The pharmaceutical landscape is developing continuously, with drug development being becoming increasingly complex due to challenging molecules, accelerated clinical templates and restrictions on existing formulation technologies. This requires an integrated approach for enabled intermediate and drug products that go beyond traditional methods to use innovations and strategic thinking.
Yizheng Cao, main scientist in the Department of Process and Product Development in Serán, gives insights into the challenges in the oral pharmaceutical tax, in drug product design, in innovative formulation strategies, the selection of manufacturing technologies and the solution of solubility and permeability concerns.
Contract machine: What are the most important challenges in the submission of oral drugs that today require new thinking and innovative formulation strategies?
Yizheng Cao: Pharmaceutical developers are now often commissioned with the design of oral products for molecules with low solubility and low permeability, including small molecules, protake, peptides and other challenging molecules. This increasing molecular complexity in conjunction with compressed clinical development time plans requires progressive and robust formulations from the beginning of development.
Contract machine: How did the approach to drug product design develop to tackle these complex molecules and compressed schedules?
Yizheng Cao: Effective development now requires a more comprehensive and integrated approach. At the same time, this means taking into account the design and manufacturing of medicines together with the development of activated intermediate products instead of concentrating exclusively on the intermediate itself. A fundamental understanding of the molecular properties in combination with a strategic plan for drug product design can lead to effective and progressive formulations for even the most demanding drug products. The aim is to develop a commercially relevant, improvable wording in phase I.
Contract machine: Can you specify an example of innovative formulation strategies for connections with poor solubility, especially if conventional methods can have restrictions?
Yizheng Cao: An innovative approach is the tablet formulation “IR+” (immediate release plus). Instead of only relying on amorphous dispersions (ASDS) – a common approach – the IR+ tablet formulates the crystalline API with an acid and precipitation inhibitor. The acid material generates a micro -enclosure micro environment with a low pH value when the tablet dissolves in the stomach, even if the pH value of the mass stomach is high, which improves the resolution of the crystalline API. At the same time, the precipitation inhibitor helps to maintain the oversaturation of the dissolved API in the transmission to the intestine, which leads to high exposure and improved robustness. This simplified wording can reduce costs, time and risks compared to more complex processes such as the ASD production.
Contract machine: If amorphous fixed dispersions (ASDS) are required, what new considerations are there for the selection of manufacturing technologies and how does it affect the drug design?
Yizheng Cao: When ASDS are required, two well-established manufacturing technologies are spray drying (SDD) and hot-melt extrusion (HME). Although both are robust and scalable, their particle properties significantly influence the downstream construction and performance of the drug.
- Spray drying (SDD): Creates small particles with a low density with a high surface. These particles are preferred for quick resolution and high compressibility and can achieve a higher obvious solubility due to the more extensive formation of pharmaceutical polyco colloids. However, their poor flowability often requires a compression process such as dry granulation for the downstream processing, which then improves tablet stability. SDD is gentle on the material and can be used on small standards, which is advantageous in early development.
- Hot melt extrusion (HME): Creates larger, denser particles. These particles typically have a better powder flow, which may make them suitable for direct compression. However, their compressibility and tabletability can be limited, which requires further optimization or lower pharmaceutical pollution in tablets. HME is a process without solvents without solvents, but requires more material for the development and low melting point components with the risk of thermal degradation.
The selection between SDD and HME depends on the specific molecule, program and problem instructions, since no single process is always superior. The advantages and disadvantages for the process throughput, the stability, particle development, bio-action and the drug product design must be carefully taken into account.
Contract machine: What are the emerging challenges and innovative approaches for the development of formulations that require improvement in permeation, especially for larger molecules?
Yizheng Cao: The integrated drug product design deals directly with the considerable permeability problems with complex molecules, especially larger ones such as peptides and protacles. The core idea is to use a comprehensive strategy that takes into account not only the components, but also the processing, manufacture and targeted delivery. Important strategies for overcoming the permeability problems are:
- Intimate mixture and technical process trains: Permation amplifiers have to be mixed closely with the API, sometimes on a molecular level, for an effective interaction with intestinal membranes.
o Spray drying with dry granulation: This process begins to dry a dispersion of the API and the enhancer in order to ensure intimate mixing at the molecular level. A dry granulation step then compresses the resulting powder, which often have poor fluid ability and enables the optional addition of more permeation amplifiers.
o wet granulation: An alternative is to insert peptides and enhancer into a wet granulation process as a solution. This ensures high unity and composition of the elements and creates a mixture with excellent fluid ability, which means that both intimate mixture and improved powder properties are achieved in a single step. These methods help maximize the pharmaceutical pollution in engineering powder properties.
- Simultaneous publication and targeted delivery: Effective permeation is based on the API Personal during a short window when the enhancer interacts with the intestinal membrane.
o Enteric coating: In order to achieve this synchronized and targeted delivery, the Enterische coating is often applied to medicines (capsules or tablets). This pH-solved coating prevents the drug release in the acid stomach and enables a quick and simultaneous release of both the API and the permeation enhancer if the pH value in the intestine increases (e.g. PH 6.8), which is crucial for the maximization of the Permatics Addition.
Diploma
Since new molecular therapies are becoming increasingly complex and accelerating schedules for clinical development, the formulators have to move beyond conventional approaches. This includes the definition of clear problem statements, researching several feasible solutions and the frequently for simplified formulations in which it is possible to reduce risks and costs. Ultimately, the solution to solubility and permeability concerns with regard to the challenging molecules requires creativity and the introduction of new technologies that also take into account performance, manufacturers, stability and patient needs. Ultimately, the optimal drug product uses the simplest technologies that meet both the target profile and the needs of the patient and emphasize a flexible, scalable and commercially relevant design.