Formulation Strategies and Optimization of Poorly Water-Soluble Drugs for Preclinical and Clinical Applications

Successful mitigation of a disease or clinical condition requires efficacious and safe drug compounds that are designed to provide the right balance of properties including potency, specificity, safety, solubility, absorption and metabolic stability. In general, performance is governed by the physicochemical properties of the drug, the composition and properties of the dosage form, and their ability to provide release in a manner that overcomes the physiological barriers limiting exposure at the site of action. That being said, it is often very challenging to obtain a new therapeutic compound that possesses an optimal balance of these properties because of the broad chemical space in which the drug candidates can possess and the significant variability in physiology that can change both intra- and inter-individually during dosing. For example, an increase in potency that is achieved through elevated lipophilicity of a compound can lead to poor water solubility, which may require a solubility enhancing formulation to achieve the desired therapeutic levels in a patient. In fact, there has been an evolving trend in the drug discovery process to improve potency of the molecules by adding lipophilic moieties needed to demonstrate efficacy in cell-based assays, and even animal models, termed molecular obesity1–4. It has been noted that this has resulted in a significant increase of the generation of highly insoluble drug candidates. However, the perceived therapeutic benefit associated with high in vitro potency may be lost due to poor absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. To overcome the challenges associated with poorly soluble drugs, the pharmaceutical industry initiated the interface of drug discovery and development. It encourages early optimization to take place as a combined effort between those two stages. Solubility-enabling formulation strategies are utilized to develop drug-like compounds that can survive through different stages of drug development and ultimately become marketed products. An alignment between drug discovery and development therefore becomes essential and requires advanced knowledge in the selection of the appropriate compounds and formulation science. Chapter 1 provides a discussion on the potential effects of commonly-used solubilizing excipients on the activities of drug transporters. The excipients at clinically-safe levels have long been thought to be inert, but many studies have led to an enhanced understanding of how many solubilizing excipients may modulate drug transporters and enzymes resulting in unexpected pharmacological effects. The relevance with respect to this chapter is the potential for these excipients to interact with a physiological barrier and modulate the functions of drug transporters and enzymes. The goal here is to review the literature in this area and provide some insights into whether these effects arise from direct interactions or as a consequence of indirect effects like solubility enhancement influencing saturation of these isoforms as predicted by Michaelis-Menten kinetics. As the continued use of these excipients is being closely monitored by the regulatory agency, the difference between direct physiological activities or indirect effects like solubility enhancement is warranted. Current literature does not always delineate the mechanisms of permeability enhancement, hence creating a significant knowledge gap in our current understanding. Consequently, there may be unwanted scrutiny placed on excipient classes due to perceived pharmacological activity which may or may not exist. Chapter 2 discusses the addition of dendrimer-like biopolymers (DLB) as the polymeric matrix to stabilize the amorphous dispersion formulation of strong crystallizing compounds (niclosamide, celecoxib and resveratrol). The crystallization inhibition and effect of DLB’s on apparent permeability of drug across Caco-2 cell monolayers are evaluated and compared to the results obtained from using commercially available polymers. The interplay between concentration (i.e. apparent solubility) and permeability is demonstrated, and physiological considerations are discussed. Chapter 3 is an introduction to pediatric drug development, and it presents the current progress made to achieve better medicines for children. The lack of pediatric drug formulation and patient-centric products has led to off-label use of adult medicines, which can affect the drug performance and causes serious side effects. Pediatric population consists of multiple subgroups including neonates, infants, children and adolescents. The changes in anatomical properties, organ capacity, drug transporter activities and enzymatic expression can alter clinical outcomes in pediatric populations. The ontogeny-related effects need to be investigated and their impact on clinical pharmacology need to be incorporated in preclinical and clinical studies. In addition, innovative solid dosage form with dose flexibility and improved patient adherence can be used to overcome challenges in drug administration to children. The effects of body development on drug ADMET properties play an important role in pediatric drug product development. Finally, a platform created to expedite preclinical testing in pediatric drug development is presented in Chapter 4. Multiple considerations were incorporated to address the main challenges in dose flexibility and patient adherence. Mini-tablets, 2 mm in diameter, were manufactured using 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 polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellose 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

Formulation Strategies and Optimization of Poorly Water-Soluble Drugs for Preclinical and Clinical Applications

Successful mitigation of a disease or clinical condition requires efficacious and safe drug compounds that are designed to provide the right balance of properties including potency, specificity, safety, solubility, absorption and metabolic stability. In general, performance is governed by the physicochemical properties of the drug, the composition and properties of the dosage form, and their ability to provide release in a manner that overcomes the physiological barriers limiting exposure at the site of action. That being said, it is often very challenging to obtain a new therapeutic compound that possesses an optimal balance of these properties because of the broad chemical space in which the drug candidates can possess and the significant variability in physiology that can change both intra- and inter-individually during dosing. For example, an increase in potency that is achieved through elevated lipophilicity of a compound can lead to poor water solubility, which may require a solubility enhancing formulation to achieve the desired therapeutic levels in a patient. In fact, there has been an evolving trend in the drug discovery process to improve potency of the molecules by adding lipophilic moieties needed to demonstrate efficacy in cell-based assays, and even animal models, termed molecular obesity. It has been noted that this has resulted in a significant increase of the generation of highly insoluble drug candidates. However, the perceived therapeutic benefit associated with high in vitro potency may be lost due to poor absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. To overcome the challenges associated with poorly soluble drugs, the pharmaceutical industry initiated the interface of drug discovery and development. It encourages early optimization to take place as a combined effort between those two stages. Solubility-enabling formulation strategies are utilized to develop drug-like compounds that can survive through different stages of drug development and ultimately become marketed products. An alignment between drug discovery and development therefore becomes essential and requires advanced knowledge in the selection of the appropriate compounds and formulation science. Chapter 1 provides a discussion on the potential effects of commonly-used solubilizing excipients on the activities of drug transporters. The excipients at clinically-safe levels have long been thought to be inert, but many studies have led to an enhanced understanding of how many solubilizing excipients may modulate drug transporters and enzymes resulting in unexpected pharmacological effects. The relevance with respect to this chapter is the potential for these excipients to interact with a physiological barrier and modulate the functions of drug transporters and enzymes. The goal here is to review the literature in this area and provide some insights into whether these effects arise from direct interactions or as a consequence of indirect effects like solubility enhancement influencing saturation of these isoforms as predicted by Michaelis-Menten kinetics. As the continued use of these excipients is being closely monitored by the regulatory agency, the difference between direct physiological activities or indirect effects like solubility enhancement is warranted. Current literature does not always delineate the mechanisms of permeability enhancement, hence creating a significant knowledge gap in our current understanding. Consequently, there may be unwanted scrutiny placed on excipient classes due to perceived pharmacological activity which may or may not exist. Chapter 2 discusses the addition of dendrimer-like biopolymers (DLB) as the polymeric matrix to stabilize the amorphous dispersion formulation of strong crystallizing compounds (niclosamide, celecoxib and resveratrol). The crystallization inhibition and effect of DLB’s on apparent permeability of drug across Caco-2 cell monolayers are evaluated and compared to the results obtained from using commercially available polymers. The interplay between concentration (i.e. apparent solubility) and permeability is demonstrated, and physiological considerations are discussed. Chapter 3 is an introduction to pediatric drug development, and it presents the current progress made to achieve better medicines for children. The lack of pediatric drug formulation and patient-centric products has led to off-label use of adult medicines, which can affect the drug performance and causes serious side effects. Pediatric population consists of multiple subgroups including neonates, infants, children and adolescents. The changes in anatomical properties, organ capacity, drug transporter activities and enzymatic expression can alter clinical outcomes in pediatric populations. The ontogeny-related effects need to be investigated and their impact on clinical pharmacology need to be incorporated in preclinical and clinical studies. In addition, innovative solid dosage form with dose flexibility and improved patient adherence can be used to overcome challenges in drug administration to children. The effects of body development on drug ADMET properties play an important role in pediatric drug product development. Finally, a platform created to expedite preclinical testing in pediatric drug development is presented in Chapter 4. Multiple considerations were incorporated to address the main challenges in dose flexibility and patient adherence. Mini-tablets, 2 mm in diameter, were manufactured using 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 polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellose 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

Polypeptoid materials: Current status and future perspectives

Polypeptoids have recently emerged as a subject of scientific interest due to their structural resemblance to existing pseudo-peptidic polymers including poly(α-peptide)s, poly(β-peptide)s, poly(2-oxazoline)s, and poly(N-substituted acrylamide)s. With demonstrated backbone degradability, biocompatibility, and thermal processability, polypeptoids are potentially useful in a variety of biotechnological applications. Before those applications can be realized, it is important to develop their synthesis and understand their fundamental properties. In this Perspective, we will review recent advances in the synthesis and characterization of polypeptoids and their copolymers as well as the development of polypeptoid-based functional and structured materials. We will conclude by discussing the future prospects for this nascent class of pseudo-peptidic polymers. © 2012 American Chemical Society

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