Nowadays, the pharmaceutical industry is facing an issue of poor aqueous solubility of drug. About 40% of the developing drugs and 60% of the directly synthesized drugs are poorly soluble in water. A poorly-aqueous-soluble drug shows poor bioavailability and high variable biological performance, especially administered through oral route, which is the most convenient and comfortable route of drug administration. Thus, a large amount of dose intake is wasted. Nanomization via high pressure homogenization is a technique that is versatile and has potential of processing those drugs to enhance their bioavailability. The principle of bioavailability enhancement by nanomization is based on the improvement of dissolution rate by size reduction. However, our literature research revealed that th...[ Read more ]

Nowadays, the pharmaceutical industry is facing an issue of poor aqueous solubility of drug. About 40% of the developing drugs and 60% of the directly synthesized drugs are poorly soluble in water. A poorly-aqueous-soluble drug shows poor bioavailability and high variable biological performance, especially administered through oral route, which is the most convenient and comfortable route of drug administration. Thus, a large amount of dose intake is wasted. Nanomization via high pressure homogenization is a technique that is versatile and has potential of processing those drugs to enhance their bioavailability. The principle of bioavailability enhancement by nanomization is based on the improvement of dissolution rate by size reduction. However, our literature research revealed that there is a lack of information of formulation and process optimization methods for the nanomization of oral administration drug via high pressure homogenization technique, and the existing methods are not designed for oral administration drug to get the best drug bioavailability and bioactivity. In addition, it is common that the research only focuses on the bioavailability enhancement of drug, but the discussion of the ability of nanomization on enhancing the true bioactivity is limited. Therefore, the objective of this thesis is to develop a method for formulating poorly-aqueous-soluble drug in nanodispersible solid form for oral administration by using high pressure homogenization technique, and optimization of the process is also the goal of this thesis in order to get high product stability, bioavailability and bioactivity.

A drug formulation method of nanomization via high pressure homogenization has been successfully developed. It involved the nanoemulsion formation, followed by a spray cooling and freeze drying processes to remove the liquid contents of the nanoemulsion and the formation of nanodispersible solids. The strategy on maximizing benefits of bioavailability and bioactivity enhancements from nanomization had two main points. Firstly, it was important to control the factors affecting the particle size during the nanomization process in order to optimize the particle size to the desire size range. Secondly, the long-term stability of nanodispersible solid was crucial for the product to retain the desired particle size throughout the route of oral administration. It could be achieved by the selection of suitable type and concentration of polymeric agent that gives good protection to resist aggregation and low reactivity during the route of oral administration. Schisandrin B (Sch B), an active ingredient of a traditional Chinese herb with poorly-aqueous-solubility, was nanomized as nanodispersible solids which disperse rapidly in water. The mean particle size of Sch B in both nanoemulsion and redispersion of nanodispersible solid were optimized to a size range of 30 to 50 nm.

Finally, the enhancement in bioavailability and bioactivity of nanomized Sch B was demonstrated by three bioassays. The bioavailability enhancement was shown by the 2.8 times relative bioavailability of nanomized Sch B (45 nm mean particle size), as compared to the coarse Sch B, in a preliminary pharmacokinetics study. Glutathione regeneration capacity (GRC) measurement from rat organ tissues revealed that nanomized Sch B (45 nm mean particle size) had a 2 fold higher drug potency than the coarse Sch B, which demonstrated the ability of nanomization on bioactivity enhancement in the whole body condition. The mean particle size of the nanomized drug had been verified to be a critical factor for the bioactivity enhancement because smaller particles preformed better due to the more efficient absorptive transport and higher net accumulation in the intestinal cells. The results of bioassays are useful as evidence to prove the developed nanomization method was effective on the bioavailability and bioactivity enhancement of poorly-aqueous-soluble drug for oral administration.