Budesonide delayed-release capsules to reduce proteinuria in adults with primary immunoglobulin A nephropathy.

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1). This Gd-IgA1 is believed to originate from mucosally sited B cells, which are abundant in the Peyer's patches-rich distal ileum. Nefecon is a targeted-release form of budesonide developed to act in the distal ileum, thereby exerting a direct action on the mucosal tissue implicated in the pathogenesis of the disease. AREAS COVERED: This review discusses IgAN pathophysiology and provides an overview of the current therapeutic landscape, focusing on Nefecon, the first drug to receive accelerated US approval and conditional EU approval for the treatment of patients with IgAN at risk of rapid disease progression. EXPERT OPINION: Nefecon trial data thus far have demonstrated a promising efficacy profile, with a predictable pattern of adverse events. Treatment with Nefecon for 9 months reduces proteinuria substantially (Part A of the Phase 3 trial and the Phase 2b trial). A nearly complete prevention of deterioration of renal function has been observed at 12 months in patients at greatest risk of rapid disease progression. Long-term data from Part B of the Phase 3 study will provide 24-month data, furthering understanding of the durability of the 9-month treatment course.

HPLC-UV/VIS for Determination of Ipratropium Bromide Mixed with Salbuterol, Beclomethasone Propionate and Budesonide using Dual Wavelength-Detection Method.

BACKGROUND: Inhalation preparation involves liquid or solid raw materials for delivering to lungs as aerosol or vapor. The liquid preparation for nebulizer is effective for convenient use and patient compliance and it has been extensively used in the treatment of clinical lung diseases. Clinical staff often mixes the compound ipratropium bromide with beclomethasone propionate and budesonide inhaler but reference values of inhalants for clinical use need to be established for simplifying the operation procedure. The high-performance liquid chromatography (HPLC) method of compound ipratropium bromide solution, beclomethasone propionate suspension and budesonide suspension after mixed atomization was studied. METHODS: The specificity, linearity, recovery (accuracy), precision and stability of compound ipratropium bromide, beclomethasone propionate and budesonide were tested to verify the developed liquid phase method. RESULTS: The developed liquid phase method had high specificity, linear R2≥0,999, recovery (accuracy) RSD (relative standard deviation) less than 2%, precision RSD less than 2,0%, and stability RSD less than 2,0%. CONCLUSION: The liquid phase methodology developed in this study can be used for the determination of compound ipratropium bromide mixed with beclomethasone propionate and budesonide. The current methodology can also be used to provide a reference for the determination of its content after mixing, and further data support for its clinical medication.

Identification and Quantification by NMR Spectroscopy of the 22R and 22S Epimers in Budesonide Pharmaceutical Forms.

The authors developed four variants of the qNMR technique (1H or 13C nucleus, DMSO-d6 or CDCl3 solvent) for identification and quantification by NMR of 22R and 22S epimers in budesonide active pharmaceutical ingredient and budesonide drugs (sprays, capsules, tablets). The choice of the qNMR technique version depends on the drug excipients. The correlation of 1H and 13C spectra signals to molecules of different budesonide epimers was carried out on the basis of a comprehensive analysis of experimental spectral NMR data (1H-1H gCOSY, 1H-13C gHSQC, 1H-13C gHMBC, 1H-1H ROESY). This technique makes it possible to identify budesonide epimers and determine their weight ratio directly, without constructing a calibration curve and using any standards. The results of measuring the 22S epimer content by qNMR are comparable with the results of measurements using the reference HPLC method.

Self-Delivery Janus-Prodrug for Precise Immuno-Chemotherapy of Colitis-Associated Colorectal Cancer.

Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.

A sensitive and high-throughput LC-ESI-MS/MS method to detect budesonide in human plasma: application to an evaluation of pharmacokinetics of budesonide intranasal formulations with and without charcoal-block in healthy volunteers.

Budesonide is one of the intranasal corticosteroids, referred as first-line therapy for allergic rhinitis. Its determination is a challenging task due to its extremely low plasma levels, which limits the progress in the investigation of pharmacokinetics and quality control of preparations. In this study, a sensitive and high-throughput method to determine budesonide in human plasma using budesonide-d8 as the internal standard was developed and validated. A small volume of plasma sample (0.2 mL) was diluted with 0.2 mL water, followed by a solid-phase extraction using Cleanert PEP-2 products. Extracted samples were analyzed by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Chromatographic separation of analytes was performed on an InertSustain AQ-C18 HP column (3 µm, 2.1 × 50 mm) under the reversed-phase condition with gradient elution. With the assay, linear calibration curves were obtained over the concentration range of 10-1200 pg/mL for budesonide, with considerable extraction recoveries (84.7-89.4%), and negligible matrix effects (<4.1). Moreover, the newly developed method was successfully applied to the evaluation of pharmacokinetics of two budesonide intranasal formulations with and without charcoal block in healthy volunteers.

Validation of a HPLC-UV method for the quantification of budesonide in skin layers.

A simple and sensitive HPLC method for the quantification of budesonide in skin layers was developed and validated. Budesonide was extracted from stratum corneum, epidermis and dermis by means of a mixture of acetonitrile:water (recovery > 90%). Budesonide quantification was performed with a RP-C18 column using methanol and water mixture (69:31, v/v) as mobile phase, pumped at 0.8 ml/min. The absorbance was monitored at 254 nm. The method resulted to be selective, linear in the range 0.05-5 or 10 µg/ml, precise and accurate. LLOQ resulted to be 0.05 µg/ml. The developed method appeared to be appropriate for the quantification of budesonide in skin layers at the end of in vitro permeation experiments since the recovery of the applied dose was 97 ± 1%, in line with requirement of the OECD guideline for the testing of the chemicals (Skin absorption: in vitro method).

The Budesonide-Hydroxypropyl-ß-Cyclodextrin Complex Attenuates ROS Generation, IL-8 Release and Cell Death Induced by Oxidant and Inflammatory Stress. Study on A549 and A-THP-1 Cells.

Synthetic glucocorticoids such as budesonide (BUD) are potent anti-inflammatory drugs commonly used to treat patients suffering from chronic inflammatory diseases. A previous animal study reported a higher anti-inflammatory activity with a 2-hydroxypropyl-ß-cyclodextrin (HPßCD)-based formulation of BUD (BUD:HPßCD). This study investigated, on cellular models (A549 and A-THP-1), the effect of BUD:HPßD in comparison with BUD and HPßCD on the effects induced by oxidative and inflammatory stress as well as the role of cholesterol. We demonstrated the protective effect afforded by BUD:HPßCD against cytotoxicity and ROS generation induced by oxidative and inflammatory stress. The effect observed for BUD:HPßCD was comparable to that observed with HPßCD with no major effect of cholesterol content. We also demonstrated (i) the involvement of the canonical molecular pathway including ROS generation, a decrease in PI3K/Akt activation, and decrease in phosphorylated/unphosphorylated HDAC2 in the effect induced by BUD:HPßCD, (ii) the maintenance of IL-8 decrease with BUD:HPßCD, and (iii) the absence of improvement in glucocorticoid insensitivity with BUD:HPßCD in comparison with BUD, in conditions where HDAC2 was inhibited. Resulting from HPßCD antioxidant and anticytotoxic potential and protective capacity against ROS-induced PI3K/Akt signaling and HDAC2 inhibition, BUD:HPßCD might be more beneficial than BUD alone in a context of concomitant oxidative and inflammatory stress.

Successful treatment of a patient with posttransplant IgA nephropathy with targeted release formulation of budesonide.

Recurrence of glomerulonephritis is the third-leading cause of allograft loss. Graft loss due to IgA nephropathy occurs in 10% at 10-year follow-up. The NEFIGAN trial demonstrated that Target Release Formulation (TRF) of budesonide is a specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation with favorable safety profile. We are reporting a case of successful treatment of a patient with posttransplant IgA nephropathy with TRF of budesonide.

Design and in vitro characterization of multistage silicon-PLGA budesonide particles for inflammatory bowel disease.

Inflammatory bowel disease (IBD) affects a confined area of the intestine and, therefore, administration of drugs via oral route is preferable. However, obstacles such as changes in the pH along gastrointestinal tract (GIT), enzymatic activity, and intraluminal pressure may cause low drug availability in the target tissue when delivered orally. Previous studies have pointed out the benefits of using micron-sized particles for targeting inflamed intestinal mucosa and nanoparticles for delivery of anti-inflammatory agents to the affected epithelial cells. We hypothesized that by combining the benefits of micro- and nano- particles, we could create a more efficient delivery system for budesonide, a glucocorticosteroid commonly used for anti-inflammatory IBD therapy. The aim of this study was to develop a novel multistage system for oral delivery designed to increase concentrations budesonidein the inflamed intestinal tissue. The multistage system consists of Stage 1 mesoporous silicon microparticles (S1MP) loaded with stage 2 poly-lactic-glycolic acid (PLGA) budesonide-encapsulating nanoparticles (BNP). BNP were efficiently loaded into S1MP (loading efficiency of 45.9 ± 14.8%) due to the large pore volume and high surface area of S1MP and exhibited controlled release profiles with enhanced drug dissolution rate in biologically relevant pHs. Due to the robustness in acidic pH and their geometry, S1MP protected the loaded budesonide in the acidic (gastric) pH with only 20% release. This allowed for the prolonged release of the BNP in the higher pH conditions (intestinal pH). The sustained release of BNP could facilitate accumulation in the inflamed tissue, enabling BNP to penetrate inflamed mucosa and release active budesonide to the target site. The multistage systems of S1MP and BNP were further evaluated in three-dimensional (3D) in vitro model of IBD and were found to (1) increase accumulation of BNP in the inflamed areas, (2) restore the barrier function of Caco-2 inflamed monolayer, and (3) significantly reduce pro-inflammatory cytokine release almost to the level of the healthy control.

Ternary nanocomposite carriers based on organic clay-lipid vesicles as an effective colon-targeted drug delivery system: preparation and in vitro/in vivo characterization.

This study aimed to develop a new colon-targeted drug delivery system via the preparation of ternary nanocomposite carriers based on organic polymer, aminoclay and lipid vesicles. Budesonide (Bud), an anti-inflammatory drug was chosen as a model drug and encapsulated into three different formulations: liposome (Bud-Lip), aminoclay-coated liposome (AC-Bud-Lip), and Eudragit® S100-aminoclay double coated liposome (EAC-Bud-Lip). The formation of the aminoclay-lipid vesicle nanocomposite was confirmed by energy dispersive X-ray spectrum, transmission electron microscopy, and Fourier-transform infrared spectroscopy. All formulations were produced with a high encapsulation efficiency in a narrow size distribution. Drug release from EAC-Bud-Lip was approximately 10% for 2-h incubation at pH 1.2, implying the minimal drug release in acidic gastric condition. At pH 7.4, EAC-Bud-Lip underwent significant size reduction and exhibited drug release profiles similar to that from AC-Bud-Lip, implying the pH-dependent removal of the outer coating layer. Compared to free Bud solution, EAC-Bud-Lip achieved a higher drug uptake in Caco-2 cells and exhibited a stronger inhibition of TNF-α and IL-6 secretion in LPS-stimulated Raw264.7 cells. Furthermore, a bio-distribution study in mice demonstrated that Eudragit® S100-aminoclay dual coating led to a higher colonic distribution with a longer residence time, which correlated well with the delayed systemic drug exposure in rats. Taken together, the present study suggests that the ternary nanocomposite carrier consisting of Eudragit® S100, aminoclay, and lipid vesicle might be useful as an effective colon-targeted drug delivery system.

Production of fast-dissolving low-density powders for improved lung deposition by spray drying of a nanosuspension.

We combined high-energy wet media milling and spray drying to engineer dry powders for inhalation consisting of geometrically large, low-density particles with superior aerodynamic properties and fast dissolution. Peclet number proved to be a useful instrument to guide choice of the additives and process conditions for generating low-density powders by spray drying. Composite dry powders consisted of milled and stabilized budesonide nanoparticles, leucine or albumin as matrix formers, and ammonium carbonate as a pore former. Powders of different composition showed fairly large and comparable geometric particle sizes (de,50 > 4.4 µm) with effective densities strongly depending on the present matrix former. Powders with lowest density reached an aerosol performance of up to 60%, which is well above most commercial, carrier-based products. It was also demonstrated that the nanomilling step was indispensable to yield such good aerosol performance. Dissolution of aerodynamically classified particle fractions showed a very fast onset and was largely completed within 30 min irrespective of the formulation and the impactor stage. Mathematical kinetic modeling was used to deduce the API dissolution rate coefficient from the results obtained using a modified USP 2 apparatus. Dissolution rate was found to be determined by the properties of the API nanoparticles rather than those of the composite particles. The employment of industrially established, solely water-based processes allows introducing the presented approach as a platform technology for the development of well-performing pulmonary formulations.

Krill Oil-Incorporated Liposomes As An Effective Nanovehicle To Ameliorate The Inflammatory Responses Of DSS-Induced Colitis.

BACKGROUND: Phosphatidylcholine (PC) and Omega-3 fatty acid (Omega-3) are promising therapeutic molecules for treating inflammatory bowel disease (IBD). PURPOSE: Based on the IBD therapeutic potential of nanoparticles, we herein sought to develop Omega-3-incorporated PC nanoparticles (liposomes) as an orally administrable vehicle for treating IBD. METHODS: Liposomes prepared with or without Omega-3 incorporation were compared in terms of colloidal stability and anitiinflammatory effects. RESULTS: The incorporation of free Omega-3 (alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid) into liposomes induced time-dependent membrane fusion, resulting in particle size increase from nm to µm during storage. In contrast, krill oil incorporation into liposomes (KO liposomes) did not induce the fusion and the particle size maintained <250 nm during storage. KO liposomes also maintained colloidal stability in simulated gastrointestinal conditions and exhibited a high capacity to entrap the IBD drug, budesonide (BDS). KO liposomes greatly suppressed the lipopolysaccharide-induced production of pro-inflammatory cytokines in cultured macrophages and completely restored inflammation-impaired membrane barrier function in an intestinal barrier model. In mice subjected to dextran sulfate sodium-induced colitis, oral administration of BDS-entrapped KO liposomes suppressed tumor necrosis factor-α production (by 84.1%), interleukin-6 production (by 35.3%), and the systemic level of endotoxin (by 96.8%), and slightly reduced the macroscopic signs of the disease. CONCLUSION: Taken together, KO liposomes may have great potential as a nanovehicle for oral delivery of IBD drugs.

Thiolated hydroxypropyl-ß-cyclodextrin as mucoadhesive excipient for oral delivery of budesonide in liquid paediatric formulation.

Budesonide (BUD) is a low water soluble (S0 = 5.028·10-5 M) corticosteroid used as preferred therapy for the treatment of Eosinophilic Esophagitis (EoE), a chronic allergic-immune condition with an increased incidence in the paediatric population. Currently there are no commercial medicines indicated for EoE, and, therefore, in the hospital pharmacy the BUD is extemporaneously formulated as viscous oral suspension at the initial dose of 1-2 mg per day for children, highlighting the need of a mucoadhesive drug delivery system (MDDS) that adheres to the site of action and prolongs the therapeutic activity of the administered drug. Considering the ability of hydroxypropyl-ß-cyclodextrin (HP-ß-CD, 100 mM) to increase the water solubility of BUD (SHP-ß-CD = 4.3·10-3 M; K1:1 = 861.11 M-1), a mucoadhesive thiolated HP-ß-CD (HP-ß-CD-SH) was synthesized and characterized by mass spectroscopy, 1H- and 13C NMR techniques. Phase-solubility studies demonstrated the capability of HP-ß-CD-SH (100 mM) to form a reversible water soluble inclusion complex with BUD (SHP-ß-CD-SH = 10.9·10-3 M; K1:1 = 2013.52 M-1), which increases its permanence on the target site as proved by mucoadhesive studies on porcine oesophagus mucosa. HP-ß-CD-SH might be a useful MDDS for the pharmacist to prepare BUD oral liquid formulations at the recommended doses, with pH values below 5, which guarantee the chemical stability of the new mucoadhesive excipient.

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease.

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting ß2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting ß2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.

Impact of drug particle shape on permeability and cellular uptake in the lung.

The generation of inhalable sized particles (1-5 µm) usually involves a particle-processing step; most commonly milling but spray drying has shown to be a suitable alternative. Besides particle size, processing may affect other particle properties, like shape and solid-state. For example, spray drying of salbutamol sulphate leads to spherical shaped predominantly amorphous particles whereas jet milling frequently maintains the irregular shape and the crystallinity of the raw material. The aim of the present study was to investigate whether particle properties, especially shape, change the biological action of the inhaled particles as well. Therefore, highly water soluble salbutamol sulphate and poorly water soluble budesonide were compared regarding dissolution, permeation and preferential uptake by epithelial cells compared to macrophages after jet milling and spray drying. For both drugs the spray dried, predominantly amorphous, particles resulted in lower respirable fractions, but higher permeability and cell uptake rates compared to the needle shaped, predominantly crystalline particles. The distinct particle properties did not affect the dissolution behaviour of salbutamol sulphate. In turn for drugs with lower solubility (budesonide), spray dried particles dissolved slower compared to jet milled particles. Preferential uptake by macrophages was higher for spray dried particles, suggesting that processing may improve targeted delivery. The comparison between murine cell lines and human monocyte derived macrophages primary cells showed similar trends in rate and preference of particle uptake.

In vitro-in vivo correlation of inhalable budesonide-loaded large porous particles for sustained treatment regimen of asthma.

Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predictive of their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior after delivery to rat lung, and finally, an in vitro/in vivo correlation (IVIVC) was established. All formulations reduced approximately 75% of the uptake by RAW264.7 macrophages compared with budesonide/lactose physical mixture and showed a drug release-dependent retention behavior in the lungs of rats. Likewise, the highest budesonide plasma concentration was measured for the formulation revealing the fastest in vitro drug release. After deconvolution of the plasma concentration/time profiles, the calculated in vivo drug release data were successfully utilized for a point-to-point IVIVC with the in vitro release profiles and the predictability of the developed IVIVC was acceptable. Finally, effective therapy was observed in an allergic asthma rat model for the sustained drug release formulations. Overall, the obtained in vitro results correlate well with the systemic drug exposure and the therapeutic performance of the investigated lung-delivered formulations, which can provide an experimental basis for IVIVC development in the pulmonary-controlled delivery system. STATEMENT OF SIGNIFICANCE: Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predicted by their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded PLGA-based LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior, and finally, an in vitro/in vivo correlation (IVIVC) was established. It was demonstrated that the influence of the in vitro drug release profile was obvious during lung retention, systemic exposure, and therapeutic efficacy measurements. An IVIVC (Level A) was successfully established for the budesonide-loaded LPPs delivered to the airspace of rats for the first time. Taken together, the present work will clearly support research and development activities in the field of controlled drug delivery to the lungs.

Biophysical and chemical stability of surfactant/budesonide and the pulmonary distribution following intra-tracheal administration.

Intra-tracheal instillation of budesonide using surfactant as a vehicle significantly decreased the incidence of bronchopulmonary dysplasia or death in preterm infants. The formularity of surfactant supplemented with budesonide and biophysical and chemical stability of the suspension has not been well reported. The aims are to investigate the biophysical and chemical stability of two surfactant preparations, Survanta and Curosurf, supplemented with budesonide. Biophysical property of the surface tension of Survanta and Survanta/budesonide suspension and of Curosurf and Curosurf/budesonide suspension was conducted by a pulsating bubble surfactometer and by a drop shape tensiometer. Chemical stability of Survanta/budesonide and of Curosurf/budesonide suspensions was tested by high-performance liquid chromatography analysis (HPLC). Pulmonary distribution of Survanta/18F-budesonide suspension was examined by a Nano/PET digital scan in rats. The Marangoni effect of Survanta, Curosurf, and budesonide was tested by digital high speed photography. For Survanta supplemented with budesonide, with a concentration ratio of ≥50, the surface tension-lowering activity was minimally affected. Similarly, the surface tension-lowering activity of Curosurf was not significantly affected by addition of budesonide, if the concentration ratio was ≥160. With these concentration ratios of both suspensions, HPLC analysis revealed no new compounds identified. Curosurf as compared to Survanta exhibited a significantly higher Marangoni effect. We conclude that with current dosage recommended for Survanta and Curosurf, both surfactant/budesonide suspensions are biophysically and chemically stable. Both surfactants can act as an effective vehicle for budesonide delivery.

Swellable polymeric particles for the local delivery of budesonide in oral mucositis.

Topical drug delivery in the oral mucosa has its set of challenges due to the unique anatomical and physiological features of the oral cavity. As such, the outcomes of local pharmacological treatments in oral disorders can fail due to unsuccessfully drug delivery. Oral mucositis, a severe inflammatory and ulcerative side effect of oncological treatments, is one of such diseases. Although the damaged tissue is within reach, no approved topical drug treatment is available. Several strategies based on its physiopathology have been implemented and clinically used. Even so, results tend to lack or be insufficient to improve patient's quality of life. The use of corticosteroids has been employed in such strategies due to their strong anti-inflammatory action. Typically, these are administrated in simple liquid formulations, where the drug is dispersed or solubilized, lacking the ability to maintain local concentration. In this work, we propose the development of a biocompatible delivery system with boosted abilities of retention and control release of budesonide, a corticosteroid with an elevated ratio of topical anti-inflammatory to systemic action. Through spray-drying, polymeric particles of Chitosan and Eudragit® E PO were produced and characterized for the vectorization of this drug.

Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

PURPOSE: Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. METHODS: Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. RESULTS: The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. CONCLUSIONS: Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.

Inhalable co-amorphous budesonide-arginine dry powders prepared by spray drying.

Spray drying is a well-established technology to produce inhalable dry powders. However, the amorphous nature of the particles typically obtained from the process can lead to physically and chemically unstable products. The purpose of this study was to investigate whether spray-drying could be used as a manufacturing method to produce co-amorphous drug amino acid powders with high physical stability and inhalable particulate properties. Budesonide (BUD), a compound for the treatment of lung inflammation, was co-spray-dried at a 1:1 M ratio with arginine (ARG) to produce co-amorphous powders. Two experimental factors, the solid concentration (0.85, 1.00 and 1.13%, w/v) and the ethanol concentration (55 and 75%, v/v) of the feed solution were varied to investigate the formation of co-amorphous BUD-ARG. X-ray powder diffraction (XRPD), modulated temperature differential scanning calorimetry (mDSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used for solid state characterization. The particle morphology, the median mass aerodynamic diameter and the aerodynamic properties of the resulting co-amorphous powders were investigated using scanning electron microscopy (SEM), an aerodynamic particle sizer (APS), and a next generation impactor (NGI), respectively. Furthermore, the physical stability of the obtained dry powder was examined. The co-spray-dried BUD-ARG samples prepared within the experimental range were predominantly amorphous. However, it was observed that while using the feed solution with both high solid and ethanol concentrations, some residual crystallinity related to budesonide was observed. The formation of co-amorphous BUD-ARG, rather than two separate amorphous phases, was confirmed by mDSC analyses. In addition, FTIR analyses indicated that hydrogen bonding occurs between the carbonyl groups of BUD and the amide groups of ARG in the co-amorphous BUD-ARG mixtures. The NGI results indicated that the particulate properties of the co-spray-dried co-amorphous BUD-ARG were at an inhalable range, with emitted doses >80%, and fine particle fractions >50%. In addition, the co-amorphous BUD-ARG was more physically stable than spray-dried BUD when stored at room temperature under dry conditions. This study demonstrated that spray drying is a useful manufacturing approach to produce physically stable co-amorphous dry powders for inhalation purposes.