Design, optimisation, in vitro and in vivo evaluation of promising once-a-day tablet formulations of the novel antihypertensive drug MT-1207

Vrettos, Napoleon Nikolaos (2022) Design, optimisation, in vitro and in vivo evaluation of promising once-a-day tablet formulations of the novel antihypertensive drug MT-1207. PhD thesis, University of Nottingham.

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Hypertension is the most common cardiovascular disease characterised by elevated systolic and diastolic blood pressure. Globally, around 1.28 billion adults have hypertension with only about 21 % having it under control. Prevalence depends on a range of different factors. Currently, there are many different drugs that are used to manage hypertension through different mechanisms of action. In recent years, guidelines suggest that hypertension should be treated with a combinatory therapy from its onset, instead of monotherapy, so that many different receptors can be targeted. However, the administration of many different drugs to hypertensive patients (polypharmacy) can in itself impede patient compliance to the treatment, reducing the desired effectiveness of this approach.

MT-1207 is a new promising antihypertensive agent that targets multiple different receptors, namely, calcium channels, α1 and serotonin (5-Hydroxytryptamine) 5-HT2A receptors. Its safety and efficacy have been indicated in preclinical animal studies and phase I clinical trials in healthy human subjects. Immediate-release tablets of MT-1207 have been developed and are currently being tested in phase Ib/IIa clinical trials.

The aim of the present study was to develop sustained-release tablet formulations of MT-1207 that could be administered as a once-a-day dosing regimen, thereby providing improved patient compliance and better control of the drug plasma levels. Initially, to achieve this, single-layer hydroxypropyl methylcellulose (HPMC) matrix tablets were prepared and characterised in vitro. Based on the results, an optimised HPMC matrix tablet formulation was selected and was forwarded to a pharmacokinetic study in Beagle dogs.

Based on the in vivo study results, further formulation optimisation was carried out by developing non-effervescent gastroretentive bilayer tablets that consisted of a novel gastroretentive layer and an MT-1207-containing layer. As part of the gastroretentive layer optimisation, a factorial experiment was designed and executed to determine the factors affecting the in vitro buoyancy behaviour of the tablets. Based on the factorial experiment results, an optimised gastroretentive layer was designed which was easy to prepare, ensured an immediate floatation of the tablets, and maintained tablet buoyancy over more than 24 hours in fasted state simulated gastric fluid (FaSSGF) pH 1.6, regardless of the drug layer composition. It was also shown that the media pH influenced the total floating time of the tablets. Based on scanning electron microscopy (SEM) imaging and viscosity analysis, a statistically significant difference in the total floating time values of the bilayer tablets over the pH range 1.0 – 6.0 was attributed to pH-dependent degradation of polyethylene oxide (PEO) in acidic conditions at temperatures above 36 °C. With regards to the drug layer, ethylcellulose was incorporated as an additional release retardant. The in vitro release testing demonstrated that the presence of the gastroretentive layer was the main factor that significantly retarded the release of MT-1207 from the bilayer tablets, rather than the amount of ethylcellulose incorporated into the drug layer. Ultimately, two bilayer formulations were developed that provided a complete sustained release of MT-1207 maintained over 24 hours.

The non-effervescent gastroretentive bilayer tablet formulations were forwarded to a second pharmacokinetic study in Beagle dogs in fed conditions. The study results demonstrated the potential of those formulations to be used for the once-a-day oral delivery of MT-1207. The bilayer tablet formulations will be the subject of clinical trials.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Zhu, Zheying
Roberts, Clive Jonathan
Keywords: Hypertension, MT-1207, Sustained-release tablets, Hydrophilic matrix, Gastroretentive, Non-effervescent, In vitro buoyancy, Drug release, Pharmacokinetics
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 68979
Depositing User: Vrettos, Napoleon Nikolaos
Date Deposited: 28 Jul 2022 04:40
Last Modified: 28 Jul 2022 04:40

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