Gastroretentive technologies in tandem with controlled-release strategies: A potent answer to oral drug bioavailability and patient compliance implications

There have been many efforts to improve oral drug bioavailability and therapeutic efficacy and patient compliance. A variety of controlled-release oral delivery systems have been developed to meet these needs. Gastroretentive drug delivery technologies have the potential to achieve retention of the dosage form in the upper gastrointestinal tract (GIT) that can be sufficient to ensure complete solubilisation of the drugs in the stomach fluids, followed by subsequent absorption in the stomach or proximal small intestine. This can be beneficial for drugs that have an “absorption window” or are absorbed to a different extent in various segments of the GIT. Therefore, gastroretentive technologies in tandem with controlled-release strategies could enhance both the therapeutic efficacy of many drugs and improve patient compliance through a reduction in dosing frequency. The paper reviews different gastroretentive drug delivery technologies and controlled-release strategies that can be combined and summarises examples of formulations currently in clinical development and commercially available gastroretentive controlled-release products. The different parameters that need to be considered and monitored during formulation development for these pharmaceutical applications are highlighted

In vitro and in vivo evaluation of a sustained-release once-a-day formulation of the novel antihypertensive drug MT-1207

Hypertension is one of the most common chronic cardiovascular disorders. Sustained-release formulations are developed to maintain drug therapeutic levels throughout the treatment of hypertension, to promote patient compliance and improve patient outcomes. We have developed and tested in in vivo trials a once-a-day tablet formulation for the novel antihypertensive drug MT-1207. The tablets based upon a hydrophilic polymer matrix underwent post-compression parameter and physicochemical characterisations, along with in vitro drug release testing. The most promising formulation containing 31% w/w HPMC K15M gave a 24-hour release of MT-1207 with an almost constant release rate up to 20 hours. Follow in in vivo studies were carried out in Beagle dogs for the optimised sustained-release tablets in comparison to immediate-release tablets. The results showed that a sustained release of MT-1207 from the new formulation was achieved with a drug t1/2 2–2.5 times longer than the immediate-release tablets. Moreover, the AUC0-24h values of both sustained- and immediate-release tablets were identical at the same dose of 30 mg, indicating that the same amount of drug was absorbed in each case. For treatments based upon MT-1207, this development is significant for future commercial exploitation via scale-up and further trials, and for improved patient outcomes

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

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

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

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

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 seconds) that lasted over 24 hours in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development