INJECTION MOLDING/MICROMOLDING APPLICATIONS TO DRUG DELIVERY

In the present work the application potential of injection molding (IM) and micromolding (\ub5IM) for the manufacturing of drug products was investigated. These techniques are largely employed in the plastics industry to process thermoplastic polymers into objects with different size, shape and possibly many details, and they could offer several advantages in the pharmaceutical area, mainly related to versatility, patentability, scalability and production costs (continuous manufacturing). Processes and equipment generally employed as well as current pharmaceutical applications already proposed in the literature were preliminarily reviewed. Drug delivery systems (DDSs) in the form of gastro-resistant containers based on HPMCAS were afterwards designed and manufactured by \ub5IM. Notably, such DDSs represent a step forward in the field as they may provide a ready-to-use alternative to enteric-coated dosage forms. Moreover, the feasibility by hot-processing techniques (hot melt extrusion and IM) of prolonged-release hydrophilic matrices and immediate release tablets was demonstrated, which could help promoting the use of continuous manufacturing in the pharmaceutical production areas

Gastroresistant capsular device prepared by injection molding

In the present work, the possibility of manufacturing by injection molding (IM) a gastro-resistant capsular device based on hydroxypropyl methyl cellulose acetate succinate (HPMCAS) was investigated. By performing as an enteric soluble container, such a device may provide a basis for the development of advantageous alternatives to coated dosage forms. Preliminarily, the processability of the selected thermoplastic polymer was evaluated, and the need for a plasticizer (polyethylene glycol 1500) in order to counterbalance the glassy nature of the molded items was assessed. However, some critical issues related to the physical/mechanical stability (shrinkage and warpage) and opening time of the device after the pH change were highlighted. Accordingly, an in-depth formulation study was carried out taking into account differing release modifiers potentially useful for enhancing the dissolution/disintegration rate of the capsular device at intestinal pH values. Capsule prototypes with thickness of 600 and 900 \u3bcm containing Kollicoat\uae IR and/or Explotab\uae CLV could be manufactured, and a promising performance was achieved with appropriate gastric resistance in pH 1.2 medium and break-up in pH 6.8 within 1 h. These results would support the design of a dedicated mold for the development of a scalable manufacturing process

3D printed multi-compartment capsular devices for two-pulse oral drug delivery

In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200\u3bcm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range

Evaluation of Hot-Melt Extrusion and Injection Molding for Continuous Manufacturing of Immediate-Release Tablets

The exploitation of hot-melt extrusion and injection molding for the manufacturing of immediate-release (IR) tablets was preliminarily investigated in view of their special suitability for continuous manufacturing, which represents a current goal of pharmaceutical production because of its possible advantages in terms of improved sustainability. Tablet-forming agents were initially screened based on processability by single-screw extruder and micromolding machine as well as disintegration/dissolution behavior of extruded/molded prototypes. Various polymers, such as low-viscosity hydroxypropylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, various sodium starch glycolate grades (e.g., Explotab\uae CLV) that could be processed with no need for technological aids, except for a plasticizer, were identified. Furthermore, the feasibility of both extruded and molded IR tablets from low-viscosity hydroxypropylcellulose or Explotab\uae CLV was assessed. Explotab\uae CLV, in particular, showed thermoplastic properties and a very good aptitude as a tablet-forming agent, starting from which disintegrating tablets were successfully obtained by either techniques. Prototypes containing a poorly soluble model drug (furosemide), based on both a simple formulation (Explotab\uae CLV and water/glycerol as plasticizers) and formulations including dissolution/disintegration adjuvants (soluble and effervescent excipients) were shown to fulfill the USP 37 dissolution requirements for furosemide tablets

In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit (R) L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A gamma-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the blood-stream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems

Retentive device for intravesical drug delivery based on water-induced shape memory response of poly(vinyl alcohol): design concept and 4D printing feasibility

The use of shape memory polymers exhibiting water-induced shape recovery at body temperature and water solubility was proposed for the development of indwelling devices for intravesical drug delivery. These could be administered via catheter in a suitable temporary shape, retained in the bladder for a programmed period of time by recovery of the original shape and eliminated with urine following dissolution/erosion. Hot melt extrusion and fused deposition modeling 3D printing were employed as the manufacturing techniques, the latter resulting in 4D printing because of the shape modifications undergone by the printed item over time. Pharmaceutical-grade poly(vinyl alcohol) was selected based on its hot-processability, availability in different molecular weights and on preliminary data showing water-induced shape memory behavior. Specimens having various original and temporary geometries as well as compositions, successfully obtained, were characterized by differential scanning calorimetry and dynamic-mechanical thermal analysis as well as for fluid uptake, mass loss, shape recovery and release behavior. The samples exhibited the desired ability to recover the original shape, consistent in kinetics with the relevant thermo-mechanical properties, and concomitant prolonged release of a tracer. Although preliminary in scope, this study indicated the viability of the proposed approach to the design of retentive intravesical delivery systems

Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling

Fused deposition modeling (FDM) is a 3D printing technique based on the deposition of successive layers of thermoplastic materials following their softening/melting. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment. Accordingly, a number of polymers of common use in pharmaceutical formulation were evaluated as starting materials for fabrication via hot melt extrusion of filaments suitable for FDM processes. By using a twin-screw extruder, filaments based on insoluble (ethylcellulose, Eudragit\uae RL), promptly soluble (polyethylene oxide, Kollicoat\uae IR), enteric soluble (Eudragit\uae L, hydroxypropyl methylcellulose acetate succinate) and swellable/erodible (hydrophilic cellulose derivatives, polyvinyl alcohol, Soluplus\uae) polymers were successfully produced, and the possibility of employing them for printing 600 \u3bcm thick disks was demonstrated. The behavior of disks as barriers when in contact with aqueous fluids was shown consistent with the functional application of the relevant polymeric components. The produced filaments were thus considered potentially suitable for printing capsules and coating layers for immediate or modified release, and, when loaded with active ingredients, any type of dosage forms