9 research outputs found
The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction
Orally Active Antiviral Tripeptide Glycyl-Prolyl-Glycinamide Is Activated by CD26 (Dipeptidyl Peptidase IV) before Transport across the Intestinal Epithelium
The tripeptide amide glycyl-prolyl-glycinamide (GPG-amide) is a new antiretroviral drug candidate, but its absorption mechanism is unknown. In this investigation, the transport and metabolism of GPG-amide were studied in a model of the human intestinal epithelium, Caco-2 cell monolayers. The results show that when the tripeptide amide came into contact with the apical enterocyte membrane, it was degraded by CD26 (dipeptidyl peptidase IV) to glycylproline and the antiretrovirally active metabolite glycinamide. Glycinamide retained antiretroviral activity in vitro after transport through the Caco-2 cell monolayers. The transport of glycinamide across Caco-2 cell monolayers occurred via passive diffusion with an apparent permeability coefficient of about 2 Ă 10(â6) cm s(â1), which suggests that it is absorbed by the oral route in sufficient amounts to be considered for oral administration. In conclusion, the tripeptide GPG-amide acts as a prodrug that is activated by CD26 to release the orally active antiretroviral compound glycinamide
Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
The main purpose of the study was to evaluate various pre-processing and quantification approaches of Raman spectrum to quantify low level of amorphous content in milled lactose powder. To improve the quantification analysis, several spectral pre-processing methods were used to adjust background effects. The effects of spectral noise on the variation of determined amorphous content were also investigated theoretically by propagation of error analysis and were compared to the experimentally obtained values. Additionally, the applicability of calibration method with crystalline or amorphous domains in the estimation of amorphous content in milled lactose powder was discussed. Two straight baseline pre-processing methods gave the best and almost equal performance. By the succeeding quantification methods, PCA performed best, although the classical least square analysis (CLS) gave comparable results, while peak parameter analysis displayed to be inferior. The standard deviations of experimental determined percentage amorphous content were 0.94% and 0.25% for pure crystalline and pure amorphous samples respectively, which was very close to the standard deviation values from propagated spectral noise. The reasonable conformity between the milled samples spectra and synthesized spectra indicated representativeness of physical mixtures with crystalline or amorphous domains in the estimation of apparent amorphous content in milled lactose
The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction
The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.
Novel lipoamino acid & liposaccharide based system for peptide delivery: application for administering tumour selective somatostatin analogues
Lipoamino acid and liposaccharide conjugates of somatostatin analogue TT-232 were synthesized to modify the physicochemical properties of the parent peptide. The relative position, the number, and the nature of the lipid and/or saccharide moieties were varied. Experiments in vitro clearly showed that many compounds modified at the N- and/or C-terminus with lipid or sugar moieties retained the biological activity of the parent compound. An interesting construct was synthesized containing lipid and sugar units at opposite ends of the somatostatin analogue, so that the entire molecule could be considered as an amphipathic surfactant
Combined in Vitroâin Vivo Approach To Assess the Hepatobiliary Disposition of a Novel Oral Thrombin Inhibitor
Two
clinical trials and a large set of in vitro transporter experiments
were performed to investigate if the hepatobiliary disposition of
the direct thrombin inhibitor prodrug AZD0837 is the mechanism for
the drugâdrug interaction with ketoconazole observed in a previous
clinical study. In Study 1, [<sup>3</sup>H]ÂAZD0837 was administered
to healthy male volunteers (<i>n</i> = 8) to quantify and
identify the metabolites excreted in bile. Bile was sampled directly
from the jejunum by duodenal aspiration via an oro-enteric tube. In
Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics
of AZD0837, the intermediate metabolite (AR-H069927), and the active
form (AR-H067637) was investigated (<i>n</i> = 17). Co-administration
with ketoconazole elevated the plasma exposure to AZD0837 and the
active form approximately 2-fold compared to placebo, which may be
explained by inhibited CYP3A4 metabolism and reduced biliary clearance,
respectively. High concentrations of the active form was measured
in bile with a bile-to-plasma AUC ratio of approximately 75, indicating
involvement of transporter-mediated excretion of the compound. AZD0837
and its metabolites were further investigated as substrates of hepatic
uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell
monolayers and P-glycoprotein (P-gp) expressing membrane vesicles
identified AZD0837, the intermediate, and the active form as substrates
of P-gp. The active form was also identified as a substrate of the
multidrug and toxin extrusion 1 (MATE1) transporter and the organic
cation transporter 1 (OCT1), in HEK cells transfected with the respective
transporter. Ketoconazole was shown to inhibit all of these three
transporters; in particular, inhibition of P-gp and MATE1 occurred
in a clinically relevant concentration range. In conclusion, the hepatobiliary
transport pathways of AZD0837 and its metabolites were identified
in vitro and in vivo. Inhibition of the canalicular transporters P-gp
and MATE1 may lead to enhanced plasma exposure to the active form,
which could, at least in part, explain the clinical interaction with
ketoconazole