Formulation of nanoparticles encapsulating hydrophilic molecules following their ionic complexation
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Part 1: Dexamethasone is one of the most widely used drug molecules for the treatment of posterior segment ocular diseases. The major problems associated with the delivery of dexamethasone include its poor aqueous solubility and poor permeability into retinal tissues. Hence, we have conceptualized a transporter targeted prodrug approach to deliver dexamethasone to the inner retinal tissue following transscleral/subconjunctival administration. We have successfully synthesized and characterized peptide prodrugs of dexamethasone (valine-valine-dexamethasone and glycine-valine-dexamethasone). The aqueous solubility of both prodrugs was significantly higher than the parent drug. The prodrugs were recognized by peptide transporters present on the apical surface of MDCKII-MDR1 cells. Although, the aqueous solubility of prodrugs was dramatically enhanced, their permeability across sclera and retina-choroid-sclera tissues was not compromised. Development of a sustained release nanoparticulate based formulation of val-val-dexamethasone was challenging due to the leaching of the prodrug into the external aqueous phase during preparation. Hence, a hydrophobic ion pairing (HIP) complexation based approach was employed using dextran sulphate as the complexing polymer. Parameters of HIP complexation were optimized and later nanoparticles were prepared. A dramatic improvement in the encapsulation of prodrug was observed along with sustained release in the synthesized nanoparticles. Part 2: Development of a sustained release nanoparticulate based dosage form for protein therapeutics is a major challenge. These molecules rapidly denature in presence of organic solvents and sonication. Moreover, encapsulation of these molecules in polymeric matrix is poor due to their hydrophilic nature. HIP complexation cannot only enhance their encapsulation in nanoparticles but also confer conformation stability and steric protection to the complexed molecule. We have chosen two model proteins (Lysozyme and bovine serum albumin) and prepared their HIP complexes with dextran sulphate. Parameters for HIP complexation were optimized and protein containing nanoparticles were prepared. A significant enhancement in encapsulation of these molecules was observed in the nanoparticles. Nanoparticles were successfully characterized with respect to size, surface morphology and crystallinity of entrapped protein. The release of protein molecules was significantly sustained from nanoparticles. HIP complexation and method of nanoparticles preparation did not affect the structure (secondary and tertiary structure) and activity of the entrapped protein molecules.
Table of Contents
Literature review -- Part IA: design and evaluation of peptide prodrugs of dexamethasone for treatment of posterior segment ocular diseases. Part IB: development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation -- Introduction -- Design and evaluation of peptide prodrugs of dexamethasone for treatment of posterior segment ocular diseases -- Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation -- Part IIA: design and evaluation of a novel nanoparticulate based formulation containing a HIP complex form of an enzyme: a case study involving lysozyme. Part IIB: encapsulation of protein-polysaccharide HIP complex in polymeric nanoparticles -- Introduciton -- Design and evaluation of a novel nanoparticulate based formulation containing a HIP complex form of an enzyme: a case study involving lysozyme -- Encapsulation of protein-polysaccharide HIP complex in polymeric nanoparticles -- Summary and recommendations