(T1030-04-24) A Simple and Facile Platform for Semi-Solid Extrusion of Different Formulations Containing a Drug-Loaded Mesoporous Material

Purpose: Poorly soluble drugs are common in the pharmaceutical industry, but their bioavailability is limited. This can be improved by converting them to their amorphous form. Methods to amorphize drugs include solid dispersion, complexation, particle size reduction, and amorphization within mesoporous materials’ pores. Mesoporous materials loaded with drugs can also be used in 3D printing to create personalized formulations, and recent research has shown that drug-loaded mesoporous material formulations printed via Fused Deposition Modelling (FDM) can achieve tunable release kinetics and supersaturation of the drug [1]. However, the range of polymers that can be used with FDM is limited due to mechanical properties of the filaments, and therefore alternative methods of 3D printing drug-loaded mesoporous materials are desirable. Semi-solid extrusion is an alternative method, and it has been previously used to create hydrogel films containing drug-loaded mesoporous silica [2].

In this study, Mesoporous Magnesium Carbonate (MMC) was loaded with Ibuprofen and mixed with PEG to form a paste for semi-solid extrusion. The paste was then used to create tablets for oral administration and suppositories for rectal administration. The hybrid approach presented in this study provides a simple and convenient platform for developing drug delivery devices for poorly soluble drugs via semi-solid extrusion, aimed at different routes of administration. The approach is aimed at increasing the bioavailability of poorly soluble drugs while maintaining the stability of the system over time.

Methods: The drug loading of Ibuprofen into the pores of MMC was performed via gas sorption. Subsequently, the loaded particles were examined via gas sorption to assess the successful loading and also to indirectly measure the loading degree. Differential scanning calorimetry (DSC) was conducted to affirm the amorphization of the drug within the mesoporous material. Thermogravimetric analysis (TGA) was used to indirectly measure the drug loading degree. The drug-loaded MMC was mixed with PEG-400 in different ratios until the formation of uniform pastes and their rheological behavior was investigated. For printing of suppositories and tablets, a modified Tool Changer and Motion system (E3D-online Ltd, Chalgrove, United Kingdom) was equipped with a syringe pump. Finally, in vitro drug dissolution studies in biorelevant media, i.e., Simulated Gastric Fluid (SGF), pH 1.2, and Phosphate Buffer (PB), pH 7.4, for the tablets and the suppositories, respectively, were performed to show the drug release from the 3D printed formulations and compared with the crystalline drug.

Results: Through gas sorption measurements the successful loading of ibuprofen in the pores of MMC was confirmed. The loading degree was calculated at 91.5% v/v, corresponding to a 28.5% w/w drug loading. DSC thermograms exhibited the successful amorphization of ibuprofen in MMC due to an absence of the melting point. TGA was utilized to indirectly measure the drug loading degree, which was calculated to be 25.8% w/w. A series of different ratios between unloaded MMC and drug loaded MMC mixed with PEG were tested for their rheological behaviors in order to acquire the optimal paste for extrusion. It was noticed that pure MMC with PEG resulted in more viscous and less flowable pastes compared to drug loaded MMC with PEG at the same ratios. This is attributed to adsorption of PEG in the empty pores of MMC as its hydrodynamic radius allows for it. Hence, the lubrication effect of PEG is diminished, resulting in a non-extrudable paste. The phenomenon is not as apparent in loaded MMC as the available empty pore volume is considerably less. Specifically, unloaded MMC/PEG 40/60 presents a similar behavior as loaded MMC/PEG 50/50. The loaded MMC/PEG 60/40 paste was found to be the optimal one, and the paste seems to exhibit shear thinning behavior, probably due to the PEG component, which is a sought-after property for a successful extrusion printing. The different pastes are represented in Image 1, with the loaded MMC/PEG 60/40 having the highest viscosity and shape stability. Loaded pastes of 70/30 and unloaded pastes of 50/50 ratio were non-extrudable and were not measured. The printed suppository samples weigh ~2.2g carrying approximately 370 mg of ibuprofen. In vitro dissolution results indicate the successful drug release from the formulation within 60 minutes (Image 2). The tablet samples weigh ~640mg and contain approximately 107mg of the drug. The drug release behavior from these samples is significantly improved compared to the crystalline drug, due to the drug being amorphized within the pores of the MMC.

Conclusion: The study shows the feasibility of a simple hybrid 3D printed system, comprising drug loaded MMC to develop different drug formulations for different administration routes. The poorly soluble drug can be loaded within the MMC pores and become amorphous thus enhancing its apparent solubility. A direct comparison of the dissolution behavior of each of the developed formulations with the crystalline drug, in the respective biorelevant media, has been conducted, which demonstrates the ability of this approach to produce drug delivery devices tailored to specific administration routes.

References: 1. Katsiotis CS, Åhlén M, Strømme M, Welch K. 3D-Printed Mesoporous Carrier System for Delivery of Poorly Soluble Drugs. Pharmaceutics. 2021;13:1096.
2. Schmidt LM, dos Santos J, de Oliveira TV, Funk NL, Petzhold CL, Benvenutti EV, et al. Drug-loaded mesoporous silica on carboxymethyl cellulose hydrogel: Development of innovative 3D printed hydrophilic films. International Journal of Pharmaceutics. 2022;620:121750.

Viscosity measurements for pastes of; drug loaded MMC with PEG at ratios of 50:50 and 60:40 and unloaded MMC with PEG at a ratio of 40:60.

In vitro % drug release of the printed formulations compared to the crystalline drug. A- Suppository formulation and crystalline drug performed in P.B., pH 7.4. B- Tablet formulation and crystalline drug performed in SGF, pH 1.2.