Local Structural Effects Due to Micronization and Amorphization on an HIV Treatment Active Pharmaceutical Ingredient.

Processing procedures for inducing domain size reduction and/or amorphous phase generation can be crucial for enhancing the bioavailability of active pharmaceutical ingredients (APIs). It is important to quantify these reduced coherence phases and to detect and characterize associated structural changes, to ensure that no deleterious effects on safety, function, or stability occur. Here, X-ray powder diffraction (XRPD), total scattering pair distribution function (TSPDF) analysis, and solid-state nuclear magnetic resonance spectroscopy (SSNMR) have been performed on samples of GSK2838232B, an investigational drug for the treatment of human immunodeficiency virus (HIV). Preparations were obtained through different mechanical treatments resulting in varying extents of domain size reduction and amorphous phase generation. Completely amorphous formulations could be prepared by milling and microfluidic injection processes. Microfluidic injection was shown to result in a different local structure due to dispersion with dichloromethane (DCM). Implications of combined TSPDF and SSNMR studies to characterize molecular compounds are also discussed, in particular, the possibility to obtain a thorough structural understanding of disordered samples from different processes.

Controlled Delivery of Dutasteride Using Dissolvable Microarrays: Initial Formulation and In Vivo Evaluation.

Dutasteride is prescribed as a once-daily oral capsule for the treatment of symptomatic benign prostatic hyperplasia. As an alternative and patient-focused drug product, this laboratory evaluated the potential to deliver dutasteride in a controlled/sustained manner when formulated as a microarray. The low oral dose, low aqueous solubility, and slow rate of elimination of dutasteride were considered ideal properties which may enable a once-weekly microarray option for patients. The concept of sustained release was initially proven in mini-pigs whereby simple intradermal administration of a nanomilled dutasteride suspension (0.12 mg/kg) was associated with an exposure period of at least 1 month. Dissolvable microarrays were successfully manufactured using a nanomilled suspension and were administered to rats at doses up to 0.32 mg/kg. In these studies, serum dutasteride was quantifiable for approximately 2 weeks after a single application. In silico modeling of the rat data using a two-compartment intradermal model was conducted and predicted that, in humans, a once-weekly dose of 2 mg, given as a microarray, could deliver cumulative and therapeutically relevant levels of dutasteride in a manner which is comparable to that observed with the current oral regimen.

Challenges and Opportunities for Patient Centric Drug Product Design: Industry Perspectives.

For an industry dedicated to preventing and treating disease, the concept of patient centric drug product design is remarkably new, yet it is beginning to transform medicinal development. The paternalistic paradigm of delivering efficacious and safe medicinal products, with inconsistent emphasis on patient centric considerations, is no longer sufficient. Patient expectations have evolved, and treatment use must complement patients' daily lives. While designing medicines to facilitate patients' use is now expected, the patient diversity across sub-populations and markets as well as industrial factors such as physicochemical properties, supply chain and shelf life aspects may preclude the development of a single, universal patient centric solution that meets all the needs of those with a particular disease. The objective of this publication is to highlight the complexities of implementing patient centric drug product design through a hypothetical HIV case study using the existing development and business processes to raise awareness and to suggest opportunities for collaboration.

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.

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 ((111)In) and samarium ((153)Sm), 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.

A novel enzymatic technique for limiting drug mobility in a hydrogel matrix.

An oral colon specific drug delivery platform has been developed to facilitate targetted release of therapeutic proteins as well as small molecule drugs. A simple enzymatic procedure is used to modify the molecular architecture of a lightly chemically crosslinked galactomannan hydrogel as well as a model drug-galactomannan oligomer conjugate, fluoroisocynate (FITC) tagged guar oligomer, to entrap the model drug. The enzyme-modified hydrogel retains the drug until it reaches the colonic environment where bacteria secrete enzymes (namely beta-mannanase) to degrade the gel and release the drug molecule. Laser scanning confocal microscopy combined with fluorescence recovery after photobleaching is used to quantify the diffusion of the drug conjugate. The diffusion coefficient of solutes in the lightly crosslinked galactomannan hydrogel is approximately equal to the diffusion coefficient in the guar solution for simple diffusional drug loading. After drug loading, alpha-galactosidase treatment generates additional physical crosslinks in the hydrogel matrix as well as between the drug-oligomer conjugate and the hydrogel, which reduces diffusion of the drug-oligomer conjugate significantly. Degradation of the hydrogel by beta-mannanase results in a slow and controlled rate of FITC-guar oligomer diffusion, which generates an extended release profile for the model drug.

Rheology of protein gels synthesized through a combined enzymatic and heat treatment method.

Whey protein gels prepared under acidic conditions (pH<4.6) remain largely unutilized because of their weak and brittle nature in contrast to the favorable elastic gels produced at neutral or basic conditions. However, such usage is important, as low pH food products are desirable due to their shelf stability and less stringent sterilization processes. In this study, we use a two-step process involving enzyme followed by heat treatment to produce whey protein gels at low pH (4.0). Dynamic rheological measurements reveal that the gel elastic modulus and yield stress increase substantially when heat treatment is supplemented with enzyme treatment. Both the elastic modulus and yield stress increase with increasing enzyme concentration or treatment time. In contrast, the dynamic yield strain decreases with enzyme concentration but increases with time of enzyme treatment. These results are explained in terms of the enzyme treatment time affecting the diffusion of the enzyme within the gel. This in turn leads to two types of gel microstructure at short and long enzyme treatment times, with the extent of enzyme diffusion modulating the structure at intermediate times.