Low aqueous solubility is one major problem associated with formulation development of new chemical entities, as well as for generic drug development. In fact, an estimated 40% of approved drugs and nearly 90% of the developmental pipeline drugs consist of poorly soluble molecules.1 Selecting the proper contract development and manufacturing organization (CDMO) can help pharma companies overcome the inherent challenges associated with these drugs.
Solubility is the phenomenon of dissolution of solute in solvent to give a homogenous system. The reason it’s such an important parameter is that it is critical to obtain the desired concentration of a drug in systemic circulation for the anticipated pharmacological response. Current approaches for improving solubility include chemical modification, salt form selection, solid dispersions, complex formation, lipid concentrate, and particle size reduction.
Some drug developers are looking for effective and efficient methods to mitigate poor solubility and bioavailability. Other pharma companies will decide to re-formulate their existing product candidates. Regardless of the chosen path, the destination is clear and vital – discover novel bioavailability and solubility enhancement methods.
To achieve success, pharma companies need to partner with the right CDMO based on a few criteria. For one, the right affiliate has an experienced team that can formulate to the specific molecule. This group of experts develops and implements a three-step approach customized for the project that:
1) Assesses the compound’s physical and chemical properties
2) Evaluates the drug and its intended target site
3) Recognizes the drug’s uptake
In addition to formulation strategies, the CDMO team needs to understand particle size reduction, solid dispersion, and lipid-based approaches. These are all key factors when working with small molecules.
A CDMO with a process to develop a specific formulation strategy is another key factor. It helps pharma companies best achieve success in overcoming small-molecule solubility and bioavailability challenges. An organization whose experienced team works in a culture of utilizing multiple technologies will establish a drug development process that results in the most effective final product within budget and on schedule.
Ascendia’s Amorsol Amorphous Solid Dispersion
Technology.
Multiple formulation technologies that address each compound’s unique properties are warranted to achieve a successful outcome of the animal toxicity and human clinical trials for each compound. Ascendia has three patented IP technologies that address poor solubility and bioavailability:
1) NanoSol is for the production of nano-sized drug particles. Formulation of a drug substance in nano-particle form significantly increases the surface area available for dissolution. In fact, a 10-20 fold increase in surface area can be realized by reducing particle size from a micronized drug substance to one that is nanonized.
2) AmorSol is an amorphous solid dispersion technology that greatly improves solubility and dissolution kinetics. It enables pharmaceutical products with enhanced bioavailability, reduced food effect, and more rapid onset-of-action. AmorSol utilizes spray drying, hot-melting extrusion or solvent evaporation to prepare solid dispersion.
3) EmulSol is for production of oil-in-water or water in oil nano-emulsions. Ascendia produces nano-emulsions using a unique high-shear homogenization process that uses no organic co-solvents, and a minimal amount of surfactant excipients. It can greatly reduce the irritation and injection site pain for a parenterally delivered product.
For example, a nano-emulsion can be used to develop a topical formulation with superior clarity and bioavailability properties. In addition, nano-emulsions can be dehydrated and incorporated into solid oral dosage forms.
That is why a specialty CDMO that offers tailored formulation solutions such as those offered by Ascendia will ensure a rapid, successful transition of compounds from preclinical to the clinic. A CDMO that understands rational design of dosage forms based on compound properties, possesses different technologies to address varied compound challenges, and offers flexibility in terms of time and deliverables is an ideal formulation partner.
Ascendia took this approach recently with a pharma company. The client wanted to develop a human formulation for an insoluble small molecule and supply GMP CTM for human clinical trials within 4-5 months. Previously, the company had worked with another CDMO to explore human formulation. It proved to be unsuccessful, however, in large part because a single technology was used.
The compound under development was classified as BCS II (low solubility and high permeability). That meant it had no pKa, logP of ~5.6 and a melting point of ~130° C. Its aqueous solubility was an extremely low <0.2 micron/mL. The result was that the crystalline form’s bioavailability in animal models was <4% and a significant food effect was observed.
Based on the assessment of the compound properties and the tight timeline, NanoSol, Emulsol, and AmorSol were simultaneously utilized for formulation screening and in vitro assessment. Ascendia was able to obtain a human formulation with an enhanced bioavailability and a reduced food effect while remaining on schedule.
Three prototype formulations (one from each technology) were developed and tested in animal models. Within three months of project initiation 3-, 5-, and 10-fold enhancements in bioavailability were respectively achieved. All the goals stated by the pharma company at project initiation were met using the Ascendia process.
Contact us today to discuss how we can partner with you to solve your bioavailability and solubility challenges.
Resource:
1https://www.sciencedirect.com/science/article/pii/S2211383515001069