Curcumin activates G protein-coupled receptor 97 (GPR97) in a manner different from glucocorticoid.

Curcumin is a yellow pigment in turmeric (Curcuma longa) with various physiological effects in the body. To elucidate the molecular mechanisms by which bioactive compounds exert their function, identification of their molecular targets is crucial. In this study, we show that curcumin activates G protein-coupled receptor 97 (GPR97). Curcumin dose-dependently activated serum-response element-, but not serum-response factor-response element-, nuclear factor of activated T-cell-response element-, or cAMP-response element-, mediated transcription in cells overexpressed with GPR97. The structure-activity relationship indicated that (i) the double-bonds of the central 7-carbon chain were essential for activation; (ii) a methoxy group on the aromatic ring was required for maximal activity; (iii) the addition of glucuronic acid moiety or a methoxy group to the aromatic ring, but not the methylation of the aromatic p-hydroxy group, eliminated the activity; (iv) the stability of curcumin would be related to receptor activation. Both mutant GPR97(T250A) lacking the cleavage at GPCR proteolysis site and mutant GPR97(ΔN) lacking the N-terminal extracellular region were activated by curcumin and its related compounds similar to wild-type GPR97. In contrast, the synthetic glucocorticoid beclomethasone dipropionate and l-Phe activated wild-type GPR97 and GPR97(T250A), but not GPR97(ΔN). Moreover, curcumin exerted an additive effect on the activation of wild-type GPR97 with beclomethasone dipropionate, but not with l-Phe. Taken together, these results indicate that curcumin activates GPR97 coupled to Gi/Go subunit, and suggest that curcumin and glucocorticoid activate GPR97 in a different manner.

Relationship Between Geometric and Aerodynamic Particle Size Distributions in the Formulation of Solution and Suspension Metered-Dose Inhalers.

The relationship between the geometric particle size distribution (GPSD) and the aerodynamic particle size distribution (APSD) of commercial solution and suspension metered-dose inhaler (MDI) formulations was assessed to clarify the use of GPSD to estimate the APSD. The size distribution of particles discharged from four suspension and four solution MDIs was measured using the Inas®100 light-scattering spectrometer and a Next Generation Impactor. The conversion factor was calculated by measuring the GPSD and APSD of MDIs. The morphology and physical properties of MDIs were studied using scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Six of the eight MDIs showed similar conversion factor profiles, irrespective of their composition and formulation types. Applying the conversion factor obtained from one of the six MDIs resulted in a particle size distribution comparable to each APSD except for some formulations. The two other solution MDIs, which contained citric acid, had much higher and variable conversion factors. SEM images and DSC scans of the solids obtained by nebulization of the solutions containing beclomethasone and/or citric acid showed the formation of a paste-like amorphous solid. These results indicated that APSD of solution and suspension MDIs that form rigid particles may be estimated by using the conversion factor and GPSD. Contrarily, the estimation is more difficult in formulations that tend to lose the particle structure during the measurement.

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.

Evaluation of Bio-relevant Mouth-Throat Models for Characterization of Metered Dose Inhalers.

For inhalation drug characterization, the traditionally used USP induction port provides limited in vivo predictive capability because it does not adequately mimic airway geometry. In this study, various bio-relevant mouth-throat (MT) models, including Alberta Idealized Throat (AIT), and 3D printed large/medium/small-sized VCU (Virginia Commonwealth University) models were evaluated using two metered dose inhaler (MDI) drug products: a solution MDI containing beclomethasone dipropionate (BDP-MDI) and a suspension MDI containing fluticasone propionate (FP-MDI). For BDP-MDI, use of VCU large and small MT models resulted in a significantly higher MT deposition and lower fine particle fraction (FPF) compared with the other MT models. In the case of FP-MDI, the three VCU models resulted in higher MT deposition and lower FPF compared with the USP induction port and AIT. Overall, the in vitro testing results for the suspension MDI were more sensitive to geometric differences of the MT models than those for the solution MDI. Our results suggest that in vitro characterization of MDI products can be influenced by many factors, including the type of formulation, the MT geometry, shape, internal space volume, and the material used to make the MT models.

Optimization and Evaluation of Beclomethasone Dipropionate Micelles Incorporated into Biocompatible Hydrogel Using a Sub-Chronic Dermatitis Animal Model.

The current study is concerned with the development and characterization of mixed micelles intended for the dermal delivery of beclomethasone dipropionate, which is a topical corticosteroid used in the management of atopic dermatitis. Mixed micelles were prepared using thin-film hydration technique, employing different concentrations of pluronic L121 with either poloxamer P84 or pluronic F127 with different surfactant mixture-to-drug ratios. The prepared formulae were characterized concerning entrapment efficiency, particle size, and zeta potential. Two formulae were chosen for ex vivo skin deposition studies: one formulated using pluronic L121/poloxamer P84 mixture while the other using pluronic L121/pluronic F127 mixture. The optimum formula with the highest dermal deposition was subjected to morphological examination and was formulated as hydroxypropyl methylcellulose hydrogel. The hydrogel was evaluated regarding viscosity and was subjected to ex vivo deposition study in comparison with the commercially available cream Beclozone®. In vivo histopathological study was conducted for both the hydrogel and Beclozone® in order to evaluate their healing efficiency. In vivo histopathological study results showed that the prepared hydrogel successfully treated sub-chronic dermatitis in an animal model within a shorter period of time compared to Beclozone®, resulting in better patient compliance and fewer side effects.

Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers.

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0-2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7-9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005-0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4-2.5 µm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.

A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition.

PURPOSE: To characterise a biorelevant simulated lung fluid (SLF) based on the composition of human respiratory tract lining fluid. SLF was compared to other media which have been utilized as lung fluid simulants in terms of fluid structure, biocompatibility and performance in inhalation biopharmaceutical assays. METHODS: The structure of SLF was investigated using cryo-transmission electron microscopy, photon correlation spectroscopy and Langmuir isotherms. Biocompatibility with A549 alveolar epithelial cells was determined by MTT assay, morphometric observations and transcriptomic analysis. Biopharmaceutical applicability was evaluated by measuring the solubility and dissolution of beclomethasone dipropionate (BDP) and fluticasone propionate (FP), in SLF. RESULTS: SLF exhibited a colloidal structure, possessing vesicles similar in nature to those found in lung fluid extracts. No adverse effect on A549 cells was apparent after exposure to the SLF for 24 h, although some metabolic changes were identified consistent with the change of culture medium to a more lung-like composition. The solubility and dissolution of BDP and FP in SLF were enhanced compared to Gamble's solution. CONCLUSION: The SLF reported herein constitutes a biorelevant synthetic simulant which is suitable to study biopharmaceutical properties of inhalation medicines such as those being proposed for an inhaled biopharmaceutics classification system.

Applicability of Bipolar Charge Analyzer (BOLAR) in Characterizing the Bipolar Electrostatic Charge Profile of Commercial Metered Dose Inhalers (MDIs).

PURPOSE: To investigate the applicability of Bipolar Charge Analyzer (BOLAR), a new commercial instrument developed by Dekati Ltd., in simultaneously characterizing the bipolar electrostatic charge profile and measuring the size distribution of commercial metered dose inhalers (MDIs). METHODS: Intal Forte(®) (sodium cromoglycate), Tilade(®) (nedocromil sodium), Ventolin(®) (salbutamol sulphate), and QVAR(®) (beclomethasone dipropionate) were used as model MDIs in this study. Three individual actuations of each MDI were introduced into the BOLAR at an air flow rate of 60 l/min. Charge and mass profiles for each actuation were determined. RESULTS: The BOLAR was found to have better performance in collecting valid charge data (≥80%) than valid mass data (≥50%). In all tested products, both positively and negatively charged particles were found in five defined size fractions between zero and 11.6 µm, with the charge magnitude decreased with increasing particle size. The net charge profiles obtained from the BOLAR qualitatively agreed with the results reported previously. In all suspension type MDIs, negligible masses were detected in the smallest size fraction (<0.95 µm), for which the charge was most likely caused by the propellant and excipients. QVAR was the only solution MDI tested and the charge and mass profiles were significantly different from the suspension-type MDIs. Its mass profile was found to follow closely with the charge profile. CONCLUSIONS: Positively and negatively charged MDI particles of different size fractions and their corresponding charge-to-mass profiles were successfully characterized by the BOLAR.

Dry powder nasal drug delivery: challenges, opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation.

PURPOSE: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development. METHODS: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction). RESULTS: Teijin Rhinocort(®) (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (Dv50 = 98 ± 1.3 µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2 ± 4.78%), while 4.64 ± 1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E. CONCLUSIONS: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.

The Effect of Active Pharmaceutical Ingredients on Aerosol Electrostatic Charges from Pressurized Metered Dose Inhalers.

PURPOSE: This study investigated the effect of different active pharmaceutical ingredients (API) on aerosol electrostatic charges and aerosol performances for pressurized metered dose inhalers (pMDIs), using both insulating and conducting actuators. METHODS: Five solution-based pMDIs containing different API ingredients including: beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FS), salbutamol base (SB) and ipratropium bromide (IPBr) were prepared using pressure filling technique. Actuator blocks made from nylon, polytetrafluoroethylene (PTFE) and aluminium were manufactured with 0.3 mm nominal orifice diameter and cone nozzle shape. Aerosol electrostatics for each pMDI formulation and actuator were evaluated using the electrical low-pressure impactor (ELPI) and drug depositions were analysed using high performance liquid chromatography (HPLC). RESULTS: All three actuator materials showed the same net charge trend across the five active drug ingredients, with BDP, BUD and FS showing positive net charges for both nylon and PTFE actuators, respectively. While SB and IPBr had significantly negative net charges across the three different actuators, which correlates to the ionic functional groups present on the drug molecule structures. CONCLUSIONS: The API present in a pMDI has a dominant effect on the electrostatic properties of the formulation, overcoming the charge effect arising from the actuator materials. Results have shown that the electrostatic charges for a solution-based pMDI could be related to the interactions of the chemical ingredients and change in the work function for the overall formulation.

Beclomethasone Dipropionate-Loaded Polymeric Nanocapsules: Development, In Vitro Cytotoxicity, and In Vivo Evaluation of Acute Lung Injury.

The aim of this work was to develop polymeric nanocapsules intended for the pulmonary delivery of beclomethasone dipropionate using ethyl cellulose or poly(ε-caprolactone). The formulations showed adequate physicochemical characteristics, namely, average diameter lower than 260 nm, low polydispersity index (< 0.2), negative zeta potential, neutral pH values, and encapsulation efficiencies close to 100%. The thermal analysis by DSC suggested that beclomethasone dipropionate encapsulated in the nanocapsules was in an amorphous state. In addition, both ethyl cellulose and poly(ε-caprolactone) nanocapsules were able to delay the drug photodegradation under UVC radiation. The in vitro drug release showed a prolonged release without burst effect using the dialysis bag diffusion technique. Moreover, ethyl cellulose and poly(ε-caprolactone) nanocapsules presented low in vitro cytotoxicity on 3T3 fibroblasts cells. In vivo, the formulations showed no acute pulmonary injury in rats. Therefore, the developed nanocapsules could be considered suitable carriers to be used for beclomethasone dipropionate pulmonary delivery.

A facile approach to manufacturing non-ionic surfactant nanodipsersions using proniosome technology and high-pressure homogenization.

In this study, a niosome nanodispersion was manufactured using high-pressure homogenization following the hydration of proniosomes. Using beclometasone dipropionate (BDP) as a model drug, the characteristics of the homogenized niosomes were compared with vesicles prepared via the conventional approach of probe-sonication. Particle size, zeta potential, and the drug entrapment efficiency were similar for both size reduction mechanisms. However, high-pressure homogenization was much more efficient than sonication in terms of homogenization output rate, avoidance of sample contamination, offering a greater potential for a large-scale manufacturing of noisome nanodispersions. For example, high-pressure homogenization was capable of producing small size niosomes (209 nm) using a short single-step of size reduction (6 min) as compared with the time-consuming process of sonication (237 nm in >18 min) and the BDP entrapment efficiency was 29.65% ± 4.04 and 36.4% ± 2.8. In addition, for homogenization, the output rate of the high-pressure homogenization was 10 ml/min compared with 0.83 ml/min using the sonication protocol. In conclusion, a facile, applicable, and highly efficient approach for preparing niosome nanodispersions has been established using proniosome technology and high-pressure homogenization.

Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations.

PURPOSE: The techniques available to study formulation stability in pressurized metered dose inhalers (pMDIs) are limited, due to the challenging conditions of working with high pressure propellants. Isothermal microcalorimetry is a valuable tool used to screen and aid in formulation development of solid and solution drug formulations; however there are currently no available methods to evaluate pMDIs. In this paper, we have developed a method that allows measurement of such pressurized systems. METHODS: Samples were prepared by cold filling ampoules with propellant (HFA 134a) and drugs of interest. Ampoule caps were fitted with a specific O-ring, coated with paraffin and pre-conditioned prior to measurement. Samples were equilibrated at 25°C, placed in a Thermal Activity Monitor III (TAM III) system and measured isothermally at 25°C for a period of at least 24 h. RESULTS: Using well-defined procedures and ampoule preparation techniques we were able to safely contain the volatile propellant and acquire a stable measurement baseline. We were able to rapidly determine, within 6 h, the physical stability of amorphous and crystalline drug forms of beclomethasone dipropionate and formoterol fumarate dihydrate when formulated with HFA 134a. CONCLUSIONS: Isothermal microcalorimetry in pressurized HFA propellant systems was shown to be a rapid screening tool to evaluate pMDI formulation physical stability. This method can potentially be applied to study pMDI formulation factors to expedite product development.

In vitro evaluation of nonconventional accessory devices for pressurized metered-dose inhalers.

BACKGROUND: The selection of accessory devices for pressurized metered-dose inhalers (pMDIs) by health care professionals is typically cost driven without consideration of how the device modifies clinical outcomes. OBJECTIVE: To evaluate nonconventional accessory devices and the open-mouth technique with and without ideal coordination of actuation and inhalation to identify and understand the considerations for recommending potential inexpensive devices. METHODS: In vitro performance parameters of the beclomethasone dipropionate pMDI were evaluated with several devices (AeroChamber, toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, bottle-holding chamber, and nebulizer reservoir tubing). RESULTS: Compared with the pMDI alone, all the accessory devices evaluated have significantly lower drug exposure and throat deposition and higher respirable fractions, with the paper towel roll having the greatest effect of the devices evaluated (exposure decreased from a mean [SD] of 76.1 [4.8] µg to 49.2 [2.0] µg, throat deposition decreased from 32.0 [3.2] µg to 0.8 [0.3] µg, and respirable fraction increased from 49.8% [3.2%] to 96.4% [0.4%]). Introduction of a delay between actuation and inhalation resulted in greater variability in performance metrics for the devices evaluated, and the bottle-holding chamber and paper towel roll were most effective in mitigating the effect of the delay. The open-mouth technique was found to decrease throat deposition and respirable mass compared with the pMDI alone. CONCLUSION: In addition to cost, the amount of drug that deposits in the throat and the lungs and the effect of asynchronous actuation and inhalation can vary with the selection of an accessory device, which may affect the therapeutic benefits of the pMDI selected.

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 demonstrate promising 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.

Beclomethasone loaded liposomes enriched with mucin: A suitable approach for the control of skin disorders.

Inflammatory skin disorders are the fourth leading cause of chronic non-fatal conditions, which have a serious impact on the patient quality of life. Due to their treatment with conventional corticosteroids, which often result in poor therapeutic efficacy, relapses and systemic side effects from prolonged therapy, these diseases represent a global burden that negatively impacts the global economy. To avoid these problems and optimize corticosteroid benefits, beclomethasone was loaded into liposome formulations specifically tailored for skin delivery. These formulations were enhanced with mucin (0.1 and 0.5 % w/v) to further ensure prolonged formulation permanence at the site of application. The addition of 0.5 % w/v mucin resulted in the formation of small unilamellar vesicles and multicompartment vesicles. Liposomes and 1mucin-liposomes were smaller (∼48 and ∼61 nm, respectively) and more monodispersed (PI ∼ 0.14 and ∼ 0.17, respectively) than 5mucin-liposomes, which were larger (∼137 nm), slightly polydispersed (PI ∼ 0.23), and less stable during storage (4 months in the dark at 25 °C). Liposomes were negatively charged (∼ -79 mV) irrespective of their composition, and capable of incorporating high amount of beclomethasone (∼ 80 %). In vitro studies on skin fibroblasts and keratinocytes confirmed the high biocompatibility of all formulations (viability ≥ 95 %). However, the use of mucin-liposomes resulted in higher efficacy against nitric oxide production and free radical damage. Finally, topical applications using 12-O-tetradecanoylphorbol-13-acetate-injured skin in vivo experiments showed that only the mucin-enriched formulations could restore healthy conditions within 4 days, underscoring promise as a treatment for skin disorders.

Preparation of enteric-coated capsules of beclomethasone dipropionate for patients with intestinal graft-versus-host disease and a case study.

Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs.

Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence.

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution-absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.

Micronized drug powders in binary mixtures and the effect of physical properties on aerosolization from combination drug dry powder inhalers.

OBJECTIVES: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. METHODS: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. RESULTS: The median SS particle diameter was larger than BDP (4.33 ± 0.37 µm compared to 2.99 ± 0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. CONCLUSIONS: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.

Practical and scalable synthesis of beclomethasone dipropionate.

Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16ß-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C17 and C21 demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.