Development of a Pediatric Mini-Tablet Formulation for Expedited Preclinical Studies.

Multiple considerations are essential to address the main challenges of dose flexibility and patient adherence in pediatric drug development, particularly for oncology. Mini-tablets, 2 mm in diameter, were manufactured using a rotary tablet press at a set weight and compression force level. The physical characteristics were consistent for mini-tablets throughout multiple batches. Polymeric amorphous solid dispersion (ASD) was used as a solubility enhancing technique to increase solubility and exposure of lapatinib. The effects of the polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellulose E3 (HPMCE3) formulation provided a higher percentage of drug release compared to hydroxypropyl methylcellulose phthalate (HPMCP). The intermolecular interaction within the ASD system plays a role in the level of apparent solubility, physical stability, and concentration of free drug available in an aqueous environment. Juvenile porcine models at two different weight groups (10 and 20 kg) were used to obtain the pharmacokinetic parameters of lapatinib. While the dose-normalized exposure of drug was found to be lower in the pig study, the dose flexibility of mini-tablets enabled a constant dose level to be administered to achieve equivalent plasma concentration-time profiles between the two groups. This linear scaling in the amount of drug in pediatric and adult population has also been observed in human clinical studies.

Considerations for Determining Direct Versus Indirect Functional Effects of Solubilizing Excipients on Drug Transporters for Enhancing Bioavailability.

Excipients used in drug formulations at clinically safe levels have been considered to be pharmacologically inert; however, numerous studies have suggested that many solubilizing agents may modulate drug transporter activities and intestinal absorption. Here, the reported interactions between various solubilizing excipients and drug transporters are evaluated to consider various potential underlying mechanisms. This forms the basis for debate in the field in regard to whether or not the effects are based on "direct" interactions or "indirect" consequences arising from the role of the excipients. For example, an increase in apparent drug solubility can give rise to saturation of transporters according to Michaelis-Menten kinetics. This is also drawing the attention of regulatory agencies as they seek to understand the role of formulation additives. The continued application of excipients as a tool in solubility enhancement is crucial in the drug development process, creating a need for additional data to verify the proposed mechanism behind these changes. A literature review is provided here with some guidance on other factors that should be considered to delineate the effects that arise from direct physiological interactions or indirect effects. The results of such studies may aid the rational design of bioavailability-enhancing formulations.

Pediatric Formulations: Knowledge Gaps Limiting the Expedited Preclinical to Clinical Translation in Children.

Traditionally, drug discovery and development research have been primarily focused on the mitigation of disease treatment for the general adult population, often overlooking the medical needs of pediatric patients. While remarkable progress toward the discovery of better medicines has been made, the pharmacological differences between children and adults are often neglected as part of the translation process. In fact, until recently, children have been considered therapeutic orphans due to the lack of significant drug discovery, formulation development, and dosage form design specifically tailored for pediatric patients. Perhaps the least understood is the significant physiological changes that occur during the maturation process from birth to adulthood. It requires careful considerations to achieve age-specific-desired therapeutic outcomes with minimal toxicity. This introduces considerable risk into the preclinical and clinical testing of new medicaments, which until recently, was avoided based on the conventional approach where a demonstration of safe and efficacious use in adults over several years potentially would minimize the chance of adverse juvenile responses. However, the lack of appropriate drug products for children has led to off-label use of adult medicines with potential life-threatening adverse reactions and health complications. Recent developments and future considerations regarding pediatric drug discovery and development using a patient-centric approach in the context of ontogenic biopharmaceutical considerations are discussed below.

Correction to: Effects of Dendrimer-Like Biopolymers on Physical Stability of Amorphous Solid Dispersions and Drug Permeability Across Caco-2 Cell Monolayers.

During the production process, an editorial error occurred where the label numbering for the first two tables were inadvertently switched. The original article has been corrected.

Effects of Dendrimer-Like Biopolymers on Physical Stability of Amorphous Solid Dispersions and Drug Permeability Across Caco-2 Cell Monolayers.

The potential applications of dendrimer-like biopolymers (DLB) as stabilizing excipients for amorphous solid dispersion (ASD) of niclosamide, celecoxib, and resveratrol were evaluated based on (1) the formation and physical stability of the ASD and (2) the permeability and flux of the agents across Caco-2 cell monolayers. The evaluation was made by comparing the performance of prototype phytoglycogen derivatives (DLB1, DLB2, and DLB3) with commonly used polymers such as HPMCAS, PVPVA, and Soluplus®. PXRD was used to confirm the formation of the dispersions and detect crystallinity peaks formed during 2- and 4-week storage at 40°C/75% RH. At concentrations below 2 g/mL, the viability of Caco-2 cells remained above 80% for all DLB samples compared to untreated cells in the MTT assay. Permeability studies revealed a repeating pattern in which an increase in the initial concentration (C0) was associated with a concomitant decrease in the apparent permeability (Papp) which we theorize is due to differences in drug-polymer interactions. Niclosamide-DLB1 dispersion had the lowest flux due to a significant reduction in Papp. The high increase in the C0 of celecoxib-DLB2, however, made up for the reduction in the Papp and produced the highest flux values compared to other polymers. Resveratrol-DLB3 had a 5× reduction in Papp, but C0 increased from 25.8 to 176 µg/mL led to a higher flux compared to the crystalline drug without polymer. Collectively, these results provide a "proof-of-concept" basis to demonstrate that DLB excipients have the ability to increase apparent solubility (Solapp), most likely due to drug-binding capacity.

Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery.

Polyethylene glycol (PEG) derivatives were conjugated onto the Cys-34 residue of human serum albumin (HSA) to determine their effects on the solubilization, permeation, and cytotoxic activity of hydrophobic drugs such as paclitaxel (PTX). PEG(C34)HSA conjugates were prepared on a multigram scale by treating native HSA (n-HSA) with 5- or 20-kDa mPEG-maleimide, resulting in up to 77% conversion of the mono-PEGylated adduct. Nanoparticle tracking analysis of PEG(C34)HSA formulations in phosphate buffer revealed an increase in the number of nanosized aggregates relative to n-HSA, both in the absence and presence of PTX. Cell viability studies conducted with MCF-7 breast cancer cells indicated that PTX cytotoxicity was enhanced by PEG(C34)HSA when mixed at 10:1 mol ratios, up to a 2-fold increase in potency relative to n-HSA. The PEG(C34)HSA conjugates were also evaluated as PTX carriers across monolayers of HUVEC and hCMEC/D3 cells, and found to have permeation profiles nearly identical to those of n-HSA.