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.

Prevalence of Malnutrition among Elderly People Living in a Rural Area of Nepal.

INTRODUCTION: Elderly population is more likely to suffer from malnutrition due to aging-associated factors that influence nutritional status like loss of appetite, swallowing difficulties, digestive problems, and chronic illness. There is insufficient information related to the nutritional status of the elderly in Nepal. Hence, this study aims to determine the prevalence of malnutrition among elderly people living in the rural area of the Kavrepalanchok district. METHODS: A descriptive cross-sectional study was conducted among 320 elderly people aged ≥60 years in a rural area of Kavre district from August to October 2019. Ethical approval was taken from the Institutional Review Committee (IRC-KUSMS: 68/19). Convenient sampling was done. Data analysis was performed using the Statistical Program for Social Sciences version 23. RESULTS: The prevalence of malnutrition and risk of malnutrition was 37 (11.6%) and 159 (49.7%), respectively. Of 320 elderly persons, 193 (60.3%) males and 127 (39.7%) females, with a mean age of 68.23±7.38 years, participated in this study. The mean BMI was 22.54±3.25 kg/m2 (Mean±SD). The prevalence of malnutrition was higher among females 19 (15%) compared to males 18 (9.3%). CONCLUSIONS: The prevalence of malnutrition and risk of malnutrition is high in the study population. Interventions to improve the nutritional status of the elderly should focus primarily on older people, females, and those who have co-morbidities.

In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates.

The majority of active pharmaceutical ingredients (APIs) are bitter. Therefore, compliance can be a problem where adequate taste masking has not been achieved; this is most problematic in pediatrics. Taste masking is thus a key stage during pharmaceutical development with an array of strategies available to the formulation scientist. Solid oral dosage forms can be taste-masked quite simply by polymer coating, which prevents drug release in the mouth, without unwantedly impairing drug release further down the gastrointestinal tract. At the early stages of pharmaceutical development, an in vitro method for the assessment of taste masking is necessary given the lack of toxicological data preventing the use of human taste panels. Currently, there is no such tool allowing prediction of taste masking efficiency. In this study, drug dissolution in the context of aversive taste thresholds was proposed as a means to bridge this knowledge gap. Thus, a biorelevant buccal dissolution test was developed in which previously determined taste thresholds in vivo were used to evaluate taste masking efficiency: if drug release exceeded said thresholds, the formulation was deemed to be poorly taste-masked, and vice versa. This novel dissolution test was compared to the USP I (basket) dissolution test, and the biopharmaceutical implications of taste masking were also assessed by performing USP I (basket) dissolution testing in simulated gastric fluid (SGF). Chlorphenamine maleate, a model bitter BCS class 1 API, was layered onto sugar spheres and taste-masked using polymer coatings. An array of coating technologies were employed and assessed single blinded: two pH-independent water-insoluble coatings (Surelease:Opadry at 8, 12, and 16% weight gain and Opadry EC at 4, 6, and 8% weight gain) and a pH-dependent water-insoluble reverse-enteric coating (developmental fully formulated system based on Kollicoat Smartseal 100P at 10% weight gain). Both the biorelevant buccal and the USP I dissolution tests were capable of discriminating between both type and level of coating used. However, only the buccal dissolution test was able to provide absolute quantification of the level of taste masking achieved in the context of previously determined taste thresholds, while the USP I test merely provided a relative comparison between the different technologies assessed. When the release data from the buccal test were assessed in parallel to that in SGF, it was possible to predict in vitro optimized taste masking without compromising bioavailability. The fully formulated system based on Smartseal 100P was identified as the most effective coating and Surelease:Opadry the least effective. The developed methodology provides true insight for the formulator, enabling more informed patient-centric formulation decisions, better taste masking, and ultimately more effective medicines.

Multivariate analysis as a method to understand variability in a complex excipient, and its contribution to formulation performance.

A key part of the Risk Assessment of excipients is to understand how raw material variability could (or does) contribute to differences in performance of the drug product. Here we demonstrate an approach which achieves the necessary understanding for a complex, functional, excipient. Multivariate analysis (MVA) of the certificates of analysis of an ethylcellulose aqueous dispersion (Surelease) formulation revealed low overall variability of the properties of the systems. Review of the scores plot to highlight batches manufactured using the same ethylcellulose raw material in the formulation, indicated that these batches tend to be more closely related than other randomly selected batches. This variability could result in potential differences in the quality of drug product lots made from these batches. Manufacture of a model drug product from Surelease batches coated using different lots of starting material revealed small differences in the release of a model drug, which could be detected by certain model dependent dissolution modeling techniques, but they were not observed when using model-independent techniques. This illustrates that the techniques are suitable for detecting and understanding excipient variability, but that, in this case, the product was still robust.

Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy.

In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC>MG>DS tablets. The mean in vivo onset time for all tablets (DC: 6.7±3.8 min, MG: 18.3±8.1 min, DS: 67±18.9 min) did not differ significantly from in vitro onset time (DC: 5.3±1 min, MG: 16.8±3.9 min, DS: 61.8±4.7 min). The mean in vivo completion times were found to be 36.6±9.7 (DC tablets), 70±18.3 min (MG tablets) and 192.5±39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds.

In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets.

The purpose of this study was to evaluate and compare the in-vitro and in-vivo erosion profiles of two tablet formulations primarily consisting of hydroxypropylmethylcellulose (HPMC) and lactose. HPMC was used at concentrations below and above the reported values for polymer percolation threshold in controlled release matrix formulations: 20 and 40% (w/w) HPMC. In-vitro erosion behaviour was studied using traditional gravimetric and scintigraphic methods, with radiolabelled charcoal used as a marker to quantify erosion profiles in scintigraphic studies. Six healthy male subjects participated in a randomised crossover scintigraphic erosion study. Both in-vitro and in-vivo erosion profiles determined using the gravimetric and/or scintigraphic method for matrix tablets were dependent upon the concentration of HPMC, and erosion was faster for tablets containing 20% (w/w) HPMC than those containing 40% (w/w) HPMC. Good correlation was found between in-vitro gravimetric and scintigraphic erosion profiles for both tablets. Tablets containing 40% (w/w) HPMC (polymer level above percolation threshold) demonstrated robust in-vivo performance and showed stronger correlation with in-vitro erosion profiles. The study demonstrated that a matrix formulation with a lower concentration of HPMC and higher lactose concentration is more likely to perform poorly in the in-vivo environment.

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.