Glargine insulin loaded lipid nanoparticles: Oral delivery of liquid and solid oral dosage forms.

BACKGROUND AND AIMS: The oral administration of insulin has so far been precluded by gastro-intestinal enzyme degradation and poor intestinal absorption. Preliminary evidence for peptide uptake by the gut has recently been obtained, by our research group, following the administration of nanostructured lipid-carrier suspensions loaded with glargine insulin in healthy animal models. METHODS AND RESULTS: In this experimental study, glargine insulin-loaded nanostructured lipid carriers have been converted into solid oral dosage forms (tablets, capsules), that are more suitable for administration in humans and have prolonged shelf-life. The liquid and solid oral dosage forms were tested for glargine insulin uptake and glucose responsivity in healthy and streptozotocin-induced diabetic rats (6 animals in each group). A suitable composition gave redispersible solid oral dosage forms from glargine insulin-loaded carriers, using both spray-drying and freeze-drying. It was observed that the liquid and solid formulations had relevant hypoglycaemic effects in healthy rats, while only capsules were efficacious in diabetic rats; probably because of gut alterations in these animal models. Detected glargine insulinaemia was consistent with a glycaemic profile. CONCLUSION: The formulations under study showed their potential as oral glucose-lowering agents, particularly when used as capsules. However, further study is needed to produce a useful orally-active insulin preparation.

Freeze-Dried Secretome (Lyosecretome) from Mesenchymal Stem/Stromal Cells Promotes the Osteoinductive and Osteoconductive Properties of Titanium Cages.

Titanium is one of the most frequently used materials in bone regeneration due to its good biocompatibility, excellent mechanical properties, and great osteogenic performance. However, osseointegration with host tissue is often not definite, which may cause implant failure at times. The present study investigates the capacity of the mesenchymal stem cell (MSC)-secretome, formulated as a ready-to-use and freeze-dried medicinal product (the Lyosecretome), to promote the osteoinductive and osteoconductive properties of titanium cages. In vitro tests were conducted using adipose tissue-derived MSCs seeded on titanium cages with or without Lyosecretome. After 14 days, in the presence of Lyosecretome, significant cell proliferation improvement was observed. Scanning electron microscopy revealed the cytocompatibility of titanium cages: the seeded MSCs showed a spread morphology and an initial formation of filopodia. After 7 days, in the presence of Lyosecretome, more frequent and complex cellular processes forming bridges across the porous surface of the scaffold were revealed. Also, after 14 and 28 days of culturing in osteogenic medium, the amount of mineralized matrix detected by alizarin red was significantly higher when Lyosecretome was used. Finally, improved osteogenesis with Lyosecretome was confirmed by confocal analysis after 28 and 56 days of treatment, and demonstrating the production by osteoblast-differentiated MSCs of osteocalcin, a specific bone matrix protein.

Preparation of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug.

The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates.

Formulation and characterization study of itraconazole-loaded microparticles.

The aim of the work was to realize itraconazole-loaded formulations in form of microparticles using a fast, simple and solvent free production procedure. The selected excipients were able to enhance wettability of the final product, to increase drug dissolution rate and to maintain drug in solution thanks to the formation of an emulsified system after contact with the gastrointestinal fluids. Itraconazole formulations contained a structuring lipid, a solubilizing agent and a surface active substance and were prepared by a hot melt method (MMS, melting-milling-sieving). The characterization included drug content determination, granulometric distribution, differential scanning calorimetry (DSC) and in vitro drug release test, physical and technological stability after 12 months of ambient condition storage. The formulations were composed of particles with diameter lower than 355 µm. DSC analysis evidenced that itraconazole was almost completely in the amorphous form; the results of the in vitro drug release tests showed that these formulations were able to increase the rate of the drug release compared to that of the free drug. Stability data showed no significant changes in the thermal and release profiles, confirming that the selected excipients protected the drug avoiding its conversion from amorphous state into crystalline form and maintaining unchanged the delivery behavior.

Chitosan for improved encapsulation of thyme aqueous extract in alginate-based microparticles.

Ionotropic gelation is a low-cost, easy and green microencapsulation technique. However, the encapsulation of highly soluble compounds is challenging because of the wide loss of material into the external water phase by passive diffusion and the consequent low encapsulation efficiency. In this work an important increase of encapsulation efficiency for Thymus vulgaris L. aqueous extract in alginate-based microparticles has been obtained. A formulation with the proper thyme extract/alginate ratio (30:70) was used as reference and then optimized by adding different co-carrier excipients. Microparticles obtained by dropping a solution containing thyme extract and alginate into a chitosan/calcium-chloride/acid acetic solution lead to a high encapsulation efficiency (70.43 ± 5.28 %). After drying, microparticles had a particle size of 1096 ± 72 µm, 20.087 ± 1.487 % of extract content, 6.2 % of residual water, and showed a complete release of thyme extract within one hour. Combining alginate and chitosan as polymeric co-carrier was a valuable option for efficiently encapsulating an aqueous extract by ionotropic gelation.

Microencapsulation of a Pickering Oil/Water Emulsion Loaded with Vitamin D3.

The ionotropic gelation technique was chosen to produce vitamin D3-loaded microparticles starting from oil-in-water (O/W) Pickering emulsion stabilized by flaxseed flour: the hydrophobic phase was a solution of vitamin D3 in a blend of vegetable oils (ω6:ω3, 4:1) composed of extra virgin olive oil (90%) and hemp oil (10%); the hydrophilic phase was a sodium alginate aqueous solution. The most adequate emulsion was selected carrying out a preliminary study on five placebo formulations which differed in the qualitative and quantitative polymeric composition (concentration and type of alginate selected). Vitamin D3-loaded microparticles in the dried state had a particle size of about 1 mm, 6% of residual water content and excellent flowability thanks to their rounded shape and smooth surface. The polymeric structure of microparticles demonstrated to preserve the vegetable oil blend from oxidation and the integrity of vitamin D3, confirming this product as an innovative ingredient for pharmaceutical and food/nutraceutical purposes.

Silk Fibroin Bioink for 3D Printing in Tissue Regeneration: Controlled Release of MSC extracellular Vesicles.

Sodium alginate (SA)-based hydrogels are often employed as bioink for three-dimensional (3D) scaffold bioprinting. They offer a suitable environment for cell proliferation and differentiation during tissue regeneration and also control the release of growth factors and mesenchymal stem cell secretome, which is useful for scaffold biointegration. However, such hydrogels show poor mechanical properties, fast-release kinetics, and low biological performance, hampering their successful clinical application. In this work, silk fibroin (SF), a protein with excellent biomechanical properties frequently used for controlled drug release, was blended with SA to obtain improved bioink and scaffold properties. Firstly, we produced a printable SA solution containing SF capable of the conformational change from Silk I (random coil) to Silk II (ß-sheet): this transition is a fundamental condition to improve the scaffold's mechanical properties. Then, the SA-SF blends' printability and shape fidelity were demonstrated, and mechanical characterization of the printed hydrogels was performed: SF significantly increased compressive elastic modulus, while no influence on tensile response was detected. Finally, the release profile of Lyosecretome-a freeze-dried formulation of MSC-secretome containing extracellular vesicles (EV)-from scaffolds was determined: SF not only dramatically slowed the EV release rate, but also modified the kinetics and mechanism release with respect to the baseline of SA hydrogel. Overall, these results lay the foundation for the development of SA-SF bioinks with modulable mechanical and EV-release properties, and their application in 3D scaffold printing.

Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access.

Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.

Spray-Dried Powder Containing Cannabigerol: A New Extemporaneous Emulgel for Topical Administration.

Cannabigerol (CBG), a cannabinoid from Cannabis sativa L., recently attracted noteworthy attention for its dermatological applications, mainly due to its anti-inflammatory, antioxidant, and antimicrobial effectiveness similar to those of cannabidiol (CBD). In this work, based on results from studies of in vitro permeation through biomimetic membranes performed with CBG and CBD in the presence and in the absence of a randomly substituted methyl-ß-cyclodextrin (MßCD), a new CBG extemporaneous emulgel (oil-in-gel emulsion) formulation was developed by spray-drying. The powder (SDE) can be easily reconstituted with purified water, leading to a product with chemical-physical and technological characteristics that are comparable to those of the starting emulgels (E). Thermogravimetric analysis (TGA), attenuated total reflection-Fourier transformed infrared spectroscopy (ATR-FTIR), x-ray powder diffraction (XRPD), and high-performance liquid chromatography (HPLC) analyses demonstrated that the spray-drying treatment did not alter the chemical properties of CBG. This product can represent a metered-dosage form for the localized treatment of cutaneous afflictions such as acne and psoriasis.

Thermodynamic Balance vs. Computational Fluid Dynamics Approach for the Outlet Temperature Estimation of a Benchtop Spray Dryer.

The use of design space (DS) is a key milestone in the quality by design (QbD) of pharmaceutical processes. It should be considered from early laboratory development to industrial production, in order to support scientists with making decisions at each step of the product's development life. Presently, there are no available data or methodologies for developing models for the implementation of design space (DS) on laboratory-scale spray dryers. Therefore, in this work, a comparison between two different modeling approaches, thermodynamics and computational fluid dynamics (CFD), to a laboratory spray dryer model have been evaluated. The models computed the outlet temperature (Tout) of the process with a new modeling strategy that includes machine learning to improve the model prediction. The model metrics calculated indicate how the thermodynamic model fits Tout data better than CFD; indeed, the error of the CFD model increases towards higher values of Tout and feed rate (FR), with a final mean absolute error of 10.43 K, compared to the 1.74 K error of the thermodynamic model. Successively, a DS of the studied spray dryer equipment has been implemented, showing how Tout is strongly affected by FR variation, which accounts for about 40 times more than the gas flow rate (Gin) in the DS. The thermodynamic model, combined with the machine learning approach here proposed, could be used as a valid tool in the QbD development of spray-dried pharmaceutical products, starting from their early laboratory stages, replacing traditional trial-and-error methodologies, preventing process errors, and helping scientists with the following scale-up.

Three-Dimensional Bioprinted Controlled Release Scaffold Containing Mesenchymal Stem/Stromal Lyosecretome for Bone Regeneration: Sterile Manufacturing and In Vitro Biological Efficacy.

Recently, 3D-printed scaffolds for the controlled release of mesenchymal stem cell (MSC) freeze-dried secretome (Lyosecretome) have been proposed to enhance scaffold osteoinduction and osteoconduction; coprinting of poly(ε-caprolactone) (PCL) with alginate hydrogels allows adequate mechanical strength to be combined with the modulable kinetics of the active principle release. This study represents the feasibility study for the sterile production of coprinted scaffolds and the proof of concept for their in vitro biological efficacy. Sterile scaffolds were obtained, and Lyosecretome enhanced their colonization by MSCs, sustaining differentiation towards the bone line in an osteogenic medium. Indeed, after 14 days, the amount of mineralized matrix detected by alizarin red was significantly higher for the Lyosecretome scaffolds. The amount of osteocalcin, a specific bone matrix protein, was significantly higher at all the times considered (14 and 28 days) for the Lyosecretome scaffolds. Confocal microscopy further confirmed such results, demonstrating improved osteogenesis with the Lyosecretome scaffolds after 14 and 28 days. Overall, these results prove the role of MSC secretome, coprinted in PCL/alginate scaffolds, in inducing bone regeneration; sterile scaffolds containing MSC secretome are now available for in vivo pre-clinical tests of bone regeneration.

Solid Lipid Microparticles by Spray Congealing of Water/Oil Emulsion: An Effective/Versatile Loading Strategy for a Highly Soluble Drug.

Spray congealing technique was exploited to produce solid lipid microparticles (SLMp) loaded with a highly water-soluble drug (metoclopramide hydrochloride) dissolved in the aqueous phase of a water in oil (W/O) emulsion. The use of an emulsion as starting material for a spray congealing treatment is not so frequent. Moreover, for this application, a W/O emulsion with a drug dissolved in water is a totally novel path. A ternary diagram was built to optimize the emulsion composition, a factorial design was used to identify the factors affecting the properties of the microparticles and a Design of Experiment strategy was applied to define the impact of process conditions and formulation variables on the SLMp properties. SLMp were characterized by particle size distribution, morphology, residual moisture, drug content, release behavior, FT-IR analysis and XRPD. The obtained microparticles presented a spherical shape, particle size distribution between 54-98 µm depending on atomizing pressure used during the production step and 2-5% residual moisture 4 days after the preparation. XRPD analysis revealed that lipid polymorphic transition alfa-beta occurs depending on the presence of water. In vitro drug release tests highlighted that all the formulations had a reduced release rate compared to the drug alone. These results suggest that spray congealing of a W/O emulsion could be proposed as a good strategy to obtain SLMp with a high loading of a hydrophilic drug and able to control its release rate.

Shellac Gum/Carrageenan Alginate-Based Core-Shell Systems Containing Peppermint Essential Oil Formulated by Mixture Design Approach.

Peppermint essential oil is encapsulated by inverse ionotropic gelation in core-shell systems, composed of alginate (ALG) alone or alginate with shellac gum (SHL) and/or carrageenan (CRG). A mixture design approach is used to evaluate the correlation between the formulation composition and some properties of the final products. Immediately after the preparation, capsules appear rounded with a smooth and homogeneous surface, having a similar particle size ranging from 3.8 mm to 4.5 mm. The drying process, carried out at 40 °C in an oven for 3 h, reduces capsules' diameters by at least 50% and has a negative impact on the shape of the systems because they lose their regular shape and their external membrane partially collapses. The peppermint essential oil content of dried capsules is between 14.84% and 33.75%. The swelling behaviour of the systems is affected by the composition of their outer shell. When the external membrane is composed of alginate and shellac gum, the capsule ability to swell is lower than that of the systems containing alginate alone. The swelling ratio reaches 31% for alginate capsules but does not exceed 21% if shellac is present. Differently, when the second polymer of the shell is carrageenan, the swelling ability increases as a function of polymer concentration and the swelling ratio reaches 360%. In the case of systems whose outer membrane is a polymeric ternary mixture, the swelling capacity increases or decreases according to the concentrations of the individual polymers. The obtained results suggest that carrageenan could be a useful excipient to increase the swelling behaviour of the systems, while shellac gum makes the system shell more hydrophobic. The use of a mixture design (i.e., the use of ternary diagrams and related calculations), in which each single component is chosen to provide specific properties to the final mixture, could be the right approach to develop improved formulations with a tailored essential oil release profile.

Effect of Methyl-ß-Cyclodextrin and Trehalose on the Freeze-Drying and Spray-Drying of Sericin for Cosmetic Purposes.

Sericin is a protein extracted from Bombyx mori silk cocoons. Over the last decade, this wastewater product of the textile industry has shown many interesting biological properties. This protein is widely used in the cosmetic and biomedical fields. In this study, sericin has been obtained via a High-Temperature High-Pressure degumming process, and was dried using the freeze-drying (fd) and spray-drying (sd) techniques. Proteins tend to collapse during drying, hence, sericin has been dried in the presence of two selected carrier agents: methyl-ß-cyclodextrin and trehalose. The obtained powders have been analyzed using thermal investigation, microscopy (optical, SEM), and granulometric and spectroscopic analyses. Moreover, the percentage yield of the spray-drying process has been calculated. Both the agents were able to significantly improve the drying process, without altering the physico-chemical properties of the protein. In particular, the co-spray-drying of sericin with methyl-ß-cyclodextrin and trehalose gave good process yields and furnished a powder with low moisture content and handling properties that are better than those of the other studied dried products. These characteristics seem to be appropriate and fruitful for the manufacturing of cosmetic raw materials.

Freeze-Dried Mesenchymal Stem Cell-Secretome Pharmaceuticalization: Optimization of Formulation and Manufacturing Process Robustness.

Producing mesenchymal stem cell (MSC)-secretome for dose escalation studies and clinical practice requires scalable and good manufacturing practice (GMP)-compliant production procedures and formulation into a standardized medicinal product. Starting from a method that combines ultrafiltration and freeze-drying to transform MSC-secretome into a pharmaceutical product, the lyosecretome, this work aims to: (i) optimize the lyosecretome formulation; (ii) investigate sources of variability that can affect the robustness of the manufacturing process; (iii) modify the ultrafiltration step to obtain a more standardized final product. Design of experiments and principal component analysis of the data were used to study the influence of batch production, lyophilization, mannitol (M)/sucrose (S) binary mixture, selected as cryoprotectant excipients, and the total amount of excipients on the extracellular vesicles (EV) particle size, the protein and lipid content and the in vitro anti-elastase. The different excipients ratios did not affect residual moisture or EV particle size; simultaneously, proteins and lipids were better preserved in the freeze-dried product using the maximum total concentration of excipients (1.5% w/v) with a M:S ratio of about 60% w/w. The anti-elastase activity was instead better preserved using 0.5% w/w of M as excipient. The secretome batch showed to be the primary source of variability; therefore, the manufacturing process has been modified and then validated: the final product is now concentrated to reach a specific protein (and lipid) concentration instead of cell equivalent concentration. The new standardization approach led to a final product with more reproducible quali-quantitative composition and higher biological activity.

Canine Mesenchymal Cell Lyosecretome Production and Safety Evaluation after Allogenic Intraarticular Injection in Osteoarthritic Dogs.

In recent years, mesenchymal stromal cells (MSCs) have shown promise as a therapy in treating musculoskeletal diseases, and it is currently believed that their therapeutic effect is mainly related to the release of proteins and extracellular vesicles (EVs), known as secretome. In this work, three batches of canine MSC-secretome were prepared by standardized processes according to the current standard ISO9001 and formulated as a freeze-dried powder named Lyosecretome. The final products were characterized in protein and lipid content, EV size distribution and tested to ensure the microbiological safety required for intraarticular injection. Lyosecretome induced the proliferation of adipose tissue-derived canine MSCs, tenocytes, and chondrocytes in a dose-dependent manner and showed anti-elastase activity, reaching 85% of inhibitory activity at a 20 mg/mL concentration. Finally, to evaluate the safety of the preparation, three patients affected by bilateral knee or elbow osteoarthritis were treated with two intra-articular injections (t = 0 and t = 40 days) of the allogeneic Lyosecretome (20 mg corresponding 2 × 106 cell equivalents) resuspended in hyaluronic acid in one joint and placebo (mannitol resuspended in hyaluronic acid) in the other joint. To establish the safety of the treatment, the follow-up included a questionnaire addressed to the owner and orthopaedic examinations to assess lameness grade, pain score, functional disability score and range of motion up to day 80 post-treatment. Overall, the collected data suggest that intra-articular injection of allogeneic Lyosecretome is safe and does not induce a clinically significant local or systemic adverse response.

Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use.

In the last decades, it has been demonstrated that the regenerative therapeutic efficacy of mesenchymal stromal cells is primarily due to the secretion of soluble factors and extracellular vesicles, collectively known as secretome. In this context, our work described the preparation and characterization of a freeze-dried secretome (Lyosecretome) from adipose tissue-derived mesenchymal stromal cells for the therapy of equine musculoskeletal disorder. An intraarticular injectable pharmaceutical powder has been formulated, and the technological process has been validated in an authorized facility for veterinary clinical-use medicinal production. Critical parameters for quality control and batch release have been identified regarding (i) physicochemical properties; (ii) extracellular vesicle morphology, size distribution, and surface biomarker; (iii) protein and lipid content; (iv) requirements for injectable pharmaceutical dosage forms such as sterility, bacterial endotoxin, and Mycoplasma; and (v) in vitro potency tests, as anti-elastase activity and proliferative activity on musculoskeletal cell lines (tenocytes and chondrocytes) and mesenchymal stromal cells. Finally, proteins putatively responsible for the biological effects have been identified by Lyosecretome proteomic investigation: IL10RA, MXRA5, RARRES2, and ANXA1 modulate the inflammatory process RARRES2, NOD1, SERPINE1, and SERPINB9 with antibacterial activity. The work provides a proof-of-concept for the manufacturing of clinical-grade equine freeze-dried secretome, and prototypes are now available for safety and efficacy clinical trials in the treatment of equine musculoskeletal diseases.

Alginate/maltodextrin and alginate/shellac gum core-shell capsules for the encapsulation of peppermint essential oil.

Encapsulation of essential oils represents a good strategy to protect and to transform them in free-flowing particles. Core-shell systems containing peppermint essential oil have been obtained by inverse ionotropic gelation. An O/W emulsion composed of essential oil (O) and aqueous CaCl2 solution enriched with hydroxyethylcellulose (W) was dripped in an alginate solution added of a secondary excipient (maltodextrin or shellac gum) at two concentrations. The qualitative/quantitative modifications of capsule shell composition had a limited impact on the essential oil content (it was more than 50% w/w), while they affected other dried capsule properties like dimensions, shell thickness, hardness and swelling behavior. Neither the type nor the amount of secondary excipient influenced wet capsule particle size (about 4 mm). After drying, particle size decreased (it was about 2 mm) and while shellac gum amount did not affect dried capsule dimensions, an increase in maltodextrin amount corresponded to an increase in their diameters. Capsule hardness diminished by increasing the amount of secondary excipient in the formulations. In addition, the amount of maltodextrin included in the formulations affected the swelling behavior of the dried capsules in water and this leads considering maltodextrin a useful excipient to modulate swelling according to the needs of the different applications.

Polyphenols-Loaded Sericin Self-Assembling Nanoparticles: A Slow-Release for Regeneration by Tissue-Resident Mesenchymal Stem/Stromal Cells.

Mesenchymal stem/stromal cells (MSCs) are a therapeutic target to promote tissue regeneration, mainly when oxidative stress-mediated damage is involved in disease pathogenesis. Here, slow-release silk sericin nanoparticles (SNPs) loaded with natural antioxidant polyphenols were developed to sustain regeneration by tissue-resident MSCs. SNPs were prepared by exploiting a self-assembly method with poloxamer and were loaded with proanthocyanidins (P), quercetin (Q) or epigallocatechin gallate (E). SNPs, with a diameter less than 150 nm, were able to encapsulate both hydrophilic (P and E) and hydrophobic (Q) drugs. A slow and controlled release was obtained from SNPs for all the actives in PBS, while in EtOH, Q and E showed a burst release but P did not. Kinetic models revealed lower diffusion of P than other biomolecules, probably due to the higher steric hindrance of P. The in vitro anti-oxidant, anti-elastase and anti-tyrosinase properties of SNPs were assessed: loading the P and E into SNPs preserved the in vitro biological activities whereas for Q, the anti-elastase activity was strongly improved. Moreover, all formulations promoted MSC metabolic activity over 72 h. Finally, SNPs exhibited a strong ability to protect MSCs from oxidative stress, which supports their potential use for regenerative purposes mediated by tissue-resident MSCs.

Calcium Alginate and Calcium Alginate-Chitosan Beads Containing Celecoxib Solubilized in a Self-Emulsifying Phase.

In this work alginate and alginate-chitosan beads containing celecoxib solubilized into a self-emulsifying phase were developed in order to obtain a drug delivery system for oral administration, able to delay the drug release in acidic environment and to promote it in the intestinal compartment. The rationale of this work was linked to the desire to improve celecoxib therapeutic effectiveness reducing its gastric adverse effects and to favor its use in the prophylaxis of colon cancer and as adjuvant in the therapy of familial polyposis. The systems were prepared by ionotropic gelation using needles with different diameters (400 and 600 µm). Morphology, particle size, swelling behavior, and in vitro drug release performance of the beads in aqueous media with different pH were investigated. The experimental results demonstrated that the presence of chitosan in the formulation caused an increase of the mechanical resistance of the bead structure and, as a consequence, a limitation of the bead swelling ability and a decrease of the drug release rate at neutral pH. Alginate-chitosan beads could be a good tool to guarantee a celecoxib colon delivery.