by Cathy Yarbrough
Global drug pipelines contain an “increasing number of low solubility and poor permeability compounds,” David Lyon, Ph.D., Research at Lonza, said when introducing the AAPS webinar, Advances in bioavailability enhancing technologies for poorly soluble molecules: in vitro and in vivo case studies. Lyon presented the webinar on April 16, 2020.
“The industry has worked to solubilize drugs for more than 25 years, resulting in a number of bioavailability enhancing (BAE) technologies,” said Lyon. The need for these advanced delivery technologies continues because scientists are identifying biological targets that require the development of complex molecules with challenging physicochemical properties, he added.
BAE technologies fall into three categories: solid-state alteration such as amorphous solid dispersions (ASDs), crystal size reduction, and polymorphs; high energy crystals including salt forms or co-crystals; and solvation/complexation such as co-solvents, surfactants, cyclodextrins, and lipid-based technologies.
Identifying the optimal BAE technology for a specific active pharmaceutical ingredient (API) is challenging, said Lyon. The adoption of a technology that is not suited to the drug’s properties will increase the cost and time required for product development as well as the risk of product failure.
To select the best solubilization technology, researchers can evaluate multiple technologies in parallel by using an empirical approach. However, this strategy increases the complexity and costs of drug development and does not guarantee success, Lyon pointed out.
The approach followed by Lyon and colleagues is science-based compound qualification and technology mapping. It was developed through the experience of evaluating and advancing thousands of challenging molecules, he said. The goal of compound qualification is to answer the question, “what are the rate limiting steps to drug absorption?” he said. Compound qualification identifies these steps through broad, in-depth evaluation of the drug’s physicochemical properties as well as the potential biological barriers to the drug’s absorption.
Technology maps leverage the large datasets of in vivo information that have been generated about preclinical compounds and the effects of key physicochemical drug properties on oral absorption. Formulation guidance comes from overlaying BAE technologies on 2D drug property maps on lipophilicity vs. solubility. On the map, compounds can lie near the interfaces between multiple technologies. In such cases, Lyon said that experiments with each technology are conducted to determine the optimum one for the compound.
Lyon described spray-dried dispersions (SDDs), an ASD technology that has been incorporated into over 100 marketed drugs. SDDs, which are molecularly dispersed API in a polymer matrix, are designed to generate super saturated drug concentrations upon dissolution. SDDs are created by dissolving the API and the polymer in an organic solvent that is then atomized into a drying chamber. Hot drying gas evaporates the solvent in milliseconds. Due to evaporative cooling, the API’s temperature exposure is mild. Because the amorphous powder properties are tunable, SDDs can be used to produce capsules, tablets, and inhaled dosage forms.
The advantages of spray drying include moderate cost and scalability. For example, Lonza’s spray drying equipment ranges from a lab scale dryer that produces one gram of product to commercial scale dryers that generate tons of product, Dr. Lyon said.
Formulation development that is both rational and efficient uses in vitro and in silico tools to identify and address the rate-determining step(s) to the absorption of an API, Lyon said. To determine the rate-limiting step(s), researchers use dimensionless numbers. These dose/dissolution/permeation numbers are derived from measured or calculated drug properties. For example, the dose number estimates how many gastrointestinal (GI) fluid volumes are required to dissolve the dose.
Dimensionless numbers can provide insight that can guide bioperformance testing strategy, he said. Lonza has advanced fiber optic-based in vitro tools that enable researchers to conduct multiple problem statement-focused tests to ascertain a compound’s amorphous solubility, dissolution rate, and other characteristics that affect bioavailability.
Lyon presented two case studies. The first study focused on the SDDs of the antifungal medication itraconazole (ITZ), a Biopharmaceutics Classification System (BCS) II compound. BCS II refers to low solubility and high permeability compounds. SDDs containing different grades of the hypromellose acetate succinate (HPMCAS) polymer were compared to the ITZ commercial formulation, Sporanox.
With the aid of dimensionless numbers and the Fraction Absorbed Classification System (FaCS), researchers identified solubility and aqueous boundary layer (ABL) permeability as limiting the absorption of ITZ. Through in vitro testing, they determined that ITZ is highly solubilized in micelles and colloids, and that freely dissolved drug concentrations were extremely low. Essentially all solubilized drug was in the form of drug/polymer colloids, Lyon said.
Dr. Lyon said that the study’s key in vitro performance tool was the membrane flux test, which assessed solubility-permeability limited absorption of each SDD formulation. In the test, the researchers added the formulation to a simulated intestinal buffer in the donor compartment. A UV probe was used to monitor the receiver compartment concentration. The test showed that ITZ’s high lipophilicity and a neutral charge state at intestinal pH drove the high lipid membrane permeability, resulting in the ABL limited flux in vitro.
The ITZ SDDs that produced the most drug/polymer colloids upon dissolution provided the highest flux and significantly outperformed the commercial formulation. The calculated flux for each ITZ formulation matched the in vitro and in vivo data. “Knowing that we have the in vitro/in vivo relationship, we can rationally choose a formulation based on the membrane test,” Lyon said.
The second case study focused on maximizing the oral bioavailability of belinostat, which is used in the treatment of peripheral T-cell lymphoma. Like ITZ, belinostat is a BCS Class II compound. Researchers evaluated three SDD formulations of belinostat, each using a different polymer. The SDDs were PVP VA64, PVP K30, and HPMCAS-M. The study, which combined in vivo and in vitro tests with in silico modeling, determined that dissolution was the rate-determining step for oral absorption of belinostat.
The dissolution rate depended on the SDD formulation that was tested as well as the testing method that the researchers used. The in vitro experiment that best indicated in vivo performance was the simulated gastric fluid (SGF)/simulated intestinal fluid (SIF) transfer test. The key aspects of the test were the solvent shift amorphous solubility measurement combined with a fiber optic-based dissolution measurement, Lyon said. The pH transfer test was more effective than the SIF single medium test in predicting belinostat’s in vivo performance, he added.
In vitro tests and in silico modeling revealed differences among the three SDDs and suggested that absorption in the small intestine was limited by the slow dissolution rate or reduced drug activity of PVP VA64 and HPMCAS-M, but not PVP K30 SDDs. The drug concentration achieved in the stomach prior to transit down the GI tract was key to maximizing in vivo performance in dogs. The PVP K30 SDD matched the bioavailability of the oral solution in the dogs.
Lyon concluded by emphasizing that in vivo and in silico tools are essential to drug development, driving pharmaceutical researchers “to continue to develop an understanding of how to characterize and use in vitro data to achieve supersaturating BAE formulations.
“With careful considerations for in vitro test methodology and design, we can transition from every compound being a ‘research project’ to a platform-minded in vitro approach for BAE formulations,” he said. The transition can be achieved through a mechanistic understanding of bioperformance from BAE formulations independent of platform technology.
Cathy Yarbrough is a science writer who can be reached at www.cathyyarbrough.wordpress.com