Can you tell us what Bioavailability Enhancement is – and why it has become such an important topic in the pharmaceutical industry?
Two of the most important pieces of information that are typically collected for each active pharmaceutical ingredient (API) are its ability to dissolve when dosed to a patient, and its ability to permeate across the gut wall into the blood. These data can then be used to classify the molecule according to both the Biopharmaceutics Classification System (BCS) and Developability Classification System (DCS). It is estimated that only a small proportion — less than 10% — of the molecules in the development pipeline have both adequate solubility (dose-solubility ratio > 500 ml) and permeability (> 1 x 10-4 cm/sec) to achieve good (>90%) bioavailability.1 Solubility can be addressed during both API form selection and during drug delivery technology selection. During API development, solubility and stability can be improved by molecule engineering - optimizing the physical form of a drug molecule’s salt, co-crystals, and polymorphs. In addition, solubility can change when purity changes.
The DCS helps to determine the optimal drug delivery technology,2 and classifies a molecule based on its dose-solubility ratio and effective permeability, and its position on the DCS plot will help guide the formulator on which drug delivery technologies are most likely to give a successful oral product.
The position in the DCS grid will determine the optimal starting point to choose formulation options. Those in Class I (good solubility and permeability) have a relatively straightforward development path where a solution, suspension, tablet, capsule and even injectable will work; the choice will hinge on what is likely to be most acceptable to patients, is cost effective, and whether there are any other factors that would discount a particular technology (like incompatibility).
What are some traditional methods for enhancing bioavailability? Have they fallen out of favor? Why are so many pharma companies looking towards newer technologies to optimize their products?
As the number of new molecular entities coming out of discovery which exhibit poor solubility rises, developers are looking to formulation technology to overcome this issue. Traditionally, developers would look to solubility enhancing excipients, such as surfactants, to improve dissolution. If simple blend excipients do not provide the necessary solubility, more conventional, yet proven techniques, such as micronization and wet and hot-melt granulation are explored. However, when such traditional technologies do not work, developers must look to more advanced techniques, such as lipid-based delivery and amorphous dispersions, to increase solubility. The identification of a suitable formulation is not a trivial exercise, and choosing a more advanced type of formulation will, inevitably, extend timelines and increase the complexity of the development process. This is why these options should be employed only when there are no other suitable alternatives. However, advanced formulation technologies can be very powerful tools to increase solubility and bioavailability. And when formulation enhancement is necessary, to solve suboptimal pharmacokinetics of lead compounds – where the main challenge is the solubility of molecules – investing early on in identifying an advanced formulation technology leads to cost and time savings by avoiding rework, program delays, or worse, shelving the molecule’s development due to poor clinical performance at a later phase.
Can you tell us about some of Catalent’s latest technologies for bioavailability enhancement? Are they designed to work with specific types of products? Can they be applied to both new products under development – or to enhance and extend the life of older products?
Each molecule is unique, and no one technology offers a onesize fits all solution, and Catalent has a broad range of enabling technologies, and the expertise to support developments. Our advanced bioavailability enhancement technologies include salt form screening, Micron particle size engineering, Pharmatek® SD spray drying technology, OptiMelt® Hot Melt Extrusion, and lipid-based formulations with RP Scherer Softgel technologies.
We have developed platform screening protocols to help quickly and inexpensively collect the data needed and, based on our deep expertise, determine which approaches are most suitable and which molecules have inherent issues that need to be resolved. To enhance collaborative scientific development between Catalent, its customers and partners, we have created a new Science and Technology function to accelerate the development of drug products through the use of advanced formulation and drug delivery technologies. This team of dedicated, seasoned development scientists can help customers identify challenges and opportunities for their candidates, and understand what drug delivery technologies can and cannot do, and to help them identify the right solution faster.
What do companies need to know when they are looking to enhance the bioavailability of existing products? Are there regulatory concerns? Product testing concerns? How can Catalent help a company efficiently test and market a product with enhanced bioavailability?
Most technologies used to enhance bioavailability require additional levels of characterization and product testing. For example, spray dried dispersions (SDD) are produced by spraying solutions of the active ingredient in solvents such as acetone or tetrahydofuran. Given the high volumes of solvent used in the process, the potential for residual solvent species in the SDDs is not insignificant. Therefore, SDDs require specialized equipment, such a gas chromatography, and additional method development and testing to ensure residual solvent levels are safe. Additionally, given the inherent nature of amorphous material, amorphous dispersion products must be tested for long-term stability to confirm the material does not recrystallize over time. Catalent offers comprehensive and deep capabilities for characterization, method development, and product testing to ensure successful development of enabled formulations.
Looking toward the future – will bioavailability enhancement become a normal part of drug development and optimization processes? Do you see more pharmaceutical companies looking for the expertise of a company like Catalent to broaden the market appeal and enhance products?
As more new molecule entities coming out of research present solubility limitations, the need for bioavailability enhancement will increase and become a normal part of development. This creates a primary need for technologies and expertise that can recognize and address bioavailability issues. The ability of a partner to develop and manufacture a stable and scalable finished dosage form goes beyond having access to these advanced technologies. Newer technologies might prove successful in preclinical testing, but have limited scalability beyond the bench. Technological expertise is needed to provide a safe drug delivery platform that also provides some opportunity for customization. Understanding how a formulation technology impacts the finished dose becomes important as the molecule transitions from early to late phase development. The experience in taking a molecule from candidate selection to market, with comprehensive characterization, solid state chemistry and formulation science, process development and scale-up, manufacturing capabilities is important for successful development and directly impact the desirable reproducibility and quality of final product. More than ever before, drug companies are reaching out to contract research, development and manufacturing partners for help.
Catalent has gained significant practical experience across many products and with many different customers of all sizes, and is known for having supported the commercial launch of products utilizing its bioavailability enhancement technologies. The company is also engaged in many more preclinical and clinical programs with smaller companies, where the attrition rate is higher. Any company that has a bigger pipeline, will benefit from a “pipeline hindsight” – experience from prior programs – and it may be in a better position to inform those companies at the earlier stages of development as to what data to collect, and how best to interpret any discrepancies that are seen.
References
- Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010; 99: 4940-54.
- Hauss, David “Oral Lipid-based Formulations: Addressing an Urgent Industrial Need”, New Jersey Centre for Biomaterials www.njbiomaterials.org/NJCB_Files/File/Skin%20 Workshop/5.%20Hauss_Presentation.pdf