Studies On Novel Oral Controlled-release Drug Delivery Systems Using Three-dimensional Printing

Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts directly from CAD (computer-aided design) models, and can handle features such as special exterior shapes, complex inner structures and so on. It has the advantages of easy process, fast prototyping, and low cost and high reproducibility. Because of breaking through some limitations of conventional formulation techniques, 3DP can offer novel strategies and approaches for the research and development of novel oral controlled-release drug delivery systems (DDS). The applications of 3DP in pharmaceutics have drawn more and more attentions.In this dissertation, many novel DDS have been conceived and fabricated using 3DP. The DDS have special design features to furnish the desired drug release profiles, which deliver the drug in a safe, efficient and convenient way. The features include special inner structures, local differences of materials and compositions, geometry, special surface texture, gradient or discrete distributions of the release-modulation materials (or active ingredients), accurate positioning and distribution of multi-drugs in the same DDS, and any combinations of these. The resulted DDS have been evaluated through routine analysis, observation of structure and surface characteristics, in vitro dissolution tests and so on. The prototyping process, the binding mechanisms of DDS, the selection and optimization of the process conditions have also been preliminary investigated.(1) The limitations of conventional technologies for preparing oral controlled-release drug delivery systems have been summarized. 3DP and its application in pharmaceutics have been introduced. It is expected that 3DP can offer new strategies and approaches for the research and development of novel oral drug delivery systems because of its outstanding manufacturing capability.(2) Compared with the tablets made by conventional direct compression method and wet granulation method, 3DP tablets showed some advantages, such as having uniform inner structure, highly drug dispersiblility, accurate dosage; reproducible and stable drug release profile, easy and highly automatic fabricating process and so on.(3) The influence of different prototyping parameters such as release-modulation powder materials, binder liquid, printing passes of binder liquid, thickness of powder layer, the designed diameters of central holes on the drug release profiles were investigated by in vitro dissolution tests. The results demonstrated that 3DP had superior preparing flexibility.The binder mechanism and its influence on the tablets'mechanical performance were investigated. Hydroxypropylmethylcellulose (HPMC), acetaminophen (ATP) and lactose were premixed and used as the layered powder, while ethanol, water, and their mixture were employed as binder liquids. The dissolution time of different powders and the volatilization rate of different binder solutions from the layered powder were determined, which were useful for the reasonable selection of particles'dimensions and interval times between two printing layers. The amount of dispensing binder liquid could be modulated by manipulating the printing passes. The values of tablets'hardness and friability under different amount of binder liquid were determined. Environmental scanning electron microscopy (ESEM) was employed to observe the binding state of particles. The reason for the alteration of mechanical performance and the relative binder mechanism was illustrated. These studies offered suitable methods for the selection of printing parameters related to the printing amount of binder solution, such as printing passes, layer thickness, line-to-line spacing, drop-todrop spacing and so on.(4) Three kinds of novel oral zero-order controlled release DDS have been fabricated using 3DP:①DDS with gradient distributions of drug and partial release-retardation surface. Routine analysis, structure analysis and in vitro dissolution results showed that the pharmaceutical properties of the DDS met the relavent standards, drug release from the axial direction was totally retarded, drug distributed according to a radial gradient increasing manner from the circumference to the center.②DDS with with gradient distributions of release-retarded materials and special surface texture. The DDS were prepared by pre-mixing the drug with the excipients and then bound together by depositing the binder liquids containing release-retardation-materials instead of printing drug-contained binder solutions. The release-retardation capabilities in HPMC matrix tablets for ethyl cellulose (EC),sodium lauryl sulfate (SLS),stearic acid (SA),Eudragit RSPO were also studied respectively.③DDS with partial-coating and donut-shape. Over 95% of the model drug ATP was released from the peripheral and inner hole surface in zero-order kinetics via erosion mechanism. The EC release-retarding layers on both sides in the axial direction were strongly bound with the drug-contained core, resulting in sustaining release-retardation effects in the whole dissolution process. The total release time of ATP could be modulated by the annular thickness and printing passes of release-retardation-material-contained binder liquids respectively. The dosage of ATP could be modulated by the annular height separately.(5) Three kinds of novel oral site-specific DDS have been fabricated using 3DP:①Fast-disintegrating helicid tablets with unbound powder in the central core. Routine analysis, disintegrating time limit, structure observation and in vitro dissolution results showed that the tablet technical performance met the related ordainments of Chinese pharmacopoeia. The dosage of loaded drug was accurate with the content deviation among tablets of±1.1%. Helicid could be dissolved out very quickly with the disintegrating time of 19.8 s and the exhausting time in vitro of 2 minutes;②Metformin hydrochloride floating DDS with complex structure features and local material and composition difference. The tablets had good buoyancy when put into the dissolution medium. The results achieved by a self-made buoyancy meter, which was reconstructed from an electronic scale, showed that the tablets could keep enough buoyancy force in the whole dissolution process. Dissolution results in vitro indicated that metformin hydrochloride was released from the tablets in zero-order kinetics for 10 hours;③Colon-targeted DDS with complex structure features. Dissolution results in vitro indicated that the target effects had the following sequence: Eudragit S100 >Eudragit L100 >HPMCP (Hydroxypropylmethyl Cellulose phthalate), when these materials were employed in the fabrication of tablets. The target effect of water insoluble drug diclofenac sodium was better than that of the water freely soluble drug chlorphenamine maleate when they were incorporated into the tablets.(6) Time-specific DDS with drug only in the center were prepared using 3DP. The initial release time was controlled by the peripheral region. Dissolution results in vitro showed that the drug release had good time-lag effect, and that the lag time could be modulated by the channeling agent's diameter, content and the dispensing times of binder liquid.Multi-phasic helicid DDS with multi-layer structure and difference of material and composition among layers were fabricated using 3DP. Different release profiles were combined together. The drug was released in a bi-phasic manner, i.e. first in pulse manner and then in zero-order manner. Dissolution results in vitro indicated that 51.64% of the drug was released in the mock gastric juice in pulse manner in the former 2 hours, and the left drug was completely released in the mock gut juice in zero-order manner in the later 11 hours.