Drug Substance Modification
Approximately 70% of the NCE's fall under the BCS class II and are poorly water soluble.
Nano suspensions, particle engineering and composite particles: Nano suspensions have been used to develop fast dissolve dosage forms as well as to prepare particle engineered composite particles that can be compressed into conventional (bioavailability enhanced) tablets. The composite particles are prepared with the end in mind to increase bioavailability of poorly soluble drugs e.g. fenofibrate.
Nanocrystals
The drug delivery challenge for poorly water-soluble compounds can be addressed via multiple formulation approaches that have different underlying mechanisms of solubility modification. The most 'tried and tested' method is particle size reduction, often to the low micron-size range using the micronization process. This approach works on the basis that a reduction in particle size increases the surface area and in turn the dissolution rate of poorly soluble particles. Unfortunately, micronization can be insufficient for those compounds with extreme solubility limitations and so more powerful approaches are often required.
In recent years, particle size reduction approaches have advanced into the sub-micron particle size region, i.e. 1-1000 nanometer range. Opinions vary as to which size can correctly be called "nano", but in the context of oral delivery, we often describe oral nanoparticle delivery as follows:
"the application of advanced size reduction methods to achieve a physically stable and deliverable dispersion of particles in the sub-micron range."
The theory that size reduction increases surface area and dissolution still applies to the advanced size reduction methods, and entry into the sub-micron range produces huge increases in the surface area of drug. As a result, the dissolution rate pay-off can be very large. Added benefits of oral nanoparticle delivery for poorly water-soluble drugs can include elimination of a food-effect on bioavailability, and the drug substance remains in its original and most chemically-stable solid form.
Nanoparticles may be delivered orally as a liquid nanosuspension or as a solid dosage form. Stabilization of nanoparticles in the solid-state is typically achieved by spray drying or freeze-drying, with the technical requirement being a unit dose that can readily resuspend the nanoparticles to the starting particle size. The 'nano' category is the subject of extensive drug delivery research, and so we can expect further advances in how nanoparticles can be formed, stabilized and delivered in the near future.
Hot Melt Extrudates
Drugs intended for oral applications must dissolve to be absorbed through the gut in such a way so as to generate adequate drug levels at the pharmacologically active site. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations. Therefore, the improvement of drug solubility and thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral drug delivery systems.
The dissolution rate can be increased by increasing the surface area, e.g. via micronization, by decreasing the diffusional layer thickness through improving the wettability, e.g. via surfactants, and by altering the solubility of the drug.
Twin-screw melt-extrusion, with controlled pressure, heat and shear stress, is a powerful way for separating the molecules of the active ingredient from each other and distributing them in the matrix homogenously. Since the carrier used is usually amorphous, the active ingredient is incorporated either in a crystalline state or an amorphous state or it can be molecularly dissolved. The most reliable and stable system is achieved, when the drug is molecularly dissolved below the saturation solubility. The formulation then dissolves in gastric or intestinal fluids to form a supersaturated solution of the drug, thus enhancing dissolution and bioavailability.
Spray Dried Dispersion
Drugs that fall into the Class II category, according to the BCS nomenclature, are defined as having high permeability and inherently low solubility. This low solubility leads to poor bioavailability due to less drug being available for absorption. The formulation scientist has the ability to overcome poor bioavailability due to low solubility of the active ingredient by creating a spray dried solid dispersion.
Solid dispersions through the spray drying process are created by dissolving the active ingredient, a dispersant (generally a polymer), and any other desired excipients in an organic solvent. The solution is then sprayed (atomized) into a heated chamber where the organic solvent is evaporated off leaving an amorphous powder to be collected and further processed if desired. The higher energy state of the amorphous powder results in faster dissolution and higher solubility. The formulation scientist can alter several characteristics of the powder (e.g., density, particle size, and morphology) to achieve the desired dissolution profile by manipulating certain parameters such as solvent type, ingredient concentration, spray rate, and inlet/outlet temperature.
Spray dried dispersion is a fast, cost-effective, and scalable method of manufacturing amorphous particles to overcome low solubility issues associated with low bioavailability.