Design and encapsulation of complex lipid based dispersions for oral delivery of active (macro) molecules

De Kruif, Jan Kendall. Design and encapsulation of complex lipid based dispersions for oral delivery of active (macro) molecules. 2015, PhD Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12007


Lipid-based (LB) formulations are versatile systems that can solubilise poorly water-soluble drugs, but also work as dispersing medium for hydrophilic formulation components. Dispersed particles can consist of more complex structures. Interesting is the dispersion of water-based microgels in LB systems to create hydrophilic compartments within a non-aqueous medium, suitable for direct capsule filling. Such systems represent a suitable milieu for protein microencapsulation to ensure protection from degradation of these macromolecules. In fact, while oral macromolecule delivery is a thriving topic in modern pharmaceutics, the first challenge is to achieve a stable drug product throughout manufacturing. Owing to the structured and complex nature of such system, a thorough characterisation is needed to gain adequate understanding of the system. Identification of critical material attributes and process parameters is key in the framework of the Quality-by-Design (QbD) initiative. The purpose of this thesis is to formulate novel LB systems suitable for capsule filling that allow oral delivery of proteins and small molecules.
The present thesis consists of four studies. The first two introduce new manufacturing approaches for protein microencapsulation using LB systems as carrying medium for oral delivery. The third and fourth studies address manufacturing criticalities of LB systems using macromolecules and small molecules as active ingredients, respectively. A special focus is kept on the development aspects of these systems by using statistical methods to design quality into the novel drugs delivery formulations.
The first study focused on the feasibility of protein microencapsulation by prilling into a LB hardening bath. Here, prilling was applied by dropping a protein-containing polymeric solution into a LB hardening bath where cross-linking occurred. Bovine serum albumin (BSA) and a chitosan derivate were used as a model protein and a polyfunctional gel-forming polymer, respectively. The hardening bath was loaded with calcium ions to allow ionotropic gelling of the polymer. Particle morphology and size were dependent on the LB hardening bath used. The microgels had high protein encapsulation efficiency and were able to rapidly release their content during in vitro dissolution testing. Additionally, the model protein remained unscathed throughout the entire manufacturing process and during preliminary stability studies in the LB hardening baths. Overall this approach demonstrated the technical viability of LB systems to act as hardening bath for the prilling process and simultaneously as dispersing medium for the thereby formed microgels to achieve liquid capsule filling.
The second study focused on improving the previously introduced LB drug delivery systems (DDS). The aim was to achieve a multi-compartmental system composed of protein-containing nanotubes embedded into the microgels obtained by prilling. To increase protein loading by better fitting the large model protein, i.e., BSA, the nanotubes’ lumen was chemically enlarged. The obtained Nanoparticles-in-Microsphere Oral System (NiMOS) showed hardening bath-dependent morphology and good protein entrapment efficiency. Protein stability during the process was confirmed. Furthermore, the proposed NiMOS demonstrated protection from enzymatic degradation after preliminary in vitro testing. Also, the multi-compartmental structure extended the protein release profile. This study showed the feasibility of this flexible multi-compartment system for oral protein delivery.
The third study investigated systematically LB formulations as hardening baths for prilling using Design of Experiments (DoE). Over 880 formulations were screened with respect to miscibility, counter-ion solubility, and droplet gelling by using 60 ternary phase diagrams comprising two co-solvents, ten different glycerides, and three so-called complementary excipients. Soft and hard capsules were filled with 245 selected hardening bath formulations for a preliminary compatibility assessment. The ternary phase diagrams’ centre points were statistically evaluated to understand the formulation effect on microgel morphology, protein encapsulation efficiency, and protein stability. The large datasets were analysed by means of partial least squares (PLS) regression to correlate the formulation and experimental factors with the chosen response variables. This work generated an improved understanding for this type of LB systems.
Finally, a fourth study introduced novel tools within the QbD initiative to evaluate complex LB dispersions such as highly concentrated suspensions. The surface energy of the particles intended for suspension was profiled using inverse gas chromatography to understand the heterogeneity in energy distribution. This was correlated to different inter-batch rheological properties at higher solid fractions after LB suspension manufacturing. A mathematical model was then used to predict experimental viscosity values as a function of suspended solid fraction. The agglomeration patterns of the manufactured suspensions were interpreted using the fractal concept of flocculation. This concept as well as the surface energy profiling showed great potential for designing quality into concentrated pharmaceutical suspensions.
This thesis introduced new complex LB systems suitable for oral delivery of proteins and small molecules. Novel formulations approaches have been investigated and developed within a QbD framework. A particular emphasis was on microgel dispersions in lipids for oral (local) protein delivery. The technical viability of this delivery approach was demonstrated on the level of manufacturing and in vitro release testing. Future research may include in vivo studies to understand and improve the biopharmaceutical performance of the proposed LB DDS, as well as a thorough mechanistic investigation for these complex LB formulations.
Advisors:Imanidis, Georgios and Borchard, Gerrit
Item Type:Thesis
Thesis no:12007
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (vii, 125 Seiten)
Identification Number:
Last Modified:13 Feb 2017 10:30
Deposited On:13 Feb 2017 10:29

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