A new formulation comprising nanogels conjugated with insulin molecules (NG-In) has been developed to be used for Alzheimer Disease (AD) therapy. Nanogels (NGs) are an emerging class of nanocarriers characterized by water-swollen, nanosized three-dimensional networks. The family of synthetized nanogels is characterized by a lightly crosslinked structure, based on poly (N-vinyl pyrrolidone), and multiple functionalities including carboxylic and primary amino groups.
Beside the soft and conformable 3D structure, their manufacturing process is particularly appealing, since it makes recourse to e-beam irradiation of aqueous solutions of the polymer, that is the same process with the same radiation doses that can be applied for sterilization. The synthesis does not require catalysts, organic solvents or surfactants, and yields to fairly monodisperse, gel nanocolloids that are easy to purify and remarkably stable upon storage, both as aqueous colloids and freeze-dried powders. The experimental conditions of the process have been optimized to control the nanogel dimensions (ca. 80 nm) and to obtain “permanent” conjugation of insulin to the nanoparticles through an amide bond. The specific features of both the production process and the product are particularly suitable for their industrial scale-up.
The new NG-In formulation allows the insulin conjugated to the nanogel to reach the brain in a biologically active form, when intra-nasally administered, and at higher doses than those obtained with free insulin. This result is obtained by enhanced absorption by the nasal mucosa and by the protective effect exerted on the protein by the nanocarrier from endogenous protease degradation. Clearance of the NG-In from the body has been demonstrated on animal model.
The existing NG-In formulation can be further developed by conjugation of directing molecules (specific ligands) and/or antioxidants that can enhance the delivery time and therapeutic activity. An alternative, patentable, material platform is also under development.
The principal innovative aspects are:
1) the e-beam processing is an easy and reproducible technique that permits to obtain high-yield in sterility conditions (essential points for an industrial scale production in biomedical field);
2) versatility and multifunctionality of the developed nanoparticles especially for biomedical applications;
3) originality due to the absence on the pharmaceutical market of a system that permits the delivery of the insulin to the brain;
4) administration through an intranasal spray that permits the delivery of the protein to the brain thus bypassing the systemic route e its undesirable side effects.
This kind of pharmaceutical formulation is not yet present on the market