Additive Manufacturing Strategies for Personalized Drug Delivery Systems and Medical Devices: Fused Filament Fabrication and Semi Solid Extrusion.

Novel additive manufacturing (AM) techniques and particularly 3D printing (3DP) have achieved a decade of success in pharmaceutical and biomedical fields. Highly innovative personalized therapeutical solutions may be designed and manufactured through a layer-by-layer approach starting from a digital model realized according to the needs of a specific patient or a patient group. The combination of patient-tailored drug dose, dosage, or diagnostic form (shape and size) and drug release adjustment has the potential to ensure the optimal patient therapy. Among the different 3D printing techniques, extrusion-based technologies, such as fused filament fabrication (FFF) and semi solid extrusion (SSE), are the most investigated for their high versatility, precision, feasibility, and cheapness. This review provides an overview on different 3DP techniques to produce personalized drug delivery systems and medical devices, highlighting, for each method, the critical printing process parameters, the main starting materials, as well as advantages and limitations. Furthermore, the recent developments of fused filament fabrication and semi solid extrusion 3DP are discussed. In this regard, the current state of the art, based on a detailed literature survey of the different 3D products printed via extrusion-based techniques, envisioning future directions in the clinical applications and diffusion of such systems, is summarized.

Technologies and Formulation Design of Polysaccharide-Based Hydrogels for Drug Delivery.

Polysaccharide-based hydrogel particles (PbHPs) are very promising carriers aiming to control and target the release of drugs with different physico-chemical properties. Such delivery systems can offer benefits through the proper encapsulation of many drugs (non-steroidal and steroidal anti-inflammatory drugs, antibiotics, etc) ensuring their proper release and targeting. This review discusses the different phases involved in the production of PbHPs in pharmaceutical technology, such as droplet formation (SOL phase), sol-gel transition of the droplets (GEL phase) and drying, as well as the different methods available for droplet production with a special focus on prilling technique. In addition, an overview of the various droplet gelation methods with particular emphasis on ionic cross-linking of several polysaccharides enabling the formation of particles with inner highly porous network or nanofibrillar structure is given. Moreover, a detailed survey of the different inner texture, in xerogels, cryogels or aerogels, each with specific arrangement and properties, which can be obtained with different drying methods, is presented. Various case studies are reported to highlight the most appropriate application of such systems in pharmaceutical field. We also describe the challenges to be faced for the breakthrough towards clinic studies and, finally, the market, focusing on the useful approach of safety-by-design (SbD).

Zinc and Calcium Cations Combination in the Production of Floating Alginate Beads as Prednisolone Delivery Systems.

The aim of this research was to verify the application of alginate in combination with Ca2+ and Zn2+ ions to produce a floating and prolonged release system for the oral administration of prednisolone. Hollow and floating gel-beads were designed using prilling/ionotropic gelation as the microencapsulation technique, zinc acetate in the gelling solution as the alginate external crosslinker, and calcium carbonate in the feed as the internal crosslinking agent able to generate gas when in contact with the acidic zinc acetate solution. To achieve this goal, drug/alginate solutions were opportunely combined with different amounts of calcium carbonate. The effect of the addition of calcium carbonate into the feed solution on buoyancy, encapsulation efficiency, morphology, size distribution, as well as in vitro drug release profile of the alginate particles was studied. Moreover, the ability of the floating beads to modulate in vivo the anti-inflammatory response was assayed using the carrageenan-induced acute oedema in rat paw. The proposed strategy allowed obtaining alginate beads with extremely high encapsulation efficiency values (up to 94%) and a very porous inner matrix conferring buoyancy in vitro in simulated gastric fluid up to 5 h. Moreover, in vivo, the best formulation, F4, resulted in the ability to prolong the anti-inflammatory effect up to 15 h compared with raw prednisolone.

Development of Chitosan/Mannitol Microparticles as Delivery System for the Oral Administration of a Spirulina Bioactive Peptide Extract.

Spirulina platensis contains several compounds showing nutritional and therapeutic benefits. Recently, a series of peptides able to reduce the blood pressure level and to enhance the endothelial vasorelaxation was isolated from the hydrolyzed highly water-soluble Spirulina extract (HSE). However, HSE shows critical organoleptic characteristics also having poor intestinal permeability, limiting absorption when orally delivered. This research aims to overcome the critical issues through the encapsulation of HSE in Chitosan/Mannitol-(CM)-based microparticles by spray drying. The produced powders (CM-HSE) showed good process yield (≈70%) and encapsulation efficiency (≈100%) also having good derived flow properties as well as stability up to six months storage. The microparticles constituting the spray-dried powder resulted in an amorphous micrometric state (d50 ≈ 14 µm) able to retain dark colour and unpleasant smell of raw HSE. Moreover, the in vitro permeation study by Franz cell indicated that the engineered microparticles are able to enhance the permeation of HSE through an intestinal biomimetic barrier (551.13 µg/cm2 CM-HSE vs. 315.46 µg/cm2 HSE at 270 min).

Design and Development of Spray-Dried Microsystems to Improve Technological and Functional Properties of Bioactive Compounds from Hazelnut Shells.

An extract obtained from hazelnut shells by-products (HSE) has antioxidant and chemopreventive effects on human melanoma and cervical cancer cell lines, inducing apoptosis by caspase-3 activation. A clinical translation is limited by poor water solubility and low bioavailability. Dried plant extracts often show critical characteristics such as sticky/gummy appearance, unpleasant smell, and instability involving practical difficulties in processing for industrial use. A spray drying method has been applied to transform raw HSE in a microparticulate powder. The biopolymeric matrix was based on l-proline as loading carrier, hydroxyethylcellulose in combination with pectin as coating polymers; lecithin and ethanol were used as solubility enhancers. A Hot-Cold-Hot method was selected to prepare the liquid feed. The thus prepared powder showed good technological properties (solid-state, particle dimensions, morphology, and water dissolution rate), stability, and unchanged chemopreventive effects with respect to the unprocessed HSE.

Influence of the Phenological State of in the Antioxidant Potential and Chemical Composition of Ageratina havanensis. Effects on the P-Glycoprotein Function.

Ageratina havanensis (Kunth) R. M. King & H. Robinson is a species of flowering shrub in the family Asteraceae, native to the Caribbean and Texas. The aim of this work was to compare the quantitative chemical composition of extracts obtained from Ageratina havanensis in its flowering and vegetative stages with the antioxidant potential and to determine the effects on P-glycoprotein (P-gp) function. The quantitative chemical composition of the extracts was determined quantifying their major flavonoids by UPLC-ESI-MS/MS and by PCA analysis. The effects of the extracts on P-gp activity was evaluated by Rhodamine 123 assay; antioxidant properties were determined by DPPH, FRAP and inhibition of lipid peroxidation methods. The obtained results show that major flavonoids were present in higher concentrations in vegetative stage than flowering stage. In particular, the extracts obtained in the flowering season showed a significantly higher ability to sequester free radicals compared to those of the vegetative season, meanwhile, the extracts obtained during the vegetative stage showed a significant inhibitory effect against brain lipid peroxidation and a strong reductive capacity. This study also showed the inhibitory effects of all ethanolic extracts on P-gp function in 4T1 cell line; these effects were unrelated to the phenological stage. This work shows, therefore, the first evidence on: the inhibition of P-gp function, the antioxidant effects and the content of major flavonoids of Ageratina havanensis. According to the obtained results, the species Ageratina havanensis (Kunth) R. M. King & H. Robinson could be a source of new potential inhibitors of drug efflux mediated by P-gp. A special focus on all these aspects must be taking into account for future studies.

Design of Aerogels, Cryogels and Xerogels of Alginate: Effect of Molecular Weight, Gelation Conditions and Drying Method on Particles' Micromeritics.

Processing and shaping of dried gels are of interest in several fields like alginate aerogel beads used as highly porous and nanostructured particles in biomedical applications. The physicochemical properties of the alginate source, the solvent used in the gelation solution and the gel drying method are key parameters influencing the characteristics of the resulting dried gels. In this work, dried gel beads in the form of xerogels, cryogels or aerogels were prepared from alginates of different molecular weights (120 and 180 kDa) and concentrations (1.25, 1.50, 2.0 and 2.25% (w/v)) using different gelation conditions (aqueous and ethanolic CaCl2 solutions) and drying methods (supercritical drying, freeze-drying and oven drying) to obtain particles with a broad range of physicochemical and textural properties. The stability of physicochemical properties of alginate aerogels under storage conditions of 25 °C and 65% relative humidity (ICH-climatic zone II) during 1 and 3 months was studied. Results showed significant effects of the studied processing parameters on the resulting alginate dried gel properties. Stability studies showed small variations in aerogels weight and specific surface area after 3 months of storage, especially, in the case of aerogels produced with medium molecular weight alginate.

Natural polysaccharides platforms for oral controlled release of ketoprofen lysine salt.

CONTEXT: Ketoprofen lysinate (KL) is one of the most widely used non-steroidal anti-inflammatory drugs in the symptomatic treatment of some chronic inflammatory diseases. Compared to ketoprofen, KL shows better pharmacokinetics and tolerability. However, due to its short half-life of 1-2 h, a multiple dose regimen is required for oral administration. Thus, the present work deals with its encapsulation in a hydrogel-based system by prilling in order to prolong its activity. OBJECTIVE: In this paper, we propose alginate and pectin as carriers and release tailoring agent for the development of hydrogel-based beads for KL retarded and sustained release. MATERIALS AND METHODS: Beads were produced by a Nisco Encapsulator® using alginate or pectin. Operative variables were optimized to produce beads with desired morphology and size. Solid state properties were analyzed by SEM and DSC. Drug release performance was studied by Pharmacopeia pH-change assay to simulate gastrointestinal environment. RESULTS AND DISCUSSION: Prilling technique was successfully used to encapsulate high soluble drugs as KL in polysaccharides-based hydrogels. Pectin proved to be a proper polymer able to encapsulate ketoprofen lysine salt. Formulation (F8) showed good morphological properties and size, high drug content (15.6%) and encapsulation efficiency (93.5%) and promising drug release profiles. Hosting F8 in an acid-resistant capsule (DR®caps) a delivery platform has been developed to control KL release in a delayed (90 min lag time) and prolonged way (270 min complete release). CONCLUSION: The platform may be proposed as potentially useful in the oral administration of NSAIDs in chronic inflammatory diseases affected by circadian rhythm.

3D printed macroporous scaffolds of PCL and inulin-g-P(D,L)LA for bone tissue engineering applications.

Bone repair and tissue-engineering (BTE) approaches require novel biomaterials to produce scaffolds with required structural and biological characteristics and enhanced performances with respect to those currently available. In this study, PCL/INU-PLA hybrid biomaterial was prepared by blending of the aliphatic polyester poly(ε-caprolactone) (PCL) with the amphiphilic graft copolymer Inulin-g-poly(D,L)lactide (INU-PLA) synthetized from biodegradable inulin (INU) and poly(lactic acid) (PLA). The hybrid material was suitable to be processed using fused filament fabrication 3D printing (FFF-3DP) technique rendering macroporous scaffolds. PCL and INU-PLA were firstly blended as thin films through solvent-casting method, and then extruded by hot melt extrusion (HME) in form of filaments processable by FFF-3DP. The physicochemical characterization of the hybrid new material showed high homogeneity, improved surface wettability/hydrophilicity as compared to PCL alone, and right thermal properties for FFF process. The 3D printed scaffolds exhibited dimensional and structural parameters very close to those of the digital model, and mechanical performances compatible with the human trabecular bone. In addition, in comparison to PCL, hybrid scaffolds showed an enhancement of surface properties, swelling ability, and in vitro biodegradation rate. In vitro biocompatibility screening through hemolysis assay, LDH cytotoxicity test on human fibroblasts, CCK-8 cell viability, and osteogenic activity (ALP evaluation) assays on human mesenchymal stem cells showed favorable results.

Development, Characterization, and Clinical Investigation of a New Topical Emulsion System Containing a Castanea sativa Spiny Burs Active Extract.

The study focused on the development and characterization of an O/W emulsion for skincare containing Castanea sativa spiny burs extract (CSE) as functional agent. The emulsion was stable and had suitable physicochemical and technological properties for dermal application and CSE showed no cytotoxicity in spontaneously immortalized keratinocytes (HaCaT) at active concentrations. A single-blind, placebo-controlled, monocentric study was designed to evaluate the skin tolerability and the skin performance of the CSE-loaded emulsion on healthy human volunteers. An improvement was observed in skin biomechanical properties such as hydration, skin elasticity and a reduction in the periorbital wrinkles in 30 days without altering the skin barrier function, sebum, pH, and erythema values. A significant skin moisturizing effect was detected while the skin barrier function was preserved. The selected natural ingredient combined with the designed formulation and the optimized preparation method has led to a final product that satisfies the physico-chemical and technological requirements underlying the safety of use and the formulative stability over time. With no negative skin reactions and highly significant effects on skin elasticity, wrinkles, and moisturization, the CSE-based emulsion achieved very satisfying outcomes representing a promising functional formulation for skin care.

1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3ß Kinase.

A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC50 values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchymal transition markers, including SNAIL-1/2 and metalloproteinase-9. Moreover, flow cytometric analysis after Annexin V-FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase-3 and PARP and a significant inhibition of GSK3ß phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3ß activity, showing IC50 values for the most active compounds against this enzyme in the micromolar range.

1,2,4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A.

The inhibition or prevention of biofilm formation represents an emerging strategy in the war against antibiotic resistance, interfering with key players in bacterial virulence. This approach includes the inhibition of the catalytic activity of transpeptidase sortase A (Srt A), a membrane enzyme responsible for covalently attaching a wide variety of adhesive matrix molecules to the peptidoglycan cell wall in Gram-positive strains. A new series of seventeen 1,2,4-oxadiazole derivatives was efficiently synthesized and screened as potential new anti-virulence agents. The ability of inhibiting biofilm formation was evaluated against both Gram-positive and Gram-negative pathogens. Remarkably, all these compounds inhibited S. aureus and/or P. aeruginosa biofilm formation in a dose dependent manner, with 50% biofilm inhibitory concentrations (BIC50s) below 10 µM for the most active compounds. Inhibition of SrtA was validated as one of the possible mechanisms of action of these new 1,2,4-oxadiazole derivatives, in the tested Gram-positive pathogen, using a specific enzymatic assay for a recombinant S. aureus SrtA. The three most active compounds, eliciting BIC50 values for S. aureus ATCC 25923 between 0.7 and 9.7 µM, showed a good activity toward the enzyme eliciting IC50 values ranging from 2.2 to 10.4 µM.

Bioactive Polyphenols from Pomegranate Juice Reduce 5-Fluorouracil-Induced Intestinal Mucositis in Intestinal Epithelial Cells.

Intestinal epithelial cells (IECs) play a pivotal role in maintaining intestinal homeostasis. Different noxious agents, among them also anticancer therapies, can impair intestinal epithelial integrity triggering inflammation and oxidative stress. A frequent complication of chemotherapy is gastrointestinal mucositis, strongly influencing the effectiveness of therapy, increasing healthcare costs, and impairing patients' quality of life. Different strategies are used to treat gastrointestinal mucositis, including products from natural sources. Our study focused on the effect of pomegranate (Punica granatum L.) juice extract on IEC-6 cells, both during inflammatory conditions and following treatment with 5-fluorouracil (5-FU). The polyphenolic profile of pomegranate juice was characterized in detail by Online Comprehensive two dimensional Liquid Chromatography-Mass Spectrometry. The evaluation of pomegranate juice extract in IEC-6 indicates a significant inhibition in proinflammatory factors, such as cytokines release, cyclooxygenase-2 and inducible nitric oxide synthase expression, and nitrotyrosine formation. Pomegranate also inhibited oxidative stress and adhesion protein expression. In 5-FU-treated IEC-6, pomegranate also inhibited both inflammatory and oxidative stress parameters and apoptosis. It promoted wound repair and tight junction expression. These results suggest a potential use of pomegranate as an adjuvant in the treatment of intestinal inflammatory and oxidative stress states, which also occur during chemotherapy-induced mucositis.

Pectin and Zinc Alginate: The Right Inner/Outer Polymer Combination for Core-Shell Drug Delivery Systems.

Core-shell beads loaded with betamethasone were developed using co-axial prilling as production technique and pectin plus alginate as polymeric carriers. During this study, many operative conditions were intensively investigated to find the best ones necessary to produce uniform core-shell particle systems in a reproducible way. Particularly, feed solutions' composition, polymers mass ratios and the effect of the main process parameters on particles production, micromeritics, inner structure, drug loading and drug-release/swelling profiles in simulated biological fluids were studied. The optimized core-shell formulation F5 produced with a pectin core concentration of 4.0% w/v and an alginate shell concentration of 2.0% w/v (2:1 core:shell ratio) acted as a sustained drug delivery system. It was able to reduce the early release of the drug in the upper part of the gastro-intestinal tract for the presence of the zinc-alginate gastro-resistant outer layer and to specifically deliver it in the colon, thanks to the selectivity of amidated low methoxy pectin core for this district. Therefore, these particles may be proposed as colon targeted drug delivery systems useful for inflammatory bowel disease (IBD) therapy.

Study on Ajuga reptans Extract: A Natural Antioxidant in Microencapsulated Powder Form as an Active Ingredient for Nutraceutical or Pharmaceutical Purposes.

The administration of natural antioxidants is considered to be a prevention strategy for chronic diseases and a useful tool for the healthcare system to reduce the administration of expensive and often not effective treatments. The chemical characterization of a methanolic extract (AJ) of Ajuga reptans L. was performed, and its antioxidant activity was evaluated. AJ and the major compounds, characterized by chromatographic techniques as phenylpropanoids and iridoids, were able to reduce the Reactive Oxygen Species levels in cancer cell lines (melanoma, A375, cervical cancer, HeLa, and alveolar adenocarcinoma, A549), stimulated by E. coli lipopolysaccharide. However, a clinical translation of these results encountered a significant limitation represented by the poor water solubility and bioavailability of the extract and compounds. Consequently, a hydro-soluble powder system (AJEP3) was developed by spray-drying encapsulating AJ into a multi-component solid matrix that is based on L-proline and hydroxyethylcellulose as loading and coating agents, and lecithin as solubility enhancer. The technological approach led to a satisfactory process yield (71.5%), encapsulation efficiency (99.9%), and stability. The in vitro water dissolution rate of the bioactive compounds appeared to be improved with respect to the extract, suggesting higher feasibility in the manufacturing and administration; even the in vitro biological activity of the produced multi-component AJEP3 was clearly enhanced.

Post-manufacture loading of filaments and 3D printed PLA scaffolds with prednisolone and dexamethasone for tissue regeneration applications.

Strategies to load prednisolone or dexamethasone in preformed poly(L-lactic acid) (PLA) filaments and 3D printed scaffolds were explored as a way of personalizing the drug, the dose and the release profile for regenerative medicine purposes. Instead of starting from a PLA filament preloaded with a given content of drug, we explored two more versatile strategies. The first one involved the soaking of PLA filaments into a drug solution prepared in a solvent that reversibly swelled PLA; during 3D printing the melting of PLA contributed to the efficient integration (encapsulation) of the drug inside the printed strand. The second strategy consisted in first printing the 3D PLA scaffolds followed by soaking in a suitable drug solution in order to exploit the higher specific surface of the printed strands compared to the filament. Sustained release profiles were recorded when either prednisolone or dexamethasone were loaded in preformed PLA filaments, while rapid release was recorded for 3D PLA scaffolds loaded after printing. The combination of the two proposed methods reported here opened the possibility of creating concentration gradients of different drugs in the same scaffold exhibiting distinct release patterns. Namely, the strand core contained an active ingredient to be slowly released, while the surface was covered with other active ingredient that could be rapidly delivered. The feasibility of this approach was confirmed through dual loading of dexamethasone in the filament and of prednisolone on the preformed scaffold. Drug-loaded scaffolds were characterized in terms of printability, structural characteristics (DSC, XRD), mechanical properties, biodegradation, and ability to promote cell attachment and proliferation. Finally, anti-inflammatory response and osteoinductive properties were verified in cell cultures.

Polysaccharides based gastroretentive system to sustain piroxicam release: Development and in vivo prolonged anti-inflammatory effect.

A gastro-retentive delivery system loaded with piroxicam with a bimodal release profile in gastrointestinal-tract was developed. Piroxicam is characterized by high oral absorption, long half-life, but its elimination is impaired in elderly patients. To overcome fluctuations in plasma levels, floating gastro-retentive gel-beads with sustained release properties were manufactured using prilling. Beads matrix was designed as a hollow/multipolymeric system based on alginate, ALM-pectin and hydroxypropilmethylcellulose. This research studied variables able to affect particles micromeritics, hollow inner structure, floating properties and drug-release profiles in gastro-intestinal tract. The gastro-retentive formulation (F4) acted as a floating-system able to provide the desired bimodal drug-release pattern controlling and delaying in vitro piroxicam release. The in vivo anti-inflammatory activity of the floating beads resulted prolonged up to 48 h, compared to standard piroxicam. This formulation may be proposed to treat chronic inflammatory-diseases in elderly patients, needing a rapid onset of drug action followed by a maintenance dose.

Prednisolone Delivery Platforms: Capsules and Beads Combination for a Right Timing Therapy.

In this work, a platform of alginate beads loaded with Prednisolone in hypromellose/gellan gum capsules (F6/Cps) able to delay steroidal anti-inflammatory drug (SAID) release as needed for chronotherapy of rheumatoid arthritis is proposed. Rheumatoid arthritis, showing a worsening in symptoms in the morning upon waking, is a pathology that can benefit from chronotherapy. With the aim to maximize prednisolone therapeutic action allowing the right timing of glucocorticoid therapy, different engineered microparticles (gel-beads) were manufactured using prilling (laminar jet break-up) as micro-encapsulation technique and Zn-alginate as gastroresistant carrier. Starting from various feed solutions and process parameters, the effect of the variables on particles size, morphology, solid state properties and drug release was studied. The optimization of operative and prilling/ionotropic gelation variables led to microspheres with almost spherical shape and a narrow dimensional range. The feed solution with the highest alginate (2.5% w/v) amount and drug/polymer ratio (1:5 w/w) gave rise to the highest encapsulation efficiency (78.5%) as in F6 formulation. As to drug release, F6 exhibited an interesting dissolution profile, releasing about 24% of the drug in simulated gastric fluid followed by a more sustained profile in simulated intestinal fluid. #F6, acting as a gastro-resistant and delayed release formulation, was selected for in vivo studies on male Wistar rats by means of a carrageenan-induced oedema model. Finally, this efficacious formulation was used as core material for the development of a final dosage form: F6/Cps allowed to significantly reduce prednisolone release in simulated gastric fluid (12.6%) and delayed drug release up to about 390 minutes.

Design and In Vivo Anti-Inflammatory Effect of Ketoprofen Delayed Delivery Systems.

For the treatment of inflammatory-based diseases affected by circadian rhythms, the development of once-daily dosage forms is required to target early morning symptoms. In this study, Zn-alginate beads containing ketoprofen (K) were developed by a tandem technique prilling/ionotropic gelation. The effect of main critical variables on particles micromeritics, inner structure as well as on drug loading and in vitro drug release was studied. The in vivo anti-inflammatory efficacy was evaluated using a modified protocol of carrageenan-induced edema in rat paw administering beads to rats by oral gavage at 0, 3, or 5 h before edema induction. Good drug loading and desired particle size and morphology were obtained for the optimized formulation F20. In vitro dissolution studies showed that F20 had a gastroresistant behavior and delayed release of the drug in simulated intestinal fluid. The in vitro delayed release pattern was clearly reflected in the prolonged anti-inflammatory effect in vivo of F20, compared to pure ketoprofen; F20, administered 3 h before edema induction, showed a significant anti-inflammatory activity, reducing maximum paw volume in response to carrageenan injection, whereas no response was observed for ketoprofen. The designed beads appear a promising platform suitable for a delayed release of anti-inflammatory drugs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3451-3458, 2015.

Novel co-axial prilling technique for the development of core-shell particles as delayed drug delivery systems.

In this study, biocompatible double layered beads consisting of pectin core and alginate shell were prepared through a single step manufacturing process based on prilling apparatus equipped with co-axial nozzles. The core was loaded with piroxicam (PRX) as model non-steroidal anti-inflammatory drug (NSAID). Morphology, size distribution and shape of the double layered beads varied depending on the operative conditions and polymer concentrations. Co-axial nozzles size, applied vibration frequency, gelling conditions and, mainly, polymers mass ratio were identified as critical variables. Particularly, the relative viscosity of polymeric feed solutions inside the nozzle was the key parameter to obtain homogeneous and well-formed coated particles. The produced beads were investigated for the release kinetic in different media. Once PRX was encapsulated within the pectin core, a controlled release pattern was observed. Particularly, beads produced with 4:1 core/shell ratio (F4) released less than 30% of PRX in simulated gastric fluid (SGF) while total liberation of the drug was achieved during the next 3h in simulated intestinal fluid (SIF). More interesting, F4 tested in SIF was able to release drug in a delayed and sustained manner at established time points (2h_8.2%, 3h_32.2%, 4h_70.1% and 5h_about 100%). Based on the above results, co-axial prilling approach is expected to provide success in manufacturing systems with delayed drug release profiles. Such systems may be potentially useful in targeting diseases which are affected by the circadian rhythm, such as chronic inflammation.