Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan Shunmugaperumal. Читать онлайн. Newlib. NEWLIB.NET

Автор: Tamilvanan Shunmugaperumal
Издательство: John Wiley & Sons Limited
Серия:
Жанр произведения: Химия
Год издания: 0
isbn: 9781119585251
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oligos or siRNA are water soluble due to their polyanionic character, the aqueous solution of these compounds need to be added directly to the o/w cationic nanosized emulsion in order to interact electrostatically with the cationic emulsion droplets and thus associate/link superficially at the oil–water interface of the emulsion (Teixeira et al. 1999; Tamilvanan 2004; Hagigit et al. 2010). During in vivo condition when administered via parenteral and ocular routes, the release of the DNA and oligos from the associated emulsion droplet surfaces should therefore initially be dependent solely on the affinity between the physiological anions of the biological fluid and cationic surface of the emulsion droplets. The mono‐ and di‐valent anions containing biological fluid available in parenteral route is plasma and in ocular topical route is tear fluid, aqueous humor, and vitreous. Moreover, these biofluids contain multitude of macromolecules and nucleases. There is a possibility that endogenous negatively charged biofluid's components could dissociate the DNA and oligos from cationic emulsion. It is noteworthy to conduct during the preformulation development stages an in vitro release study for therapeutic DNA and oligos‐containing cationic nanoemulsion in these biological fluids and this type of study could be considered as an indicator for the strength of the interaction occurred between DNA or oligo and the emulsion (Hagigit et al. 2008). Interestingly, the stability of oligos (a 17‐base oligonucleotide, partially phosphorothioated) was validated using a gel‐electrophoresis method. After incorporating the oligos into the cationic nanosized emulsion as well as during in vitro experiments of oligos‐containing emulsion in vitreous fluid at different time periods, the emulsions were phase separated by Triton X‐100 and then the degradation of oligos was also monitored following the same validated gel‐electrophoresis method (Hagigit et al. 2008). No appearance of new band was seen in comparison to the standard aqueous oligos solution. This result indicates that the oligos did not undergo degradation against the conditions applied to prepare a sterile emulsion.

Schematic illustration of typical steps involved for the new drug products during their formulation development stage as per the quality by design approach of formulation by design.

      This traditional framework has certain drawbacks. Any minor changes made in input materials and processes (including equipment) for anticipated variability are empirical and addressed via the OFAT experimental approach. This development practice is not cost‐effective and results in incomplete product and process understandings, which in turn leads to restrictive (or fixed) manufacturing processes that are unable to compensate for the regular variability in input materials, processes, manufacturing equipment, and laboratory instrumentation (Debevec et al. 2018). As mentioned earlier, the QbT approach also requires extensive testing to comply with restrictive FDA‐approved specifications (Yu 2008).

      The need for transition from traditional QbT to an enhanced approach was formally communicated through an ICH Q8 guidance published in May 2006, which emphasized that “quality cannot be tested into products, rather it should be built into products by design” (FDA Guidance for Industry 2006).

      These innovative frameworks are fully reflected in current regulatory guidance on QbD and PAT [FDA Guidance for Industry 2004; ICH Q8(R2) guideline 2009] and are encouraged for industry practice.

      Both QbD and PAT share common goals of providing a rapid and science‐ and risk‐based road map for product development and economically effective strategies for process monitoring and analytical testing. The QbD strategy involves an end‐to‐end integration of six key elements, which are quality target product profile (QTPP), risk assessments related to process and product design, DOEs, design space, control