The Evolving Landscape: Cutting-Edge Approaches for Difficult-to-Deliver Molecules

The pharmaceutical landscape is continuously evolving, with drug development becoming increasingly complex due to challenging molecules, accelerated clinical timelines, and limitations of existing formulation technologies. This necessitates an integrated approach to enabled intermediates and drug product design, moving beyond traditional methods to embrace innovation and strategic thinking.

Yizheng Cao, Principal Scientist in the Process and Product Development department at Serán, shares insight on challenges in oral drug delivery, drug product design, innovative formulation strategies, selecting manufacturing technologies, and resolving solubility and permeability concerns.

Contract Pharma: What are the primary challenges in oral drug delivery that necessitate new thinking and innovative formulation strategies today?

Yizheng Cao: Drug developers are now frequently tasked with designing oral products for molecules with low solubility and low permeability, including small molecules, PROTACs, peptides, and other challenging molecules. This increasing molecular complexity, coupled with compressed clinical development timelines, demands advanceable and robust formulations right from the start of development.

Contract Pharma: How has the approach to drug product design evolved to address these complex molecules and compressed timelines?

Yizheng Cao: Effective development now requires a more comprehensive and integrated approach. This means simultaneously considering drug product design and manufacturability along with the development of enabled intermediates, rather than solely focusing on the intermediate itself. A fundamental understanding of molecular properties combined with a strategic plan for drug product design can lead to effective and advanceable formulations for even the most challenging drug products. The goal is to develop a commercially relevant, advanceable formulation as early as Phase I.

Contract Pharma: Can you provide an example of innovative formulation strategies for compounds with poor solubility, particularly when traditional methods might have limitations?

Yizheng Cao: One innovative approach is the “IR+” (immediate release plus) tablet formulation. Instead of solely relying on amorphous solid dispersions (ASDs) – a common approach – the IR+ tablet formulates the crystalline API with an acidulant and a precipitation inhibitor. The acidulant creates a low pH microenvironment when the tablet disintegrates in the stomach, even if the bulk gastric pH is high, thereby improving the dissolution of the crystalline API. Simultaneously, the precipitation inhibitor helps maintain supersaturation of the dissolved API as it transfers to the intestine, leading to high exposure and enhanced robustness. This simplified formulation can reduce costs, time, and risks compared to more complex processes like ASD manufacturing.

Contract Pharma: When amorphous solid dispersions (ASDs) are necessary, what new considerations are there for selecting manufacturing technologies, and how do they impact drug product design?

Yizheng Cao: When ASDs are required, two well-established manufacturing technologies are spray drying (SDD) and hot melt extrusion (HME). While both are robust and scalable, their particle properties significantly influence downstream drug product design and performance.

• Spray Drying (SDD): Generates small, low-density particles with a high surface area. These particles are favored for rapid dissolution, high compressibility, and can achieve higher apparent solubility due to more extensive formation of drug-polymer colloids. However, their poor flowability often requires a densification process like dry granulation for downstream processing, which then improves tabletability. SDD is material-sparing and can be used at small scales, advantageous in early development.
• Hot Melt Extrusion (HME): Produces larger, denser particles. These particles typically exhibit better powder flow, making them potentially suitable for direct compression. However, their compressibility and tabletability may be limited, requiring further optimization or a lower drug loading in tablets. HME is a solvent-less process but requires more material for development and low-melting point components, with a risk of thermal degradation.

The choice between SDD and HME depends on the specific molecule, program, and problem statement, as no single process is always superior; the pros and cons for process throughput, stability, particle engineering, bioperformance, and drug product design must be carefully considered.

Contract Pharma: What are the emerging challenges and innovative approaches for developing formulations that require permeation enhancement, especially for larger molecules?

Yizheng Cao: Integrated drug product design directly addresses the significant permeability challenges encountered with complex molecules, particularly larger ones like peptides and PROTACs. The core idea is to employ a comprehensive strategy that considers not just the components, but also their processing, manufacturability, and targeted delivery. Key strategies for overcoming permeability challenges include:

• Intimate Mixing and Engineered Process Trains: Permeation enhancers need to be intimately mixed with the API, sometimes at a molecular level, for effective interaction with intestinal membranes.

o   Spray Drying with Dry Granulation: This process begins by spray drying a dispersion of the API and enhancer, ensuring intimate mixing at a molecular level. Subsequently, a dry granulation step densifies the resulting powders, which often have poor flowability, and allows for the optional addition of more permeation enhancers.

o   Wet Granulation: An alternative is to introduce peptides and enhancers as a solution into a wet granulation process. This ensures high uniformity and composition of the elements and produces a blend with excellent flowability, achieving both intimate mixing and improved powder properties in a single step. These methods help engineer powder properties to maximize drug loading.

• Simultaneous Release and Targeted Delivery: Effective permeation relies on the API permeating during a short window when the enhancer interacts with the intestinal membrane.

o   Enteric Coating: To achieve this synchronized and targeted delivery, enteric coating is often applied to drug products (capsules or tablets). This pH-triggered coating prevents drug release in the acidic stomach and allows for a rapid and simultaneous release of both the API and the permeation enhancer when the pH elevates in the intestine (e.g., pH 6.8), which is crucial for maximizing permeation enhancement.

Conclusion
As new molecular therapies become increasingly complex and clinical development timelines accelerate, formulators must move beyond conventional approaches. This involves defining clear problem statements, exploring multiple feasible solutions, and often opting for simplified formulations where it is possible to reduce risks and costs. Ultimately, resolving solubility and permeability concerns of challenging molecules demands creativity and the adoption of new technologies that simultaneously consider performance, manufacturability, stability, and patient needs. Ultimately, the optimal drug product uses the simplest technologies that meet both the target product profile and the patient’s needs, emphasizing a flexible, scalable, and commercially relevant design.