrates their potential use in ophthalmic formulations

Texture and rheological characterization of kappa and iota carrageenan in the presence of counter ions

The effect of cation concentration and ion valency (0-0.2% (w/v) of KCl or CaCl2·2H2O) on the mechanical, micro-structural and rheological properties of aqueous kappa (?) and iota (?) carrageenan dispersions were investigated using a texture analyzer, cryo-SEM and an oscillatory rheometer, respectively. The probe penetration method demonstrated a decrease in &quot;hardness&quot; of carrageenan systems with increasing cation concentration, after exhibiting an initial maximum. The Young&#039;s modulus (E) of ?-carrageenan gels was determined using the uniaxial compression method. E was approximately 3 times the shear modulus recorded under the same experimental conditions; indicating the elimination of slip by the use of roughened parallel plates. The storage modulus of ?-carrageenan gels with Ca2+ demonstrated a similar trend to mechanical properties. However the syneresis observed in ?-carrageenan systems with storage, may have reduced the sensitivity of probe penetration method. Cryo-SEM observation of gels revealed a microstructure consistent with the observed mechanical propertie