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1.
Mol Pharm ; 21(5): 2456-2472, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38568423

RESUMO

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.


Assuntos
Cápsulas , Dabigatrana , Jejum , Esvaziamento Gástrico , Dabigatrana/química , Dabigatrana/administração & dosagem , Dabigatrana/farmacologia , Cápsulas/química , Esvaziamento Gástrico/fisiologia , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , Liberação Controlada de Fármacos , Administração Oral , Simulação por Computador , Estômago/fisiologia , Estômago/efeitos dos fármacos
2.
Pharmaceutics ; 15(8)2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37631270

RESUMO

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule's opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms.

3.
Int J Pharm ; 641: 123061, 2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37211237

RESUMO

Biorelevant dissolution tests of oral solid dosage forms open the gate to valid in vitro-in vivo predictions (IVIVP). A recently developed apparatus, PhysioCell, allows mimicking the fluid flow and pressure waves occurring in the human fasted stomach. In this work, we used the PhysioCell to perform IVIVP for vortioxetine immediate-release (IR) tablets: the originator (Brintellix) and generic product candidates (VORTIO). The dissolved drug was monitored in the gastric (StressCell) and intestinal (Collection Vessel) compartments that contained biorelevant media. Simulated intermittent gastric stress at 15 min and "housekeeping wave" at 30 min increased the dissolution of Brintellix formulations only. A mechanistic model that best described the observations involved the first-order tablet disintegration with a stress-induced enhancement for Brintellix, dissolution of solid particles in the StressCell, and drug transfer to the Collection Vessel. Then, a semi-mechanistic pharmacokinetic model with dissolution parameters as inputs simulated vortioxetine plasma concentrations in healthy volunteers after single and multiple dosing of Brintellix. Despite different dissolution characteristics, VORTIO provided similar concentration profiles to the originator. In conclusion, PhysioCell dissolution tests, combined with semi-mechanistic IVIVP, can be successfully used to develop IR dosage forms exhibiting gastric stress-related effects.


Assuntos
Química Farmacêutica , Humanos , Solubilidade , Vortioxetina , Fluxo de Trabalho , Administração Oral , Comprimidos , Liberação Controlada de Fármacos
5.
AAPS PharmSciTech ; 24(2): 65, 2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36788168

RESUMO

The physiologically relevant dissolution apparatuses simulate various aspects of gastrointestinal physiology and help to understand and predict the in vivo behavior of an oral dosage form. In this paper, we present and characterize for the first time a novel bio-relevant dissolution apparatus - PhysioCell®;. We evaluated the impact of several factors on the hydrodynamic conditions in the key vessel of the apparatus - the StressCell. We observed that the medium flow rate, but not the glass beads' size or amount, significantly influenced the dissolution rate. The relationship was disproportional: the increase in the flow rate from 4.6 to 9.0 mL/min reduced the dissolution time of 85% (T85) of the NaCl tablet by 46%, but from 134 to 300 mL/min decreased the T85 only by 24%. At the same time, the contractions of the StressCell's elastic walls promoted the content mixing and enhanced the dissolution rate of the paracetamol tablets: even very rare mixing contractions (1 per 10 min) decreased the T85 over twofold for the flow rate of 8 mL/min. In conclusion, the hydrodynamic conditions in the StressCell affect the dissolution of solid dosage forms and the understanding of these effects is crucial for modeling physiologically-based test conditions in the novel apparatus. Combinations of the unique PhysioCell®;features - adjustable medium flow, temperature control, controllable pH gradients and predefined mechanical agitation - can create a set of dissolution test scenarios for characterization of oral dosage forms and, in the future, making the in vitro-in vivo predictions. Graphical Abstract.


Assuntos
Química Farmacêutica , Hidrodinâmica , Solubilidade , Comprimidos/química , Acetaminofen
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