Potential application of low molecular weight excipients for amorphization and dissolution enhancement of carvedilol.

In this study, four low molecular weight (LMW) excipients, tryptophan (TRY), phenylalanine (PHE), lysine (LYS) and saccharin (SAC) were evaluated as co-formers to generate co-amorphous systems (CAMS) by ball milling with carvedilol (CRV). Mixtures of CRV and LMW excipient in 1:0.5, 1:1 and 1:2 drug:excipient molar ratios were ball milled and analysed by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform (FT-IR) infrared spectroscopy and dissolution testing. CAMS were formed by milling of a mixture of CRV with TRY in 1:2 M ratio and SAC in 1:1 M ratio, while amorphization of only CRV was achieved in other mixtures with SAC. In other samples containing TRY and PHE, milling resulted in partial amorphization, while LYS was the least suitable excipient for the amorphization of CRV. Unexpectedly, the highest supersaturation of CRV was achieved from samples containing CRV and LYS in 1:1 and 1:2 M ratios, despite the absence of a significant reduction in CRV crystallinity upon milling of these samples. Increase of hydrophobic surface area caused by milling of samples with TRY and PHE and agglomeration during dissolution testing of samples containing SAC are likely causes of poor dissolution performance of mixtures containing fully or partially amorphous CRV.

Digital Light Processing (DLP) 3D Printing of Atomoxetine Hydrochloride Tablets Using Photoreactive Suspensions.

Three-dimensional (3D) printing technologies are based on successive material printing layer-by-layer and are considered suitable for the production of dosage forms customized for a patient's needs. In this study, tablets of atomoxetine hydrochloride (ATH) have been successfully fabricated by a digital light processing (DLP) 3D printing technology. Initial materials were photoreactive suspensions, composed of poly(ethylene glycol) diacrylate 700 (PEGDA 700), poly(ethylene glycol) 400 (PEG 400), photoinitiator and suspended ATH. The amount of ATH was varied from 10.00 to 25.00% (w/w), and a range of doses from 12.21 to 40.07 mg has been achieved, indicating the possibility of personalized therapy. The rheological characteristics of all photoreactive suspensions were appropriate for the printing process, while the amount of the suspended particles in the photoreactive suspensions had an impact on the 3D printing process, as well as on mechanical and biopharmaceutical characteristics of tablets. Only the formulation with the highest content of ATH had significantly different tensile strength compared to other formulations. All tablets showed sustained drug release during at least the 8h. ATH crystals were observed with polarized light microscopy of photoreactive suspensions and the cross-sections of the tablets, while no interactions between ATH and polymers were detected by FT-IR spectroscopy.

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading.

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers.

Risk factors for potential drug-drug interactions in intensive care unit patients.

PURPOSE: To determine risk factors for each severity-based category of potential drug-drug interactions (DDIs) encountered at intensive care unit (ICU) patients. METHODS: This was a retrospective cohort analysis of patients treated at the ICU of the Clinical Center Kragujevac, a public tertiary care hospital in Kragujevac, Serbia. Three interaction checkers were used to reveal drug-drug interactions: Medscape, Epocrates and Micromedex. RESULTS: The study included 201 patients, 66.19±16.11 years of age. Average number of DDIs per patient ranged from 10.49±8.80 (Micromedex) to 29.43±21.51 (Medscape). Antiarrhythmic or anticonvulsant drug prescription, Charlson Comorbidity Index, male sex, length of hospitalization, number of drugs or therapeutic groups prescribed and surgery increased the risk of DDIs in ICU patients, while presence of delirium or dementia and transfer from emergency department to ICU protected against. CONCLUSIONS: The rate of the DDIs in ICU patients at a tertiary care hospital is high, and adversely influenced by number of drugs or drug groups prescribed per patient, antiarrhythmic or anticonvulsant drug prescription, comorbidities, length of hospitalization and surgery. On the other hand, presence of cognitive deficit and transfer from emergency department to ICU protect ICU patients from the DDIs.