Beclomethasone Research Articles

Investigation of Spray Drying Parameters to Formulate Novel Spray-Dried Proliposome Powder Formulations Followed by Their Aerosolization Performance

Background: Spray drying, whilst a popularly employed technique for powder formulations, has limited applications for large-scale proliposome manufacture. Objectives: Thus, the aim of this study was to investigate spray drying parameters, such as inlet temperature (80, 120, 160, and 200 °C), airflow rate (357, 473, and 601 L/h) and pump feed rate (5, 15, and 25%), for individual carbohydrate carriers (trehalose, lactose monohydrate (LMH), and mannitol) for 24 spray-dried (SD) formulations (F1–F24). Methods: Following optimization, the SD parameters were trialed on proliposome formulations based on the same carriers and named as spray-dried proliposome (SDP) formulations. Drug delivery of the formulations was assessed using a dry powder inhaler (DPI) in combination with a next-generation impactor (NGI). Results: Upon analysis, formulations F6 (SD-mannitol), F15 (SD-trehalose), and F20 (SD-LMH) demonstrated high production yields (84.01 ± 3.25, 72.55 ± 5.42, and 70.03 ± 3.39%, respectively), small particle sizes (2.96 ± 1.42, 4.55 ± 0.46, and 5.16 ± 1.32 µm, respectively) and low moisture contents (0.25 ± 0.03, 3.76 ± 0.75, and 1.99 ± 0.77%). These SD optimized parameters were then employed for SDP formulations employing dimyristoly phosphatidylcholine (DMPC) as a phospholipid and beclomethasone dipropionate (BDP) as the model drug. Upon spray drying, SDP-mannitol provided the highest production yield (82.45%) and smallest particle size (2.64 µm), as well as high entrapment efficiency (98%) and a high fine particle dose, fine particle fraction, and respirable fraction (285.81 µg, 56.84%, 86.44%, respectively). Conclusions: The study results are a promising step in the optimization of the large-scale manufacture of proliposome formulations and highlight the versatility of the instrument and variability of formulation properties with respect to the carriers employed for targeting the pulmonary system using dry powder inhalers.

Pharmaceutical, Clinical, and Regulatory Challenges of Reformulating Pressurized Metered-Dose Inhalers to Reduce Their Environmental Impact.

The chlorofluorocarbons (CFCs) that were used as propellants in early pressurized metered-dose inhalers (pMDIs) had substantial ozone-depleting potential. Following the Montreal Protocol in 1987, the manufacture of a range of ozone-depleting substances, including CFCs, was gradually phased out, which required the propellants used in pMDIs to be replaced. Current pMDIs use hydrofluoroalkanes (HFAs) as propellants, such as 1,1,1,2-tetrafluoroethane (HFA-134a). Although these HFAs have no ozone-depleting potential, they have a high global warming potential (GWP), and consequently, their use is being phased down. One option for the discontinuation of HFA use in inhalers would be to discontinue all pMDIs, switching patients to dry powder inhalers (DPIs). However, a switch from pMDIs to DPIs may not be a clinically appropriate option for some patients; furthermore, the full lifecycle carbon footprint and the overall environmental impact of different inhalers should be considered. An alternative is therefore to reformulate the current HFA pMDIs to use low-GWP propellants, such as 1,1-difluoroethane (HFA-152a). This article summarizes the various steps and challenges associated with this change, illustrated using data from the inhaled triple combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide, a complex formulation of three molecules in a solution that contains liquid-phase propellant.

Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial

BackgroundThe single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD.MethodsThis double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7–10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3.ResultsOf 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate.ConclusionsIn patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance.Trial registrationClinicalTrials.gov (NCT05097014), registered 27th October 2021.

Choice of therapy for patients who do not achieve control over bronchial asthma on basic therapy with medium doses of inhaled glucocorticosteroids/long-acting β2-agonists. Resolution of the Expert Council

Recently, new drugs for the treatment of bronchial asthma (BA) have been registered in the Russian Federation: fixed triple combinations, which include inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) and anticholinergics, high-dose combinations of beclomethasone dipropionate (BDP) and formoterol (FORM) in the form of an extrafine metered-dose aerosol, which allows prescribing 800 mcg of extrafine BDP and 24 mcg of FORM per day.The aim of publishing the resolution of the Expert Council “Choice of therapy for patients who do not achieve control over bronchial asthma on basic therapy with medium doses of inhaled corticosteroids/long-acting β2-agonists” was to compare possible ways of therapy optimization and propose criteria for choosing therapeutic alternatives based on the individual clinical and phenotypic characteristics.Conclusion. If a patient does not achieve asthma control (or had asthma exacerbations over the past year) with alternative therapy at step 4, it is advisable to switch to a maintenance and relief therapy (MART) regimen with fixed combination of inhaled corticosteroids/formoterol and with medium doses of ICS in the maintenance part of the regimen. In patients with poor control on alternative therapy with a medium dose of ICS, it is advisable to consider increasing the dose of ICS as part of an ICS/LABA combination or as part of a triple combination instead of switching to MART. Switching to a medium- or high-dose triple combination is especially useful for patients with fixed obstruction and when bronchial asthma is combined with chronic obstructive pulmonary disease. In patients who require high-dose therapy, it is advisable to consider prescribing high doses of ICS using an extrafine combination of BDP/FORM (400/12 mcg in the morning and evening). If MART with a medium dose of ICS does not prevent exacerbations, provide normal spirometry results and/or good control of symptoms, MART in combination with an anticholinergic drug should be used at step 5. If triple therapy or high doses of ICS/LABA are insufficiently effective, biological therapy should be considered.

Exposure effects of synthetic glucocorticoid drugs on skeletal developmental and immune cell function in zebrafish

Synthetic glucocorticoids (GCs) are used to treat a wide range of human health conditions and as such are frequently detected in the aquatic environment. This, together with the highly conserved nature of the glucocorticoid system across vertebrates means that the potential for biological effects of GCs in fish is relatively high. Here, we found that exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of 4 of the most widely used synthetic GCs (beclomethasone dipropionate, budesonide, fluticasone propionate, and prednisolone), from 0 to 4 days post fertilisation (dpf), resulted in no effects on embryo-larval development or bone and cartilage formation. However, after exposure to equivalents of human therapeutic plasma levels, developmental abnormalities were observed that included pericardial oedema, blood pooling and alterations in jaw cartilage. Furthermore, using a double transgenic zebrafish osteoblast and chondrocyte reporter line, exposure up to 10 dpf resulted in alterations to lower jaw cartilage and bone development for all compounds at, and above, human therapeutic plasma concentrations. In the case of beclomethasone dipropionate, a reduction in lower jaw intercranial distance was observed at the environmentally relevant concentration of 0.1 μg/L. Using further transgenic reporter lines with fluorescently tagged neutrophils and macrophages, we also show exposure of embryo-larvae (0–4 dpf) to the GCs tested resulted in altered immune cell migration, but only at relatively high exposure concentrations. Collectively, our findings show GC exposure impacts embryo-larval zebrafish development, immune function, and skeletal formation, but predominantly at concentrations greater than those currently reported for the aquatic environment. Despite this, however, it is suggested that studies with longer exposure times, and to mixtures of multiple GCs (many GCs act via the same mechanism of action) are warranted before we can confidently assert that these commonly detected contaminants do not pose a risk to fish in the wild.

The First Validation HPTLC Method for Simultaneous Estimation of Beclomethasone Dipropionate and Fusidic Acid in Pure and Pharmaceutical Dosage Form

The First Validation HPTLC Method for Simultaneous Estimation of Beclomethasone Dipropionate and Fusidic Acid in Pure and Pharmaceutical Dosage Form

Efficacy of Beclomethasone Dipropionate in Lowering Fecal Calprotectin Levels in Patients with Ulcerative Colitis in Clinical Remission and at Risk of Relapse: The Becalcu Randomized, Controlled Trial

Introduction: Identifying novel treatment strategies for patients with ulcerative colitis (UC) and at risk of relapse is critical. The objective of this study was to assess the efficacy of beclomethasone dipropionate (BDP) in lowering fecal calprotectin (FC) levels in UC patients in clinical remission and at risk of relapse. Methods: This multicenter study comprised a double-blind, randomized, placebo-controlled phase (part I) and an open-label, non-randomized phase (part II). Eligible participants with UC in clinical remission treated with 5-aminosalicylic acid and with FC levels ≥250 μg/g were randomized to receive 5 mg/day of BDP or placebo for 4 weeks (part I). At week 5, patients with FC ≥100 μg/g were treated with 5 mg/day of BDP for 4 weeks (part II), and FC levels were tested at week 9. Results: Forty-three patients were randomized: 22 received BDP (group A) and 21 placebo (group B). At week 4, 13 patients (59.1%) in group A and 3 (17.6%) in group B had FC levels <100 μg/g (p value = 0.010). In the double-blind phase of the study, no patient relapsed in group A and 4 in group B (p value = 0.049). Both treatment groups showed a favorable safety profile, with the most common adverse events being gastrointestinal disorders. Conclusion: In this multicenter, randomized clinical trial including patients with UC in clinical remission but with elevated FC, BDP was efficacious in reducing FC and well-tolerated.

Otitis in paediatric practice: clinic presentation, diagnosis, role of topical therapy

The article considers the main pathological processes in the outer and middle ear, which are detected at the primary paediatric visit. A particular focus has been placed on the importance of otoscopy and the need for sustainable routing of a child with ear pain. The basic principles for the treatment of acute external and otitis media in children are outlined, and indications for additional examinations and systemic antimicrobial therapy are determined. The benefits of topical combination ear drops in the treatment of acute external and otitis media are presented. The benefits of combination ear drops in the treatment of ear pathology in children from 6 years of age are demonstrated by examples of clinical studies and retrospective analysis of clinical efficacy. Clinical cases from our own observations are presented: a 7-year-old patient with acute non-perforative otitis media and a 12-year-old patient with acute exacerbation of chronic external otitis, myringitis. The combination ear drops containing chloramphenicol, beclomethasone dipropionate (anhydrous), clotrimazole and lidocaine hydrochloride monohydrate demonstrated high clinical efficacy. The combination drug with a beneficial and clinically proven effect can help solve the issue of otitis in children from 6 years of age. The authors have developed a treatment and prevention reminder for ear pathologies in children, which will help the paediatrician explain the main principles of treatment and prevention of otitis media to parents in an easily accessible form. It was concluded that ear pathology is a current and multi-etiological challenge that requires attention and expert knowledge of a paediatrician. The active parental involvement in ear pathology prevention in their child will help their children to grow physically healthy.

Advances in inhaler therapy for asthma and chronic obstructive pulmonary disease: a comprehensive review of Fostair™ and Trimbow™.

The management of asthma and chronic obstructive pulmonary disease (COPD) poses considerable challenges due to the intricate nature of these respiratory conditions. Fostair™ and Trimbow™, two pressurized metered dose inhalers, have emerged as noteworthy therapeutic options for treating both asthma and COPD. Fostair combines an inhaled corticosteroid, specifically beclometasone dipropionate, with a long-acting beta2-agonist, formoterol fumarate dihydrate, offering a dual-action approach to mitigate airway inflammation and bronchoconstriction. Conversely, Trimbow integrates a tri-particulate formulation consisting of beclometasone dipropionate, formoterol fumarate dihydrate, and glycopyrronium bromide, providing a comprehensive strategy to target the pathophysiology of COPD and asthma. Recent clinical trials have underscored Trimbow's superior efficacy compared with Fostair, particularly in terms of reducing exacerbation rates and enhancing lung function. However, despite their therapeutic promise, both inhalers encounter challenges, including limited generalizability of study findings and a disparity between in vitro and human trial results. This literature review offers an in-depth analysis of Fostair and Trimbow, delving into their mechanisms of action, clinical applications, and outcomes in human studies for asthma and COPD. Additionally, the review discusses the role of combination therapy in managing respiratory diseases and underscores the necessity for further research to address existing knowledge gaps and optimize therapeutic outcomes.

Optimization of an in vitro method for assessing pulmonary permeability of inhaled drugs using alveolar epithelial cells

IntroductionInhalation of drugs for the treatment of pulmonary diseases has been used since a long time. Due to lungs' larger absorptive surface area, delivery of drugs to the lungs is the method of choice for different disorders. Here we present the establishment of a comprehensive permeability model using Type II alveolar epithelial cells and Beclomethasone Dipropionate (BDP) as a model drug delivered by pressurized metered dose inhaler (pMDI). MethodsUsing Type II alveolar epithelial cells, the method was standardized for parameters viz., cell density, viability, incubation period and membrane integrity. The delivery and deposition of drug were using the pMDI device with a Twin Stage Impinger (TSI) modified to accommodate cell culture insert having monolayer of cells. The analytical method for simultaneous estimation of BDP and Beclomathasone-17-Monopropionate (17-BMP) was validated as per the bioanalytical guidelines. The extent and rate of absorption of BDP was determined by quantifying the amount of drug permeated and the data represented by calculating its apparent permeability. ResultsType II alveolar epithelial cells cultured at 0.55 × 105 cells/cm2 for 8–12 days under air-liquid interface were optimized for conducting permeability studies. The data obtained for absorptive transport showed a linear increase in the drug permeated against time for both BDP and 17-BMP along with proportional permeability profile. DiscussionWe have developed a robust in vitro model to study absorptive rate of drug transport across alveolar layer. Such models would create potential value during formulation development for comparative studies and selection of clinical candidates.

Anti-Inflammatory Potential of Beclometasone-Loaded Filomicelles on Activated Human Monocytes.

Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, is encapsulated. Therefore, this work used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease (IBD). The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into nontargeted cells. This work successfully establishes a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles is further investigated on lipopolysaccharide (LPS) stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a, and IL-23 release after 24 h. Additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstratepromising results with significant immune response suppression in stimulated monocytes after 2 and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids.

Quality by design‐engineered reversed‐phase high‐performance liquid chromatography method development and validation for simultaneous estimation of neomycin sulfate and beclomethasone dipropionate in bulk and pharmaceutical dosage form

AbstractThe aim of this study was to develop and validate a robust reversed‐phase high‐performance liquid chromatography (RP‐HPLC) method for the simultaneous estimation of neomycin sulfate (NEO) and beclomethasone dipropionate (BECLO) in both bulk drug and pharmaceutical dosage forms. The analysis was conducted using the Box‐Behnken design. The separation of NEO and BECLO was conducted on a Phenomenex Luna C‐18 column (4.6 × 150 mm, 5 µm), employing a mobile phase comprising a mixture of methanol and trifluoroacetic acid in a ratio of 88:12% v/v. The separation was performed at a flow rate of 0.6 mL/min. NEO and BECLO were analyzed at a wavelength of 240 nm employing a photodiode array detector. The validation of the methodology followed the guidelines outlined in the International Council for Harmonization Q2 R (1). The validation process involved assessing critical parameters such as linearity, accuracy, system suitability, precision, and robustness. The results for each parameter were found to be within the acceptable range. The results indicate that the established RP‐HPLC method can effectively be employed for the routine analysis of NEO and BECLO in bulk drug and pharmaceutical dosage forms.

Budesonide Attains Its Wide Clinical Profile by Alternative Kinetics.

The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.

A systematic review of randomised controlled trials on topical nasal steroids.

Intranasal corticosteroids (INCs) are the first line of therapy for chronic sinonasal conditions such as rhinitis and rhinosinusitis. Among these, one of the most frequently used is beclomethasone dipropionate (BDP). Over the years many studies have evaluated the efficacy of BDP as part of therapy for chronic rhinosinusitis (CRS) and allergic rhinitis (AR) along with nasal washes, which seems to be very well tolerated. To analyse the data in the literature regarding the various therapeutic regimens of BDP in different sinonasal disease and their efficacy and tolerability. Using different search engines, the posology, efficacy, and tolerability of BDP were reviewed and a total of 64 full-length articles were examined for eligibility. After applying inclusion and exclusion criteria, 4 articles were reviewed. BDP is among the group of INCs with significant improvement of nasal symptoms and has good efficacy and safety. BDP nasal spray is one of the most frequently prescribed INC for rhinitis and rhinosinusitis. Treatment with BDP resulted in significant and clinically meaningful improvements in nasal symptoms associated with AR and CRS. BDP is well tolerated, and the safety profile is similar to that of placebo in most patients. These results, in conjunction with the significant benefit reported in subjects with CRS and AR, provide convincing evidence of the overall effectiveness of BDP for the treatment of the full spectrum of sinonasal disease.

Beclomethasone dipropionate-loaded colon-targeting UniORV® for effective treatment of colitis

This study was undertaken to develop novel colon-targeting UniORV® (cUO) of beclomethasone dipropionate (BDP) for strategic oral delivery to the disease site of colitis. BDP-loaded cUO (cUO/BDP) was characterized regarding morphology and dissolution behaviors. Plasma levels of beclomethasone 17-monopropionate (17-BMP), a metabolite of BDP, were measured after oral administration of BDP samples to rats. Anti-inflammatory effects of oral BDP samples (50 μg-BDP/kg) were assessed in a rat model of colitis. The cUO/BDP was found to be a 300 μm-sized spherical particle. Compared with crystalline BDP, cUO/BDP exhibited a marked improvement in dissolution behavior only under colonic conditions, and the dissolution of BDP from cUO was negligible under upper gastrointestinal conditions. Oral BDP solution (5 mg-BDP/kg) led to a rapid increase in the plasma 17-BMP level with a maximum plasma concentration (Cmax) as high as 620 ng/mL and time to Cmax of 0.9 h. In contrast, Cmax of oral cUO/BDP was below 5 ng/mL, suggesting suppressed upper gastrointestinal absorption and enhanced delivery to the colon. In the rat model of colitis, compared with BDP solution, oral cUO/BDP significantly attenuated neutrophilia in the colon. The use of cUO may be a promising strategy to enhance the efficacy of BDP against colitis.

Development and Validation of a Viable and User-Friendly Spectrophotometric Analytical Method for Estimation of Assay of Formoterol and Beclomethasone in Metered Dose Inhaler Formulation

The primary aim of this research endeavor is to innovate a viable and user-friendly UV spectroscopic approach for quantifying formoterol and beclomethasone within metered dose inhalers (MDIs). These formulations, amalgamating Beclomethasone Dipropionate (BDP) and Formoterol Fumarate (FF), are extensively employed in managing bronchial asthma and chronic obstructive pulmonary diseases. Although analytical techniques already exist for assessing formoterol and beclomethasone in combination dry powder inhalers, this study concentrates on devising and validating a UV spectrophotometric method for simultaneously quantifying formoterol fumarate and Anhydrous Beclomethasone Dipropionate in Pressurized Metered Dose Inhalers (pMDIs). The estimation is performed at a wavelength of 240 nm for Beclomethasone Dipropionate and 216 nm for Formoterol Fumarate. Both drugs demonstrate satisfactory linearity within the concentration range of 10-30 μg/ml for BDP and 0.3 to 0.9 μg/ml for FF at wavelengths of 240 nm (r^2=0.999) and 216 nm (r^2=0.999), respectively. The Beer-Lambert law is adhered to within the concentration range of 10-30 μg/ml for BDP and 0.3-0.9 μg/ml for FF. The proposed methods are subjected to validation following ICH guidelines to assess accuracy, method precision, specificity, among other parameters. As a result, the proposed method can be effectively employed for the simultaneous determination of Beclomethasone Dipropionate and Formoterol Fumarate in routine analytical applications, offering a rapid and reliable solution for pharmaceutical analysis in the field.

Alginate aerogels by spray gelation for enhanced pulmonary delivery and solubilization of beclomethasone dipropionate

Aerogel technology is an emerging platform that offers alternative and cost-effective dry carriers with advanced performances for the pharmaceutical industry. The innovative combination of compressed air-assisted spray gelation and “green” supercritical fluid (SCF) technology was used in this study to produce alginate aerogel microparticles with adequate properties for pulmonary drug delivery. Beclomethasone dipropionate (BDP), a poorly water-soluble anti-inflammatory drug for asthma treatment, was loaded into alginate aerogel particles by SCF-assisted impregnation ensuring high loading, as well as the amorphization of the drug. The production of aerogels was optimized through the fine-tuning of parameters in compressed air-assisted spray gelation, specifically adjusting the air flow rate and the pump speed. Alginate aerogels were aimed to be produced with an appropriate aerodynamic diameter from 1 to 5 µm, measured by in vitro deposition tests with Next Generation impactor and potential for deep lung penetration. Nuclear magnetic resonance (NMR) relaxometry was used to assess aerogel hydration and unveiled structure–property relationships leading to the sudden release of the drug. Finally, in vitro cytotoxicity tests in fibroblasts and ex vivo permeability tests were conducted. These biological tests confirmed the excellent biocompatibility of the aerogel formulations and demonstrated the efficient deposition of BDP in porcine bronchial tissues assisted by the porous alginate aerogel carrier.

Drug solubility in biorelevant media in the context of an inhalation-based biopharmaceutics classification system (iBCS)

An inhalation-based Biopharmaceutics Classification System for pulmonary drugs (iBCS) holds the perspective to allow for scientifically sound prediction of differences in the in vivo performance of orally inhaled drug products (OIDPs).A set of nine drug substances were selected, that are administered via both the oral and pulmonary routes. Their solubility was determined in media representative for the oral (Fasted State Simulated Intestinal Fluid (FaSSIF)) and pulmonary (Alveofact medium and Simulated Lung Fluid (SLF)) routes of administration to confirm the need for a novel approach for inhaled drugs. The complexity of these media was then stepwise reduced with the purpose of understanding the contribution of their components to the solubilizing capacity of the media. A second reason for varying the complexity was to identify a medium that would allow robust but accurate dissolution testing. Hence, Hank’s balanced salt solution (HBSS) as a medium used in many in vitro biological tests, non-buffered saline solution, and water were included.For some drug substances (salbutamol sulfate, tobramycin, isoniazid, and tiotropium bromide), no significant differences were observed between the solubility in the media used. For other drugs, however, we observed either just small (rifampicin, budesonide, salmeterol) or unexpectedly large differences (beclomethasone dipropionate).Based on the minimum theoretical solubility required for their common pulmonary dose in 10 ml of lung lining fluid, drug solubility was classified as either high or low. Two high solubility and two low solubility compounds were then selected for refined solubility testing in pulmonary relevant media by varying their content of phospholipids, surfactant proteins and other proteins.The solubility of drug substances in simulated lung lining fluids was found to be dependent on the physicochemical properties of the drug substance and the composition of the media. While a pulmonary dissolution medium that would fit all drugs could not be established, our approach may provide guidance for finding the most suitable dissolution medium for a given drug substance and better designing in vitro tests for predicting the in vivo performance of inhalable drug products.

P1023 Variability in Mesalazine Management for Ulcerative Proctitis Include Doses, Route of Administration and Use of Fecal Calprotectin: Insights from Clinical Practice Across Spain Beyond Clinical Guidelines

Abstract Background Despite universal use of mesalazine in ulcerative colitis treatment, many aspects of clinical practice remain unclear or are not even addressed in clinical guidelines, leading to significant variations in mesalazine management among clinicians. We aimed to gather different approaches of mesalazine use in ulcerative proctitis (UP). Methods After discussion of a clinical case, a predefined questionnaire was anonymously answered throughout a series of meetings held at 10 different locations in Spain. Results were categorized according to experience levels and inflammatory bowel disease (IBD) focus. Results 259 IBD treating gastroenterologists were engaged; 84% had &amp;lt;10 years of experience and 25% had a specific focus on IBD. Most participants (84%) manage UP based on clinical symptoms (i.e. fecal urgency). In case of a clinically moderate-severe UP, 81% would initiate treatment with high dose of combined mesalazine, while 11% proposed only suppositories. 60% of participants would assess response at 4 weeks. If clinical remission achieved, 85% would use fecal calprotectin (FC) to assess deep remission. Upon initial failure of combined mesalazine treatment at standard dose, 59% attempt optimizing mesalazine doses, while 38% add beclomethasone dipropionate. Younger physicians without specific focus on IBD prefer modifying mesalazine doses (70.5% vs 37.1%), (P=0,006), whereas more experienced physicians with monographic dedication prefer adding beclomethasone dipropionate (60% vs 29.4%), (P=0,006). For maintenance therapy (oral or topical mesalazine) the most important drivers in therapeutic decision-making were severity of the initial flare (40%) and patient preferences (36%). After a moderate-severe flare of UP, 80% would recommend maintenance therapy with high dose oral mesalazine and 3 suppositories/week. For monitoring, less experienced physicians and those not working in IBD units more frequently relied only on clinical parameters (26.6% vs. 8.7%, p=0.01), using FC to a lesser extent (73% vs. 88%, p=0.1) compared to more experienced and IBD focused physicians. In the case of elevated FC in asymptomatic patients, 49% would prefer to scope, while 47% increase mesalazine dose directly. The preferred high dose of mesalazine was 4g (55%) or 4-5g (44%). 73% would not reduce the dose upon achieving remission. Only 75% actively investigate therapeutic adherence. Conclusion Management of mesalazine in UP patients is highly heterogeneous, and clinical guidelines do not address all issues arising in clinical practice. Nevertheless, clinicians in our setting often use high oral and rectal mesalazine doses for both induction and maintenance and they commonly monitor patients using FC.

Analytical Method Development and Validation of Beclomethasone Dipropionate and Fusidic Acid in pure and Pharmaceutical Dosage Form (Cream) by RP-HPLC

A simple, rapid, specific, cheap, eco-friendly, and accurate RP-HPLC method for simultaneous estimation of Beclomethasone Dipropionate and Fusidic Acid in pure and combination drugs has been developed and validated. A stationary phase of BDS Hypersil C18 ((250mm x 4.6m, 5m) and a mobile phase of Acetonitrile: Methanol: Orthophosphoric acid (60:20:20v/v) were used for the separation. The flow rate was continued at 1.0 ml/min and the effluent was observed at 230nm. The designated situations were appropriate for separating Beclomethasone Dipropionate and Fusidic acid eluted with a mean retention time of 7.2 and 5.1 minutes, respectively. The planned technique was validated as per the International Council for Harmonisation recommendation. Its linearity, specificity, system suitability, accuracy and precision, limit of detection, limit of quantitation, and robustness are some of the parameters that have been validated. The concentration range produced linear calibration curves of 1-6g/ml and 2-12g/ml for Beclomethasone Dipropionate and Fusidic Acid with R2 = 0.9961 and 0.9963. Percent RSD values for both intraday and interday were determined to be less than 2.0%. Demonstrating the accuracy of the approach. The technique was proven to be reliable. A successful application of the developed RP-HPLC method for the quantification of Beclomethasone Dipropionate and Fusidic Acid in marketed semi-solid dosage form (Cream).