On the usefulness of four in vitro methods in assessing the intraluminal performance of poorly soluble, ionisable compounds in the fasted state

Εργασία εν εξελίξει (Preprint) uoadl:2962522 45 Αναγνώσεις

Τμήμα Φαρμακευτικής
On the usefulness of four in vitro methods in assessing the intraluminal performance of poorly soluble, ionisable compounds in the fasted state
Γλώσσες Τεκμηρίου:
A small-scale two-stage biphasic system, a small-scale two-stage dissolution-permeation system, the Erweka mini-paddle apparatus, and the BioGIT system were evaluated for their usefulness in assessing the intraluminal performance of two low solubility drugs in the fasted state, one with weakly acidic properties (tested in a salt form, diclofenac potassium) and one with weakly alkaline properties [ritonavir, tested as an amorphous solid dispersion (ASD)].
In all in vitro methods, an immediate-release tablet and a powder formulation of diclofenac potassium were both rapidly dissolved in Level II biorelevant media simulating the conditions in the upper small intestine. Physiologically based biopharmaceutics (PBB) modelling for the tablet formulation resulted in a successful simulation of the average plasma profile in adults, whereas for the powder formulation modelling indicated that gastric emptying and transport through the intestinal epithelium limit the absorption rates.
Detailed information on the behaviour of the ritonavir ASD under both simulated gastric and upper small intestinal conditions were crucial for understanding the luminal performance. PBB modelling showed that the dissolution and precipitation parameters, estimated from the Erweka mini-paddle apparatus data and the small-scale two-stage biphasic system data, respectively, were necessary to adequately simulate the average plasma profile after administration of the ritonavir ASD formulation. Simulation of the gastrointestinal transfer process from the stomach to the small intestine was necessary to evaluate the effects of hypochlorhydric conditions on the luminal performance of the ritonavir ASD.
Based on this study, the selection of the appropriate in vitro method for evaluating the intraluminal performance of ionisable lipophilic drugs depends on the characteristics of the drug substance. The results suggest that for (salts of) acidic drugs (e.g., diclofenac potassium) it is only an issue of availability and ease of operation of the apparatus. For weakly alkaline substances (e.g., ritonavir), the results indicate that the dynamic dissolution process needs to be simulated, with the type of requested information (e.g., dissolution parameters, precipitation parameters, luminal concentrations) being key for selecting the most appropriate method. Regardless of the ionisation characteristics, early in the drug development process the use of small-scale systems may be inevitable, due to the limited quantities of drug substance available.
Έτος δημιουργίας:
Patrick J. O’Dwyer
Karl J. Box
Georgios Imanidis
Maria Vertzoni
Christos Reppas
dissolution, precipitation, PBPK modelling, biphasic, dissolution-permeation, BioGIT
Κύρια θεματική κατηγορία:
Θετικές Επιστήμες
Comparison of Four in vitro Setups MS_Revision_03-09-21.pdf (661 KB) Άνοιγμα σε νέο παράθυρο