Cinnamyl O-amine functionalized chitosan as a new excipient in direct compressed tablets with improved drug delivery.

The use of chitosan as a potential excipient in pharmaceutical formulations for the delivery of drugs produced via direct compression tableting has been investigated. Chitosan, N-cinnamyl substituted O-amine functionalized chitosan (cinnamyl-chitosan) and microcrystalline cellulose (MCC) were formulated, alongside acetaminophen as the active pharmaceutical ingredient (API), and magnesium stearate (Mg-St) as lubricant in a series of formulated blends. A control blend of MCC, acetaminophen (20 wt%) and Mg-St (0.5 wt%) was studied alongside two chitosan-bearing blends, containing 20 wt% chitosan and 20 wt% cinnamyl-chitosan separately. Particle size, shape and morphology of the raw powders were studied along with flowability of both raw powders and formulated powder blends. A single-punch tablet machine was used for tablet compaction. The relationship between tablet hardness and compression pressure was evaluated, while the plasticity factor (PF) and elasticity factor (EF) were derived from force-displacement curves. Disintegration and dissolution studies were also carried out to investigate the drug delivery potential of the blends. Blends containing chitosan and cinnamyl-chitosan possess good compaction properties with high elasticity due to their large particle sizes, and show excellent dissolution properties, releasing >80% API within 30 min. With good mechanical strength and superior drug delivery performance, in addition to its enhanced antibacterial and antioxidative effect gained though chemical modification, cinnamyl-chitosan exhibits potential to be used as a new cost-effective pharmaceutical excipient in direct compression tableting.

Systematic development of a high dosage formulation to enable direct compression of a poorly flowing API: A case study.

In this work, the transfer of oral solid dosage forms, currently manufactured via wet granulation, to a continuous direct compression process was considered. Two main challenges were addressed: (1) a poorly flowing API (Canagliflozin) and (2) high drug loading (51 wt%). A scientific approach was utilised for formulation development, targeting flow and compaction behaviour suitable for manufacturing scale. This was achieved through systematic screening of excipients to identify feasible formulations. Targeted design of experiments based on factors such as formulation mixture and processing parameters were utilised to investigate key responses for tablet properties, flow and compaction behaviour. Flow behaviour was primarily evaluated from percentage compressibility and shear cell testing on a powder flow rheometer (FT4). The compaction behaviour was studied using a compaction simulator (Gamlen). The relationships between tablet porosity, tensile strength and compaction pressure were used to evaluate tabletability, compactibility and compressibility to assess scale-up. The success of this design procedure is illustrated by scaling up from the compaction simulator to a Riva Piccola rotary tablet press, while maintaining critical quality attributes (CQAs). Compactibility was identified as a suitable scale-up relationship. The developed procedure should allow accelerated development of formulations for continuous direct compression.

Mercapturic acids as metabolites of alkylating substances in urine samples of German inhabitants.

Hydroxyalkyl mercapturic acids (HAMA) are the main urinary metabolites of several alkylating substances that possess a carcinogenic potential, like acrolein, 1,3-butadiene, ethylene oxide, propylene oxide and glycidol. These alkylating substances are used extensively in industrial processes, but they do also occur environmentally, e.g. in tobacco smoke. The aim of this study was the determination of six HAMA, as biomarkers of exposure, in human urine of smokers and non-smokers. We applied a sensitive analytical method, using hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS) for the determination of 2-hydroxyethyl mercapturic acid (HEMA, biomarker for ethylene oxide), 2-hydroxypropyl mercapturic acid (2-HPMA, biomarker for propylene oxide), 3-hydroxypropyl mercapturic acid (3-HPMA, biomarker for acrolein), 2,3-dihydroxypropyl mercapturic acid (DHPMA, biomarker for glycidol) as well as 3,4-dihydroxybutyl mercapturic acid and 3-monohydroxybutenyl mercapturic acids (DHBMA and MHBMA, biomarkers for 1,3-butadiene). Background concentrations of four HAMA were detected in each urine sample we analyzed. The mercapturic acids HEMA and MHBMA were detected in 55% and 10% of the samples, respectively. In the urine of non-smokers (n = 54) we observed median levels of 206, 1.6, 12.1, 146, 159, and <5.0 µg/g creatinine for DHPMA, HEMA, 2-HPMA, 3-HPMA, DHBMA and MHBMA, respectively. Among smokers (n = 40) median levels of DHPMA, HEMA, 2-HPMA, 3-HPMA, DHBMA and MHBMA were determined to be 217, 4.9, 46.2, 884, 211 and <5.0 µg/g creatinine, respectively. The excretion rate of the biomarkers HEMA, 2-HPMA and 3-HPMA was distinctly higher in smokers than in non-smokers. Furthermore, our study revealed a comparatively high background level of DHPMA in urine of smokers and non-smokers whose origin is still unknown. The presented data may contribute to the evaluation of reference values for urinary HAMA levels in the general population.

Non-invasive bioengineering methods in an intervention study in 1020 male metal workers: results and implications for occupational dermatology.

BACKGROUND: Measurements of transepidermal water loss (TEWL) as an indicator of skin barrier function and colorimetry for quantifying erythema have been recommended for monitoring persons at risk of occupational hand dermatitis. OBJECTIVE: This study examines the practicability and usefulness of biophysical measurements at the workplace. PATIENTS/MATERIAL/METHODS: A sample of 1020 male metal workers was enrolled; 800 participants were followed up for 1 year. TEWL results and colorimetry (a* value), respectively, were used as effectiveness outcomes, comparing the findings in the four study arms (skin care, skin protection, both combined, and control group). RESULTS: At 1 year follow-up, the TEWL was slightly but significantly lower in the group of participants randomized for application of barrier cream alone, indicating a protective effect. However, addressing both the individual absolute change of a* value and the differences of TEWL (delta-TEWL) of the dominant hand over the study period, no significant difference was found between the four groups. CONCLUSIONS: Dermatological examinations at the workplace cannot be replaced by bioengineering techniques. The supplementary benefit is apparently low, possibly because of difficulties in achieving standardized measurement conditions and other technical reasons.