Overcoming poor solubility in formulation development
Dr. Julien Meissonnier, Pharmaceutical Softgel Europe, Catalent looks at lipid-based formulations to increase the bioavailability of poorly soluble drugs.
Poor solubility remains an ongoing challenge in formulation development. The number of poorly soluble compounds is estimated to be 40% of molecules on the market, however, more than 70% of drugs in development are classified as poorly soluble.1,2
There are a number of existing technologies and approaches available to overcome this challenge, as well as several emerging solutions. One of the most established approaches is to create a crystalline formulation of the drug, however, the size of a drug particle is critical to its bioavailability. Particle size engineering, and increasing surface area by creating micro-crystals and nano-crystals using techniques such as jet or ball milling crystalline drugs along with a surfactant, is one method used to increase solubility, and therefore bioavailability.
Crystalline drugs that are poorly soluble in water may dissolve in lipids. Adding emulsifiers creates a semi-solid oil or paste that then self-emulsifies into a micro-emulsion or nano-emulsion when taken orally (self-emulsifying drug delivery systems or SEDDS). These formulations can be readily made into softgels or capsules, which have numerous patient experience benefits, as well as formulation benefits of ensuring dose uniformity and offering an established scale-up route.
A successful lipid formulation must first resist its dispersion in the gastrointestinal (GI) fluids by maintaining the drug in solution. Upon dispersion, the formulation could be present in different states, ranging from coarse emulsions to thermodynamically stable microemulsions, which present different features. After the lipid components of the formulation are subjected to the action of enzymes, which act specifically at the oil/water interface, the lipids undergo de-esterification into fatty acids and partial glycerides. Upon digestion, it is important to ensure that the poorly soluble drug remains in solution form before facing the enterocytes within the GI tract.
SEDDS and self-microemulsifying drug-delivery systems (SMEDDS) are categorised on an effective classification system for lipid-based formulations3 based upon their qualitative and quantitative composition. Each of the four categories within the system exhibit different behaviours upon dispersion and digestion based upon their hydrophobic-hydrophilic excipient composition.
As with any formulation development project, once a lipid-based delivery approach has been selected, working towards a target product profile (TPP) defines the parameters which any drug candidate must meet. Formulation-specific analytical techniques must be developed and refined to enable access to a more complete and accurate dataset from as early as possible in the process.
Pre-formulation studies must be based upon the kinetic evaluation of drug solubility in various classes of ingredients, in parallel with chemical compatibility screens. Catalent operates proprietary in-vitro and in-silico models, including a computerised database of digestion profiles, and also pseudo-ternary diagrams based upon its experience in lipid-based system development. This simulation and modelling approach minimises the amount of potentially valuable API that needs to be used, and improves the efficiency of formulation determination as well as predictability to progress in further clinical studies.
The excipient selection process is also based upon careful selection of the ingredients in light of their global approvability and existing safety status. A wide variety of lipid ingredients are generally recognised as safe and several studies are underway on novel functional lipids to broaden their existing safety data to increase the number of options open in formulation.
A notable success of applying SMEDDS to an existing therapy is with oral cyclosporine where a lipid-based formulation has revolutionised organ transplant therapies. After overcoming challenges in development, the microemulsion delivery is perfectly suited to enhancing exposure to the API, while resolving variability issues and food effects. Being thermodynamically stable by definition, SEDDS and SMEDDS are much less sensitive to change in physiological conditions such as food intake, bile salts, and pH, and are particularly suitable for drugs with narrow therapeutic windows. These requisites, however, do not apply to all TPPs where simpler, fast-to-develop lipid systems would be suitable.
There are many benefits of using lipid-based drug-delivery systems to assist in the delivery of poorly soluble drugs and bringing better treatments to the market, especially that the technology addresses both physiochemical and biological bioavailability barriers. Lipid-based formulations do not have the associated challenges of some of the current solubility enhancing technologies, which can lead to longer development timelines because of increased incompatibilities, complex scale-up, and clinical acceptability. Using a rational approach in preformulation operations with liquid systems not only enables accelerated predictability of drug/ingredient interactions but also, with the use of in-vitro and in-silico development tools, assists in tailoring the optimum lipid formulation system and increasing predictability of in-vivo performance.