Matthew D. Burke

A novel method to radiolabel gastric retentive formulations for gamma scintigraphy assessment.

Purpose.To develop a robust radiolabeling technique to enable evaluation of difficult to radiolabel gastric retentive formulations using gamma scintigraphy. The use of a successful radiolabel will allow accurate assessment of the gastric residence time of the formulations.Materials and Methods.The retention of two radionuclides, indium (111In) and samarium (153Sm), with and without further processing to improve radiolabel performance were evaluated in simulated gastric pH in vitro. The most successful formulation from the in vitro screening was further evaluated in preclinical and clinical studies.Results.In vitro evaluation revealed significant radionuclide leakage at pH 1.5 for most radiolabeling attempts. Radionuclide leakage at pH 4.5 was less pronounced. The most successful radiolabel was formulated by adsorbing indium chloride onto activated charcoal, followed by entrapment in a cellulose acetate polymer melt. This provided the best radiolabel retention under both pH conditions in vitro. The radiolabel also proved to be successful during preclinical and clinical evaluations, allowing evaluation of gastric retention performance as well as complete gastrointestinal transit.Conclusion.A simple, yet robust radiolabel was developed for gastric retentive formulations to be evaluated pre-clinically or in a clinical setting by entrapping the radionuclide in an insoluble polymer through a simple polymer melt process.

Stability Enhancement of Drug Layered Pellets in a Fixed Dose Combination Tablet

The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.

Controlling Release by Gastroretention

A perpetual challenge in the pharmaceutical industry is the development of drug products that overcome inherent biopharmaceutical challenges while maximizing the therapeutic benefit and minimizing the potential for adverse events. The concept of a gastric retentive formulation is often very enticing as it has the potential to overcome many common challenges. In this chapter, we provide guidance on key preclinical and clinical concepts to consider when developing a potential gastric retentive formulation to ensure it can survive the “valley of death.” In addition, we discuss alternative approaches including bio-inspired concepts and provide “real-world” examples of attempts to develop novel gastric retentive formulations.

The safety, tolerability, and pharmacokinetic profile of GSK2838232, a novel 2nd generation HIV maturation inhibitor, as assessed in healthy subjects

This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose‐escalation studies in healthy subjects which assessed single oral doses (5‐250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug‐related AEs. GSK2838232 tested fasted was quickly absorbed with a tmax of 2‐3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and Cmax. Overall, following single doses GSK2838232 AUC and Cmax generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20‐200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and Cmax by 10‐ and 3‐fold, respectively. Half‐life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat‐dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once‐daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.