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Various strategies to improve bioavailability are being continuously evaluated, affording greater commercial prospects for the future.
Oral solids remain the most widely used dosage forms for pharmaceuticals to date, namely as a result of the convenience the form offers developers, manufacturers, and patients. Despite significant industry growth being witnessed in the area of large-molecule drugs, the oral solid dosage (OSD) pharmaceutical formulation market is anticipated to be worth more than US $926.1 billion by the end of 2027 (1).
However, it is also extensively reported that a sizable proportion of drug candidates in development are poorly water-soluble, an aspect that can contribute to higher attrition rates and is directly related to poor oral bioavailability. Low bioavailability is a frequent cause of failure in drug development (2) and is known to lead to high variability and poor control of therapeutic effects (3).
Oral bioavailability of a drug product can be affected via several factors, such as poor solubility, gastrointestinal degradation, and high first-pass metabolism rates. Aqueous solubility and membrane permeability have been identified as key influencers of oral bioavailability of drug products (4). Strategies employed to overcome the challenges that result in low oral bioavailability include manipulation of drug properties or methods to interfere with physiological barriers to drug absorption (3).
Drug properties can be altered via formulation strategies, manufacturing processes, or by modifying physicochemical properties to improve solubility and hence bioavailability. Many techniques have been well documented and researched over the years, providing valuable insight into the mechanism of action of various strategies and pathways for potential future advancement.
A review paper, authored by van der Merwe et al. in 2020, provided a comprehensive overview of selected excipients suitable for use to improve oral bioavailability. In their review, the authors noted that despite the variety of approaches available and the indication from several studies that functional excipients can have a beneficial effect on the bioavailability of APIs, there were also some clinical limitations. When evaluating specific excipient groups, such as pH-adjusting excipients, there were limited in-vivo and clinical data available and mostly, the studies only evaluated one poorly soluble API, demonstrating a clear need for further research (4).
However, it is patently clear that excipients are rightfully considered as more than an ‘inert’ vessel in drug delivery. As the complexity of drug development has increased, so too has the requirement for more sophisticated excipients to manipulate the properties of the final product, for example, multifunctional (co-processed) and high functionality excipients, which are able to fulfill multiple roles in performance improvement of a dosage form (4).
Specifically focusing on amorphous solid dispersions (ASDs), there are several specific excipient functionalities that should be considered. These considerations include the solubilizing effect of the excipient, the capability of the excipient to provide a strong molecular interaction with the API, whether the excipient exhibits thermoplastic behavior, and if the excipient displays a broad range of dissolution behaviors. Critically, the API and the polymer systems in ASDs must have a strong affinity for one another, and if the solubilization of the API within the polymer is done properly, it is possible to gain a thermodynamically stable end product (5).
Despite the capability of ASDs to improve solubility and bioavailability of drug products, there are complexities to overcome to ensure commercial success. In seeking to provide a greater understanding of the mechanisms underlying how ASDs improve bioavailability, Schittny, Huwyler, and Puchkov performed a literature review of all available research in 2019. Reflecting on both theoretical considerations and experimental data, the authors’ literature review led them to the conclusion that dissolution of an ASD can be attributed to three main mechanisms—carrier controlled, dissolution controlled, and drug controlled—and that dissolution is influenced by drug load, homogeneity of the solid ASD, interactions between the polymer and the drug, and surfactants (6).
Other key findings from the research included the fact that the dissolved states of ASDs are in a dynamic equilibrium; the higher drug absorption of ASDs can be mainly credited to the increased concentrations of molecularly dissolved API and is aided by diffusion by drug-rich particles. Additionally, it was found that, although polymers have the capacity to stabilize supersaturated solutions, they can also lower the amorphous solubility, and surfactants, although useful for enhancing dissolution properties, can not only stabilize but also destabilize supersaturated solutions. Furthermore, translational studies, moving from in-vitro to in-vivo performance, are limited (6).
An investigation by Wilson et al. in 2020 was aimed at evaluating the in-vivo absorption performance following oral dosage of a high-drug load formulation. The researchers evaluated enzalutamide in particular, as it is a lipophilic compound, Biopharmaceutics Classification System class II, that has low drug loading in its current commercially available formulation. As a result of low drug loading, the pill burden for patients is high, and, therefore, there is a desire to increase the drug loading without compromising absorption of the API (7).
Choosing two newly synthesized cellulose derivatives for ASD formulation, Wilson et al. determined that it is important for the polymer used in ASD formulations to have the correct balance of hydrophilic and hydrophobic substituent groups to be effective. Ultimately, after performing both in-vitro and in-vivo tests, the authors discerned that ASD formulation with the cellulose derivative, CPHPC-106, provided a five-fold improvement in enzalutamide absorption relative to crystalline control. Conversely, the polymer that was more effective an inhibiting crystallization yielded minimal improvements in oral absorption, highlighting the fact that ASD performance is a “complex interplay of drug and polymer properties” (7).
Another research paper on ASDs, published in 2020, detailed the possibility of reducing tablet mass using novel architecture. Compared with a typical ASD formulation, in which the dispersion polymer allows for physical stability of the solid-state and the maintenance of dissolution rate in the gastrointestinal tract, the novel high loaded dosage form (HLDF) architecture combines two different polymers to achieve physical stability and dissolution. The drug product evaluated was erlotinib, which is a rapidly crystallizing drug with a low glass transition temperature, formulated as an ASD with Eudragit L100 as the dispersion polymer and hydroxypropyl methyl cellulose acetate succinate as the concentration-sustaining polymer. The authors found that by using the novel HLDF architecture comprising two different polymers—one inside the ASD and the other outside—it was possible to achieve equivalent in-vitro performance as a single dispersion polymer ASD with a reduced dosage form size by 40% (8).
This brief review of some of the recent work being performed to assess various strategies to improve bioavailability demonstrates significant advances in mechanistic understanding and developments to approaches. Furthermore, thanks to research being undertaken in this area, commercial opportunities to improve dosage forms for patient convenience and reduce development attrition rates of poorly-water soluble compounds are coming to the fore.
1. FutureWise, Oral Solid Dosage Pharmaceutical Formulation Market by Dosage Form, by Drug Release Mechanism, by Distribution Channel, and by Region: Industry Analysis, Market Share, Revenue Opportunity, Competitive Analysis, and Forecast 2020–2027, Market Report, January 2021.
2. M.J. Waring, et al., Nat. Rev. Drug Discov., 14 (7) 475–486 (2015).
3. P. Fasinu, et al., Biopharm. Drug Dispos., 32 (4) 185–209 (2011).
4. J. van der Merwe, et al., Pharmaceutics, 12 (5) 393 (2020).
5. F. Romanski, “Role of Excipients in Amorphous Solid Dispersions,” Solubilizer Symposium (Ludwigshafen, Germany), Oct. 11, 2017.
6. A. Schittny, J. Huwyler, and M. Puchkov, Drug Delivery, 27 (1) 110–127 (2019).
7. V.R. Wilson, et al., Sci. Rep., 10 (Oct.) 18535 (2020).
8. D.M. Mudie, et al, Int. J. Pharm. X, 2 (Dec.) 100042 (2020).
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 45, No. 3
When referring to this article, please cite it as F. Thomas, “Reviewing Recent Bioavailability Research,” Pharmaceutical Technology 45 (3) 2021.