ABSTRACT
Beyond the therapeutic purpose, the impact of drug delivery microparticles on the local tissue and inflammatory responses remains to be further elucidated specifically for reactions mediated by the host immune cells. Such immediate and prolonged reactions may adversely influence the release efficacy and intended therapeutic pathway. The lack of suitable in vitro platforms limits our ability to gain insight into the nature of immune responses at a single cell level. In order to establish an in vitro 3D system mimicking the connective host tissue counterpart, we utilized reproducible, compressed, rat-tail collagen polymerized matrices. THP1 cells (human acute monocytic leukaemia cells) differentiated into macrophage-like cells were chosen as cell model and their functionality was retained in the dense rat-tail collagen matrix. Placebo microparticles were later combined in the immune cell seeded system during collagen polymerization and secreted pro-inflammatory factors: TNFα and IL-8 were used as immune response readout (ELISA). Our data showed an elevated TNFα and IL-8 secretion by macrophage THP1 cells indicating that Placebo microparticles trigger certain immune cell responses under 3D in vivo like conditions. Furthermore, we have shown that the system is sensitive to measure the differences in THP1 macrophage pro-inflammatory responses to Active Pharmaceutical Ingredient (API) microparticles with different API release kinetics. We have successfully developed a tissue-like, advanced, in vitro system enabling selective "readouts" of specific responses of immune-related cells. Such system may provide the basis of an advanced toolbox enabling systemic evaluation and prediction of in vivo microparticle reactions on human immune-related cells.
Subject(s)
Collagen/chemistry , Drug Carriers , Animals , Cell Line , Humans , Lactic Acid , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Reproducibility of Results , RheologyABSTRACT
The aim of this study was to investigate coating characteristics of push-pull osmotic systems (PPOS) using three-dimensional terahertz pulsed imaging (3D-TPI) and to detect physical alterations potentially impacting the drug release. The terahertz time-domain reflection signal was used to obtain information on both the spatial distribution of the coating thickness and the coating internal physical mapping. The results showed that (i) the thickness distribution of PPOS coating can be non-destructively analysed using 3D-TPI and (ii) internal physical alterations impacting the drug release kinetics were detectable by using the terahertz time-domain signal. Based on the results, the potential benefits of implementing 3D-TPI as quality control analytical tool were discussed.
Subject(s)
Delayed-Action Preparations/chemistry , Terahertz Imaging/methods , Imaging, Three-Dimensional/methods , Kinetics , Osmosis , Solubility , Surface Properties , Tablets/chemistry , Technology, PharmaceuticalABSTRACT
The number of marketed oral osmotically driven systems (OODS) has doubled in the last 10 years. The main clinical benefits of OODS are their ability to improve treatment tolerability and patient compliance. These advantages are mainly driven by the capacity to deliver drugs in a sustained manner, independent of the drug chemical properties, of the patient's physiological factors or concomitant food intake. However, access to these technologies has been restricted by the crowded patent landscape and manufacturing challenges. In this review article, we intend to give an overview of the OODS development in the last 30 years, detailing the technologies, specific products and their clinical use. General guidance on technology selection is described in light of the recent advances in the field. The clinical performance of these technologies is also discussed, with a focus on food effects and the in vivo-in vitro correlation. Special attention is paid to safety given the controversial case study of Osmosin. Overall, oral osmotically driven systems appear to be a promising technology for product life-cycle strategies.
Subject(s)
Drug Delivery Systems/methods , Pharmaceutical Preparations/administration & dosage , Technology, Pharmaceutical/methods , Administration, Oral , Chemistry, Pharmaceutical , Delayed-Action Preparations , Drug Delivery Systems/trends , Drug-Related Side Effects and Adverse Reactions , Humans , Indomethacin/administration & dosage , Infusion Pumps/trends , Osmotic Pressure , Technology, Pharmaceutical/trendsABSTRACT
Despite more than 30 years of clinical use, only few studies have been published reporting on the release mechanism underlying the drug delivery from push-pull osmotic pumps (PPOP). The aim of this study is to understand which factors have an effect on the drug delivery for modelling the drug release and to develop a mathematical model predictive of the drug release kinetics. The influence of the drug property was tested on two model drugs, isradipine (ISR) and chlorpheniramine (CPA) which are respectively practically insoluble and freely soluble. Results show that, regardless of the drug properties which do not significantly affect the drug delivery, the release kinetics is mainly controlled by four factors, (i) the PEG proportion in the membrane, (ii) the tablet surface area, (iii) the osmotic agent proportion and (iv) the drug layer polymer grade. The influence of each key formulation factors on the release mechanism was investigated defining their applicability range. A mathematical approach was developed to predict the drug delivery kinetics varying the PPOP controlling factors and helps to more efficiently design PPOP.
Subject(s)
Drug Compounding/methods , Drug Delivery Systems/methods , Osmosis , Tablets/pharmacokinetics , Chlorpheniramine/pharmacokinetics , Isradipine/pharmacokinetics , Models, Statistical , Polyethylene Glycols/pharmacokineticsABSTRACT
Push-pull osmotic systems have been developed to deliver poorly soluble drugs in a modified-release fashion. The aim of this study was to investigate the influence of the tablet core factors on the drug release kinetics and loadability. The release kinetics was efficiently modulated by varying either the proportion of osmotic agent or the drug layer polymer grade as an alternative to change the membrane characteristics. High osmotic agent proportions and viscous-grade polymers were recommended to formulate high drug loads up to 20% without losing both the release completeness and the zero-order drug release kinetics.
Subject(s)
Calcium Channel Blockers/administration & dosage , Isradipine/administration & dosage , Technology, Pharmaceutical/methods , Calcium Channel Blockers/chemistry , Chemistry, Pharmaceutical , Delayed-Action Preparations , Drug Compounding , Drug Delivery Systems , Drug Stability , Equipment Design , Excipients/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate , Hydrogen-Ion Concentration , Isradipine/chemistry , Kinetics , Osmotic Pressure , Polyethylene Glycols/chemistry , Solubility , TabletsABSTRACT
The mechanism of drug release from push-pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push-pull osmotic systems, which enable a more efficient optimization of such formulations.
