Inkjet printing of a thermolabile model drug onto FDM-printed substrates: formulation and evaluation.

OBJECTIVE: The inkjet printing (IP) and fused deposition modeling (FDM) technologies have emerged in the pharmaceutical field as novel and personalized formulation approaches. Specific manufacturing factors must be considered in each adopted methodology, i.e. the development of suitable substrates for IP and the incorporation of highly thermostable active pharmaceutical compounds (APIs) for FDM. In this study, IP and FDM printing technologies were investigated for the fabrication of hydroxypropyl methylcellulose-based mucoadhesive films for the buccal delivery of a thermolabile model drug. Significance: This proof-of-concept approach was expected to provide an alternative formulation methodology for personalized mucoadhesive buccal films. METHODS: Mucoadhesive substrates were prepared by FDM and were subjected to sequential IP of an ibuprofen-loaded liquid ink. The interactions between these processes and the performance of the films were evaluated by various analytical and spectroscopic techniques, as well as by in vitro and ex vivo studies. RESULTS: The model drug was efficiently deposited by sequential IP passes onto the FDM-printed substrates. Significant variations were revealed on the morphological, physicochemical and mechanical properties of the prepared films, and linked to the number of IP passes. The mechanism of drug release, the mucoadhesion and the permeation of the drug through the buccal epithelium were evaluated, in view of the extent of ink deposition onto the buccal films, as well as the distribution of the API. CONCLUSIONS: The presented methodology provided a proof-of-concept formulation approach for the development of personalized mucoadhesive films.

Polymer-Lipid Microparticles for Pulmonary Delivery.

Toward engineering approaches that are designed to optimize the particle size, morphology, and mucoadhesion behavior of the particulate component of inhaler formulations, this paper presents the preparation, physicochemical characterization, and preliminary in vitro evaluation of multicomponent polymer-lipid systems that are based on "spray-drying engineered" α-lactose monohydrate microparticles. The formulations combine an active (budesonide) with a lung surfactant (dipalmitoylphosphatidylcholine) and with materials that are known for their desirable effects on morphology (polyvinyl alcohol), aerosolization (l-leucine), and mucoadhesion (chitosan). The effect of the composition of formulations on the morphology, distribution, and in vitro mucoadhesion profiles is presented along with "Calu-3 cell monolayers" data that indicate good cytocompatibility and also with simulated-lung-fluid data that are consistent with the therapeutically useful release of budesonide.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy.

PURPOSE: Tumor cell heterogeneity and microenvironment represent major hindering factors in the clinical setting toward achieving the desired selectivity and specificity to malignant tissues for molecularly targeted cancer therapeutics. In this study, the cellular and molecular evaluation of several delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents is presented. METHODS: The anticancer potential assessment of the DLC-carboranes was performed in established normal (MRC-5, Vero), cancer (U-87 MG, HSC-3) and primary glioblastoma cancer stem (EGFR(pos), EGFR(neg)) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed. RESULTS: The pharmacological anticancer profile of DLC-functionalized carboranes is characterized by: a) a marked in vitro selectivity, due to lower concentration range needed (ca. 10 fold) to exert their cell growth-arrest effect on U-87 MG and HSC-3, as compared with that on MRC-5 and Vero; b) a similar selective growth inhibition behavior towards EGFR(pos) and EGFR(neg) cultures (>10 fold difference in potency) without, however, the activation of apoptosis in cultures; c) notably, in marked contrast to cancer cells, normal cells are capable of recapitulating their full proliferation potential following exposure to DLC-carboranes; and, d) such pharmacological effects of DLC-carboranes has been unveiled to be elicited at the molecular level through activation of the p53/p21 axis. CONCLUSIONS: Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that may be used autonomously or in therapies involving radiation with thermal neutrons. Importantly, such bifunctional capacity may be beneficial in cancer therapy.

Towards boron neutron capture therapy: the formulation and preliminary in vitro evaluation of liposomal vehicles for the therapeutic delivery of the dequalinium salt of bis-nido-carborane.

Liposomes of phosphatidylcholine or of dimyristoylphosphatidylcholine that incorporate bis-nido-carborane dequalinium salt are stable in physiologically relevant media and have in vitro toxicity profiles that appear to be compatible with potential therapeutic applications. These features render the structures suitable candidate boron-delivery vehicles for evaluation in the boron neutron capture therapy of cancer.

In vitro assessment of alkylglyceryl-functionalized chitosan nanoparticles as permeating vectors for the blood-brain barrier.

A series of O-substituted alkylglyceryl chitosans with systematically varied alkyl chain length and degree of grafting has been employed for the formulation of aqueous nanoparticulate systems, which were in turn investigated for their effects on a modeled blood-brain-barrier system of mouse-brain endothelial cells. Barrier function measurements employing electric cell-substrate impedance sensing and analyses of tight junction-specific protein profiles have indicated that the alkylglyceryl-modified chitosan nanoparticles impact upon the integrity of the model blood-brain barrier, whereas confocal microscopy experiments have demonstrated the efficient cellular uptake and the perinuclear localization of these nanoparticles. The application of nanoparticles to the model blood-brain barrier effected an increase in its permeability, as demonstrated by following the transport of the tracer molecule fluorescein isothiocyanate.

Toward drug delivery into the brain: synthesis, characterization, and preliminary in vitro assessment of alkylglyceryl-functionalized chitosan nanoparticles.

A series of O-substituted alkylglyceryl chitosans with systematically varied degrees of grafting was prepared through synthetic steps that involved the protection of amino moieties via phthaloylation and employed for the formulation of aqueous nanoparticulate systems that may be capable of delivering drugs to the brain. Dynamic light scattering studies have shown that nanoparticles with physiologically relevant aqueous stabilities may be prepared following the partial quaternization of these alkylglyceryl-modified chitosans. Preliminary in vitro tests using a mouse-brain endothelial cell model have indicated the efficient cellular uptake of these nanoparticles and identified butylglyceryl chitosan and butylglyceryl N,N,N-trimethyl chitosan as promising materials for the formulation of colloidal systems that could act as drug carriers into the brain.

Hybrid polymeric hydrogels for ocular drug delivery: nanoparticulate systems from copolymers of acrylic acid-functionalized chitosan and N-isopropylacrylamide or 2-hydroxyethyl methacrylate.

Nanoparticulate hybrid polymeric hydrogels (10-70 nm) have been obtained via the radical-induced co-polymerization of acrylic acid-functionalized chitosan with either N-isopropylacrylamide or 2-hydroxyethyl methacrylate, and the materials have been investigated for their ability to act as controlled release vehicles in ophthalmic drug delivery. Studies on the effects of network structure upon swelling properties, adhesiveness to substrates that mimic mucosal surfaces and biodegradability, coupled with in vitro drug release investigations employing ophthalmic drugs with differing aqueous solubilities, have identified nanoparticle compositions for each of the candidate drug molecules. The hybrid nanoparticles combine the temperature sensitivity of N-isopropylacrylamide or the good swelling characteristics of 2-hydroxyethyl methacrylate with the susceptibility of chitosan to lysozyme-induced biodegradation.

Liposome formulations of o-carborane for the boron neutron capture therapy of cancer.

Based on the promise of liposomes as convenient vehicles for the transport of boronated agents for the boron neutron capture therapy (BCNT) of cancer, this paper reports a method for the formulation and characterisation of stable o-carborane-loaded liposomes (ca. 80-100 nm) of dipalmitoyl-phosphatidylcholine (DPPC) or 1,2-distearol-sn-glycerol-3-phosphocholine (DSPC). Preliminary pharmaceutical characterisation experiments have demonstrated the integrity of both DPPC and DSPC liposomal membranes in serum and in PBS and also indicate that these o-carborane-loaded liposomes are candidate carrier vehicles for further evaluation with a view to exploitation in BNCT.

Fluoropolymers as low-surface-energy tooth coatings for oral care.

A range of low-surface-energy fluoropolymers has been synthesised and their effectiveness as dental-care coatings for plaque, stain and erosion prevention has been evaluated using a series of oral care models employing pressed discs of calcium hydroxyapatite or sections of human teeth. Since the blocking of dentinal tubules is a key mechanistic strategy in the treatment of dentine hypersensitivity, the capability of these non-permanent fluoropolymer coatings to occlude the pore structure of human dentine and to reduce the outward flow of simulated dentinal fluid has also been investigated. Several of the fluoropolymer coatings have been found to inhibit bacterial adhesion but no correlation has been established between anti-adhesion efficacy and fluorine content or surface energy. All the fluoropolymers have been seen to reduce stain uptake by pellicle-coated HA discs, with homopolymers being considerably more effective than copolymers. Some fluoropolymer coatings have also been shown to inhibit the acid demineralisation of hydroxyapatite discs and to reduce dentine permeability. Coatings of the 2:1 copolymer of 1H,1H,2H,2H-perfluorodecyl acrylate and 2-hydroxyethyl acrylate are most promising, exhibiting significant anti-adhesion and anti-erosion efficacy and reducing dentine permeability to a level that is comparable with that achieved with the standard treatment employed in commercial anti-sensitivity formulations.

Towards carborane-functionalised structures for the treatment of brain cancer.

Boron neutron capture therapy (BNCT) is a promising targeted chemoradiotherapeutic technique for the management of invasive brain tumors, such as glioblastoma multiforme (GBM). A prerequisite for effective BNCT is the selective targeting of tumour cells with 10B-rich therapeutic moieties. To this end, polyhedral boranes, especially carboranes, have received considerable attention because they combine a high boron content with relative low toxicity and metabolic inertness. Here, we review progress in the molecular design of recently investigated carborane derivatives in light of the widely accepted performance requirements for effective BNCT.

Azo compounds in colon-specific drug delivery.

Azo compounds have the potential to act as drug carriers that facilitate the selective release of therapeutic agents to the colon, and also to effect the oral administration of those macromolecular drugs that require colon-specific drug delivery. With some further research-driven refinements, these materials may lead to more efficient treatments for local conditions, such as colonic cancer or inflammatory bowel disease. This article provides an overview of the azo-based systems developed to date, identifies the requirements for an ideal carrier, and highlights the directions for further developments in the field of azo group-facilitated colonic delivery.

Correction: Boron-containing delocalised lipophilic cations for the selective targeting of cancer cells.

[This corrects the article DOI: 10.1039/C6MD00383D.].

Nano carriers for drug transport across the blood-brain barrier.

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed.

Functionalized chitosan/NIPAM (HEMA) hybrid polymer networks as inserts for ocular drug delivery: synthesis, in vitro assessment, and in vivo evaluation.

A series of hybrid polymeric hydrogels, prepared by the reaction of acrylic acid-functionalized chitosan with either N-isopropylacrylamide or 2-hydroxyethyl methacrylate monomers, were synthesized, pressed into minitablets, and investigated for their ability to act as controlled release vehicles for ophthalmic drug delivery. For comparison, interpolymeric complex analogues synthesized using the same monomers and pure, unfunctionalized chitosan were examined by means of an identical characterization protocol. The effects of network structure and composition upon the swelling properties, adhesion behavior, and drug release characteristics were investigated. Comparative in vitro studies employing chloramphenicol, atropine, norfloxacin, or pilocarpine informed the selection of drug-specific carrier compositions for the controlled delivery of these compounds. In addition, in vivo (rabbit model) experiments involving the delivery of pilocarpine indicated that chitosan-based hybrid polymer networks containing 2-hydroxyethyl methacrylate are useful carriers for the delivery of this therapeutic agent.

Orally administered, colon-specific mucoadhesive azopolymer particles for the treatment of inflammatory bowel disease: An in vivo study.

Radiolabeled congeners of a series of azopolymers have been synthesized and characterized. The in vivo (rat) gastrointestinal transit profile of millimeter-sized particles of these azopolymers has been determined and used to facilitate the selection of a candidate material for therapeutic applications. The efficacy of the selected material as a protective coating for the colonic mucosa has been tested in a hapten-reactivated, in vivo model of inflammatory bowel disease: 7 days after reactivation of the condition, the myeloperoxidase activity of animals that had received doses of the selected azopolymer was determined to be at the same level as that of healthy animals or that of the negative control group, highlighting the therapeutic promise of this material.

Vinylpyrrolidone-co-(meth)acrylic acid inserts for ocular drug delivery: synthesis and evaluation.

Copolymeric hydrogels constituting of vinylpyrrolidone and methacrylic or acrylic acid repeat units have been prepared and investigated for their ability to act as controlled release vehicles in ophthalmic drug delivery. The materials were synthesized by radical-induced polymerization in the presence of N,N'-methylenebisacrylamide crosslinker, and the influences of network composition and drug solubility upon the swelling properties, adhesion behavior, and drug release characteristics were studied. In vitro release experiments showed that some of these materials could be useful vehicles for the delivery of drugs such as pilocarpine or chloramphenicol, while in vivo studies, using the rabbit model, confirmed their high potential for the controlled ocular delivery of pilocarpine hydrochloride.

Mucoadhesive, triclosan-loaded polymer microspheres for application to the oral cavity: preparation and controlled release characteristics.

The aim of this study was to develop mucoadhesive microspheres that can be utilised for the controlled release of triclosan in oral-care formulations, specifically dental pastes. Using a double-emulsion solvent evaporation technique, triclosan was incorporated into microspheres that were prepared from Gantreztrade mark MS-955, Carbopol 974P, polycarbophil or chitosan and the profiles for its release were established under simulated 'in use' conditions. Triclosan was rapidly released into a sodium lauryl sulphate containing buffer from all but the chitosan microspheres. The release of triclosan from microspheres suspended in a non-aqueous paste, was found to be sustained over considerable time-periods, which were influenced strongly by the nature of the polymeric carrier. For microspheres that were fabricated from Gantrez, Carbopol or polycarbophil, the release appeared to obey zero-order kinetics whereas in the case of chitosan-derived vehicles, the release profile fitted the Baker and Lonsdale model. The work has demonstrated that these polymeric microspheres, particularly those of chitosan, are promising candidates for the sustained release of triclosan in the oral cavity.

An evaluation of the adhesion of solid oral dosage form coatings to the oesophagus.

There is a requirement for the development of oral dosage forms that are adhesive and allow extended oesophageal residence time for localised therapies, or are non-adhesive for ease of swallowing. This study provides an initial assessment of the in vitro oesophageal retention characteristics of several widely utilised pharmaceutical coating materials. To this end, a previously described apparatus has been used to measure the force required to pull a coated disc-shaped model tablet across a section of excised oesophageal tissue. Of the materials tested, the well-studied mucoadhesive polymer sodium alginate was found to be associated with significant oesophageal adhesion properties that was capable of 'self-repairing'. Hydroxypropylmethylcellulose exhibited less pronounced bioadhesive behaviour and blending this with plasticiser or with low molecular weight polymers and surfactants did not significantly affect this. Low molecular weight water soluble polymers, were found to behave similarly to the uncoated glass control disc. Polysorbates exhibited bioadhesion behaviour that was majorly influenced by the nature of the surfactant. The insoluble polymer ethylcellulose, and the relatively lipophilic surfactant sorbitan monooleate were seen to move more readily than the uncoated disc, suggesting that these may have a role as 'easy-to-swallow' coatings.

Nanoparticles of alkylglyceryl-dextran-graft-poly(lactic acid) for drug delivery to the brain: Preparation and in vitro investigation.

Poly(lactic acid), which has an inherent tendency to form colloidal systems of low polydispersity, and alkylglyceryl-modified dextran - a material designed to combine the non-immunogenic and stabilising properties of dextran with the demonstrated permeation enhancing ability of alkylglycerols - have been combined for the development of nanoparticulate, blood-brain barrier-permeating, non-viral vectors. To this end, dextran, that had been functionalised via treatment with epoxide precursors of alkylglycerol, was covalently linked to poly(lactic acid) using a carbodiimide cross-linker to form alkylglyceryl-modified dextran-graft-poly(lactic acid). Solvent displacement and electrospray methods allowed the formulation of these materials into nanoparticles having a unimodal size distribution profile of about 100-200nm and good stability at physiologically relevant pH (7.4). The nanoparticles were characterised in terms of hydrodynamic size (by Dynamic Light Scattering and Nanoparticle Tracking Analysis), morphology (by Scanning Electron Microscopy and Atomic Force Microscopy) and zeta potential, and their toxicity was evaluated using MTT and PrestoBlue assays. Cellular uptake was evidenced by confocal microscopy employing nanoparticles that had been loaded with the easy-to-detect Rhodamine B fluorescent marker. Transwell-model experiments employing mouse (bEnd3) and human (hCMEC/D3) brain endothelial cells revealed enhanced permeation (statistically significant for hCMEC/D3) of the fluorescent markers in the presence of the nanoparticles. Results of studies using Electric Cell Substrate Impedance Sensing suggested a transient decrease of the barrier function in an in vitro blood-brain barrier model following incubation with these nanoformulations. An in ovo study using 3-day chicken embryos indicated the absence of whole-organism acute toxicity effects. The collective in vitro data suggest that these alkylglyceryl-modified dextran-graft-poly(lactic acid) nanoparticles are promising candidates for in vivo evaluations that would test their capability to transport therapeutic actives to the brain.

Polymeric microspheres for drug delivery to the oral cavity: an in vitro evaluation of mucoadhesive potential.

Polymeric microparticles were fabricated from Carbopol, polycarbophil, chitosan, or Gantrez using a "water-in-oil emulsification" solvent evaporation method. Mean particle sizes, as determined by laser diffraction, were in the range 23-38 microm. Electron microscopy revealed that all microparticles were spherical and of smooth surface morphology. In pH 7.0 phosphate buffered saline, the microspheres exhibited significantly increased swelling ratios and longer half-times of swelling than the corresponding powdered polymers. The relative merits of the potential usefulness of these microspheres as formulation tools for the enhanced retention of a therapeutic entity within the oral mucosa were evaluated by in vitro mucoadhesion tests. Tensile tests showed that all microspheres under consideration were capable of adhering to porcine esophageal mucosa, with particles prepared from the poly(acrylic acid)s exhibiting greater mucoadhesive strength than those constructed from chitosan or Gantrez. However, in elution experiments involving a challenge with artificial saliva, particles of chitosan or Gantrez were retained onto mucosal tissue for longer time periods than those assembled from the poly(acrylic acid)s.