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QUALITY BY DESIGN APPROACH TO DEVELOP 3D INTEGRATED PHARMACEUTICALS FOR PERSONALIZED MEDICINE
thesisposted on 31.01.2022, 15:38 authored by Mario Alberto Cano-VegaMario Alberto Cano-Vega
The advent of Patient-Centric therapy demands technologies capable of producing multiple versions of a given product, each tailored for specific segments of the population/individual, but in a time- and cost-effective manner. Prevailing manufacturing methods for oral dosage forms do not easily lend themselves for the transition to the Patient-Centric area. The purpose of this research was to develop a formulation/manufacturing platform technology meeting the flexibility requirements for Patient-Centric formulation and product development for oral dosage forms. The approach is based on the molecular designing and manufacturing of the dosage form. The dosage form consists of a 3D assembly of prefabricated functional modules, each with a specific pharmaceutical performance function.
The characterization of individual modules showed that solvent casting produced API-loaded HPMC films with homogeneous content distribution. The release profile of 3D assemblies was significantly influenced by the physicochemical properties of single modules. API-loading, thickness, and diameter had a significant effect on the release kinetics. In contrast, the hydrophobicity of the casting substrate did not affect the release kinetics. The initial geometry of the final 3D assembly given by the number of modules and their diameter was proved to have a significant impact on the release kinetics as well.
The 3D assemblies were used to produce dosage forms with customizable release profiles. Two API-loaded thin HPMC-based films with fast (FRA) and slow (SRB) release rates were produced by the solvent casting method. Accurate dose control (API loading) was accomplished by varying the number of individual modules in the 3D assemblies, whereas control of release kinetics was achieved by combining different ratios FRA and SRB film modules in the assembled dosage form.
The modular design was also tested for its ability to generate a dosage form of a weak-base API. This part was accomplished using a module containing citric acid (CA) interspaced between weak-base loaded FRA modules. Characterization of the 3D assemblies that were devoid of CA modules showed that the API release rate from modular assemblies containing weekly basic API exhibited strong pH-dependence. The 3D assemblies featuring CA modules in their design exhibited nearly pH-independent release kinetics.
Electrospinning was used as an enabling technology to produce HPMC-based fibrous films. HPMC films were able to encapsulate a wide variety of APIs with different aqueous solubility. All fibers produced were in the range of a few hundred nanometers to a few microns. X-ray diffraction and differential scanning calorimetry exhibited the amorphous or crystalline state of the API dispersed. Disintegration and release tests showed the fast dissolution of the fibrous system.