Oral drug delivery systems using core-shell structure additive manufacturing technologies: a proof-of-concept study.

OBJECTIVES: The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core-shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment. METHODS: Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets. KEY FINDINGS: Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release. CONCLUSIONS: The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations.

Hot-Melt Extruded Amorphous Solid Dispersion for Solubility, Stability, and Bioavailability Enhancement of Telmisartan.

Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pHM-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pHM-SD formulations by varying the ratio of the drug (TEL, 10-60% w/w), the hydrophilic polymer (Soluplus®, 30-90% w/w), and pH-modifier (sodium carbonate, 0-10% w/w). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (Cmax) and area under the drug concentration-time curve (AUC0-∞) of the TEL pHM-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug's physical stability.

Continuous Manufacturing of Ketoprofen Delayed Release Pellets Using Melt Extrusion Technology: Application of QbD Design Space, Inline Near Infrared, and Inline Pellet Size Analysis.

Delayed-release dosage forms are mainly manufactured as batch processes and include coated tablets, pellets, or particles with gastric resistant polymers. Authors propose a novel approach using the hot-melt extrusion technique to prepare delayed release dosage forms via a continuous manufacturing process, a new trend in the pharmaceutical industry. A full factorial design was employed to correlate input variables, including stearic acid (SA) content, drug content, and pellet size with drug release properties of the pellets. PLS fit method suitably elaborated the relationship between input and output variables with reasonably good fit and goodness of prediction. All three input factors influenced drug release in enzyme-free simulated gastric fluid (SGF) after 120 min; however, SA content did not significantly affect drug dissolution in the enzyme-free simulated intestinal fluid (SIF). An optimized formulation and design space were determined by overlaying multiple contours established from regression equations. The continuous manufacturing process was successfully monitored using inline near-infrared (NIR) and inline particle size analysis, with drug load and pellet size being well-controlled within the design space. The obtained pellets released less than 5% after 120 min in SGF and more than 85% and 95% after 30 min and 45 min, respectively, after switching to SIF.

Hot melt extrusion paired fused deposition modeling 3D printing to develop hydroxypropyl cellulose based floating tablets of cinnarizine.

Three-dimensional printing could serve as a platform to fabricate individualized medicines and complex-structured solid dosage forms. Herein, hot melt extrusion was coupled with 3D printing to develop a unique gastro retentive dosage form to personalize treatment of cinnarizine or other narrow absorption window drugs. The mechanical strength of the extruded strands was optimized for printing by combining two polymers, hydroxypropyl cellulose and vinylpyrrolidone vinyl acetate copolymer. The unit dose, floating force, and release profile were controlled by the printing parameters and object design. The tablets floated immediately within the FaSSGF, and floating force was relatively constant up to 12 h. Drug release followed zero-order kinetics and could be controlled from 6 h to ≥ 12 h. Input variables had a good correlation (R > 0.95) with unit dose, floating force, and dissolution profile (p < 0.05). Authors successfully proposed and tested a new paradigm of individualized medicine fabrication to meet individual patient needs.

Dual mechanism of microenvironmental pH modulation and foam melt extrusion to enhance performance of HPMCAS based amorphous solid dispersion.

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is an excellent polymeric carrier for melt extrusion amorphous solid dispersion. However, its pH-dependent solubility limits its application, especially for narrow absorption window drugs. The current study proposed a novel dual approach of foam extrusion and microenvironmental pH modulation to overcome this limitation. Sodium bicarbonate was used as a blowing agent and the remaining sodium carbonate acted as an internal pH modifier. Compared with conventional extrusion, foam extrusion dramatically lowered the extrudate physical strength (breaking force and hardness decreased by 20-fold; breaking energy and deformation energy decreased by >30-fold). Milling efficiency of foam extrudate was largely improved compared with that of conventional extrudates, demonstrating smaller particle size, larger specific surface area, and ability to pass through a smaller milling screen. The foam extrudate could generate a supersaturation concentration up to 8-fold higher than the solubility of the pure drug. It also significantly enhanced drug dissolution in a two-step biorelevant medium (p < 0.05). This novel approach improved both manufacturing processability and dissolution of HPMCAS-based solid dispersions.

Application of FT-NIR Analysis for In-line and Real-Time Monitoring of Pharmaceutical Hot Melt Extrusion: a Technical Note.

Continuous manufacturing, a gaining interest paradigm in the pharmaceutical industry, requires in-process monitoring of critical process parameters to ensure product consistency. This study demonstrated the application of Fourier transform near-infrared (FT-NIR) spectroscopy in conjunction with chemometrics modeling for in-line hot melt extrusion process monitoring. The obtained results suggested that inline FT-NIR analysis, along with a tailored NIR reflector, is a viable process analytical tool to monitor active pharmaceutical ingredient concentration as well as processing parameters.

Pharmaceutical Additive Manufacturing: a Novel Tool for Complex and Personalized Drug Delivery Systems.

Inter-individual variability is always an issue when treating patients of different races, genders, ages, pharmacogenetics, and pharmacokinetic characteristics. However, the development of novel dosage forms is limited by the huge investments required for production line modifications and dosages diversity. Additive manufacturing (AM) or 3D printing can be a novel alternative solution for the development of controlled release dosages because it can produce personalized or unique dosage forms and more complex drug-release profiles. The primary objective of this manuscript is to review the 3D printing processes that have been used in the pharmaceutical area, including their general aspects, materials, and the operation of each AM technique. Advantages and shortcomings of the technologies are discussed with respect to practice and practical applications. Thus, this review will provide an overview and discussion on advanced pharmaceutical AM technologies, which can be used to produce unique controlled drug delivery systems and personalized dosages for the future of personalized medicine.

Melt extrusion with poorly soluble drugs - An integrated review.

Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly soluble drugs. This review is focused on the recent reports on the solubility enhancement via HME and provides an update for the manufacturing/scaling up aspects of melt extrusion. In addition, drug characterization methods and dissolution studies are discussed. The application of process analytical technology (PAT) tools and use of HME as a continuous manufacturing process may shorten the drug development process; as a result, the latter is becoming the most widely utilized technique in the pharmaceutical industry. The advantages, disadvantages, and practical applications of various PAT tools such as near and mid-infrared, ultraviolet/visible, fluorescence, and Raman spectroscopies are summarized, and the characteristics of other techniques are briefly discussed. Overall, this review also provides an outline for the currently marketed products and analyzes the strengths, weaknesses, opportunities and threats of HME application in the pharmaceutical industry.

Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: Structure and drug release correlation.

The objective of this study was to develop a new approach for fabrication of zero order release of active pharmaceutical ingredients (APIs) using hot-melt extrusion (HME) and 3D printing technology to generate tablets with specific 3D structures. By correlating the geometry of the 3D printed tablets with their dissolution and drug release rates, mathematical models that have been developed to describe drug release mechanisms were also studied. Acetaminophen was used as a model drug, and Benecel™ hydroxypropyl methylcellulose (HPMC) E5 and Soluplus® were used to formulate nine fuse depositional 3D-printed tablets with different inner core fill densities and outside shell thicknesses. This work reports the successful fabrication of solid-dispersion filaments with an API dispersed in HPMC based matrix via HME technology, and the production of zero order controlled release tablets with different 3D structures (tablets #3, 5, 6, and 9) using a 3D printer.

Dual-mechanism gastroretentive drug delivery system loaded with an amorphous solid dispersion prepared by hot-melt extrusion.

In the present study, we aimed to prepare a gastroretentive drug delivery system that would be both highly resistant to gastric emptying via multiple mechanisms and would also potentially induce in situ supersaturation. The bioadhesive floating pellets, loaded with an amorphous solid dispersion, were prepared in a single step of hot-melt extrusion technology. Hydroxypropyl cellulose (Klucel™ MF) and hypromellose (Benecel™ K15M) were used as matrix-forming polymers, and felodipine was used as the model drug. The foam pellets were fabricated based on the expansion of CO2, which was generated from sodium bicarbonate during the melt-extrusion process. A 2n full factorial experimental design was utilized to investigate the effects of formulation compositions to the pellet properties. The melt-extrusion process transformed the crystalline felodipine into an amorphous state that was dispersed and "frozen" in the polymer matrix. All formulations showed high porosity and were able to float immediately, without lag time, on top of gastric fluid, and maintained their buoyancy over 12h. The pellet-specific floating force, which could be as high as 4800µN/g, increased significantly during the first hour, and was relatively stable until 9h. The sodium bicarbonate percentage was found to be most significantly effect to the floating force. The ex vivo bioadhesion force of the pellets to porcine stomach mucosa was approximately 5mN/pellet, which was more than five times higher than the gravitation force of the pellet saturated with water. Drug release was well controlled up to 12h in the sink condition of 0.5% sodium lauryl sulphate in 0.1N HCl. The dissolution at 1, 3, 5, and 8h were 5-12%, 25-45%, 55-80%, and ≥75% respectively for all 11 formulations. In biorelevant dissolution medium, a supersaturated solution was formed, and the concentration was maintained at around 2µg/mL, approximately 10-folds higher than that of the pure felodipine. All input factors significantly affected dissolution in the first 3h, but afterwards, only drug load and hypromellose (HPMC) content had significant effects. The prepared drug delivery system has great potential in overcoming low and fluctuating bioavailability of poorly soluble drugs. CHEMICAL: Felodipine (PubChem CID: 3333); hypromellose (PubChem CID: 57503849), hydroxypropyl cellulose (PubChem CID: 71306830), sodium bicarbonate (PubChem CID: 516892); sodium carbonate (PubChem CID: 10340).

A novel floating controlled release drug delivery system prepared by hot-melt extrusion.

Floating dosage forms are an important formulation strategy for drugs with a narrow absorption window and low intestinal solubility, and for localized gastric treatment. Novel floating pellets were prepared using the hot-melt extrusion (HME) technology. Uniformly foamed strands were created by liquid injection pumping and screw configuration modification. The ammonio methacrylate copolymer (Eudragit® RSPO) foaming structure was formed by a liquid-vapor phase transition inside the strand upon die exiting resulting from the sudden decrease in external pressure, vaporizing the liquid ethanol and vacating the extruded material. This generated uniform vacuous regions in the extrudate. The pellets' internal structure was investigated using scanning electron microscopy (SEM). The formulation constituents' and processing parameters' effects on the drug release profiles, floating force, and the pellets' micromeritic properties were evaluated by design of experiments: all formulations showed zero lag time and excellent floating strength, indicating immediate-floating pellet formation. The pellets' drug release profiles were controlled by multiple independent variables at different time points (⩽ 24 h). Drug loading significantly affected drug release within the first hour, the hydroxypropyl methylcellulose (HPMC) content thereafter. Understanding the variables' effects on the formulations allows for the tailoring of this delivery system to obtain various drug release profiles.