Erodible drug delivery systems for time-controlled release into the gastrointestinal tract

In oral delivery, lag phases of programmable duration that precede drug release may be advantageous in a number of instances, e.g. to meet chronotherapeutic needs or pursue colonic delivery. Systems that give rise to characteristic lag phases in their release profiles, i.e. intended for time-controlled release, are generally composed of a drug-containing core and a functional polymeric barrier. According to the nature of the polymer, the latter may delay the onset of drug release by acting as a rupturable, permeable or erodible boundary layer. Erodible systems are mostly based on water swellable polymers, such as hydrophilic cellulose ethers, and the release of the incorporated drug is deferred through the progressive hydration and erosion of the polymeric barrier upon contact with aqueous fluids. The extent of delay depends on the employed polymer, particularly on its viscosity grade, and on the thickness of the layer applied. The manufacturing technique may also have an impact on the performance of such systems. Double-compression and spray-coating have mainly been used, resulting in differing technical issues and release outcomes. In this article, an update on delivery systems based on erodible polymer barriers (coatings, shells) for time-controlled release is presented

Erodible time-dependent colon delivery systems with improved efficiency in delaying the onset of drug release

To prepare swellable/erodible time-dependent colon delivery systems with improved efficiency in delaying drug release, the application of an outer Eudragit\uae NE film, which contained the superdisintegrant Explotab\uae V17 as a pore former, was attempted. Tablet cores were successively spray-coated with a hydroxypropyl methylcellulose (HPMC) solution and diluted Eudragit\uae NE 30 D, wherein fixed amounts of Explotab\uae V17 were present. The resulting two-layer systems yielded lag phases of extended duration as compared with formulations provided with the HPMC layer only. By raising the thickness of the outer film, longer lag times were generally observed, whereas the effectiveness in deferring the drug liberation was reduced by increasing the pore former content, which, however, also resulted in a lower data variability. The films containing 20% of Explotab\uae V17 effectively and consistently prolonged the in vitro lag phase imparted by HPMC as a function of their thickness. Stored for 3 years under ambient conditions, a two-layer system with this outer film composition pointed out unmodified release patterns. The same system proved to meet gastroresistance criteria when enteric coated. The results obtained indicated that the proposed strategy would enable the preparation of erodible delivery systems with reduced size, possibly suitable as multiple-unit dosage forms

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

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

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

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

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

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

Fatal systemic toxoplasmosis in a 3-month-old young tibetan goat (Capra hircus)

Background: Toxoplasmosis is one of the most common parasitic infections in both humans and animals. It is a frequent cause of abortion and stillbirth in intermediate hosts, especially sheep and goats but rarely causes fatal clinical form in adult animals. Case presentation: In contrast, the study reports an unusual fatal case of toxoplasmosis in a young goat naturally infected with type II strain of Toxoplasma gondii. A three-month-old female goat was presented with dyspnea and died few days later. Grossly, lungs were firm, edematous and mottled with disseminated whitish areas. Generalized lymphadenopathy was found. The histopathological examination showed necrotic interstitial bronchopneumonia and necrotizing lymphadenitis with intralesional free and clustered within macrophages tachyzoites of T. gondii. DNA extracted from lungs and lymph nodes was positive for T. gondii by a fast qPCR. PCR-RFLP analysis and sequencing of GRA6 gene showed that the isolated strains belonged to type II genotype. Conclusions: This is an unusual report of acute systemic toxoplasmosis caused by the type II strain of T. gondii with a fatal outcome in a young goat