Enteric-Coated Capsules Providing Reliable Site-Specific Drug Delivery to the Distal Ileum.

Nefecon, a targeted-release capsule formulation of budesonide approved for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy, targets overproduction of galactose-deficient immunoglobulin A type 1 in the Peyer's patches at the gut mucosal level. To investigate whether the commercial formulation of Nefecon capsules reliably releases budesonide to the distal ileum, a human study was conducted with test capsules reproducing the delayed-release function of Nefecon capsules. Caffeine was included in the test capsules as a marker for capsule opening in the gut since it appears rapidly in saliva after release from orally administered dosage forms. Magnetic resonance imaging with black iron oxide was used to determine the capsule's position in the gut at the time caffeine was first measured in saliva and additionally to directly visualize dispersion of the capsule contents in the gut. In vitro dissolution results confirmed that the test capsules had the same delayed-release characteristics as Nefecon capsules. In 10 of 12 human volunteers, the capsule was demonstrated to open in the distal ileum; in the other two subjects, it opened just past the ileocecal junction. These results compared favorably with the high degree of variability seen in other published imaging studies of delayed-release formulations targeting the gut. The test capsules were shown to reliably deliver their contents to the distal ileum, the region with the highest concentration of Peyer's patches.

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.

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.

Molecular dissection of an inhibitor targeting the HIV integrase dependent preintegration complex nuclear import.

Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti-IN compound, budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, budesonide or its analogue flunisolide, were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2-LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. The work presented here represents a platform for further development of these specific inhibitors of HIV replication with therapeutic and prophylactic potential.

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.

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.

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.

Central composite rotatable design for optimization of budesonide-loaded cross-linked chitosan-dextran sulfate nanodispersion: characterization, in vitro diffusion and aerodynamic study.

Budesonide is a BCS class II drug with low water solubility (0.045 mg/mL) and low oral bioavailability (6-8%) due to high first pass effect. The aim is to prepare cross-linked chitosan-dextran sulfate nanoparticles and/or nanodispersion. Nebulizable cross-linked nanodispersion was prepared by the solvent evaporation technique and characterized through XRPD, FTIR, mean particle size (MPS), polydispersity index (PDI), zeta potential (ZP), drug loading, entrapment efficiency, SEM, % production yield, in vitro diffusion, aerodynamic and stability study. The optimization of formulation was done by using central composite rotatable design to study the effect of independent variables, concentration of chitosan (X1) and concentration dextran sulfate (X2) on the dependent variables, MPS (Y1), drug loading (Y2) and % CDR (% cumulative drug release) (Y3). The MPS, PDI, and ZP of budesonide-loaded nanoparticles were 160.8 ± 0.27 nm, 0.36 ± 0.04, and 13 ± 0.894 mV, respectively. The percent drug loading of all the batches was found in range of 10-16%. The emitted drug in target region (alveoli) was measured by using HPLC and it was found to be 18.26%. It was found that, nanodispersion had the optimum in vitro aerodynamic behavior. Stability study results showed no significant change in MPS, PDI, ZP, and % CDR after three month storage. In conclusion, cross-linked chitosan-dextran sulfate nanoparticles had properties suitable for nebulizable dispersion of increased drug loading, in vitro drug release and avoiding the first pass effect.

Design of Inhalable Solid Dosage Forms of Budesonide and Theophylline for Pulmonary Combination Therapy.

Corticosteroid resistance poses a major challenge to effective treatment of chronic obstructive pulmonary diseases. However, corticosteroid resistance can be overcome by co-administration of theophylline. The aim of this study was to formulate the corticosteroid budesonide with theophylline into inhalable dry powders intended for pulmonary combination therapy. Four types of spray-dried powders were prepared: (i) budesonide and theophylline co-dissolved and processed using a 2-fluid nozzle spray drier, (ii) budesonide nanocrystals and dissolved theophylline co-dispersed and processed using a 2-fluid nozzle spray drier, (iii) dissolved budesonide and dissolved theophylline processed using a 3-fluid nozzle spray drier, and (iv) budesonide nanocrystals and dissolved theophylline processed using a 3-fluid nozzle spray drier. Spray drying from the solutions resulted in co-amorphous (i) and partially amorphous powders (iii), whereas spray drying of the nanosuspensions resulted in crystalline products (ii and iv). Even though budesonide was amorphous in (i) and (iii), it failed to exhibit any dissolution advantage over the unprocessed budesonide. In contrast, the dissolution of budesonide from its nanocrystalline formulations, i.e., (ii) and (iv), was significantly higher compared to a physical mixture or unprocessed budesonide. Furthermore, the spray-dried powders obtained from the 2-fluid nozzle spray drier, i.e., (i) and (ii), exhibited co-deposition of budesonide and theophylline at the same weight ratio in the aerodynamic assessment using the New Generation Impactor. In contrast, the depositions of budesonide and theophylline deviated from the starting weight ratio in the aerodynamic assessment of spray-dried powders obtained from the 3-fluid nozzle spray drier, i.e., (iii) and (iv). Based on these results, the powders spray-dried from the suspension by using the 2-fluid nozzle spray drier, i.e., (ii), offered the best formulation properties given the physically stable crystalline solid-state properties and the co-deposition profile.

Polymer-Lipid Microparticles for Pulmonary Delivery.

Toward engineering approaches that are designed to optimize the particle size, morphology, and mucoadhesion behavior of the particulate component of inhaler formulations, this paper presents the preparation, physicochemical characterization, and preliminary in vitro evaluation of multicomponent polymer-lipid systems that are based on "spray-drying engineered" α-lactose monohydrate microparticles. The formulations combine an active (budesonide) with a lung surfactant (dipalmitoylphosphatidylcholine) and with materials that are known for their desirable effects on morphology (polyvinyl alcohol), aerosolization (l-leucine), and mucoadhesion (chitosan). The effect of the composition of formulations on the morphology, distribution, and in vitro mucoadhesion profiles is presented along with "Calu-3 cell monolayers" data that indicate good cytocompatibility and also with simulated-lung-fluid data that are consistent with the therapeutically useful release of budesonide.

Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying.

PURPOSE: The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders. METHODS: Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray drying process. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders. RESULTS: XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio. CONCLUSIONS: Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.

pH-triggered surface charge-reversal nanoparticles alleviate experimental murine colitis via selective accumulation in inflamed colon regions.

In this study, we developed pH-triggered surface charge-reversal lipid nanoparticles (LNPs), loaded with budesonide, which could precisely deliver the drug to inflamed colon segments for the treatment of ulcerative colitis. Polyethyleneimine (PEI) was used to render LNPs cationic (PEI-LNPs), and Eudragit® S100 (ES) was coated on PEI-LNPs to obtain pH-triggered charge-reversal LNPs (ES-PEI-LNPs). ES coating avoided a burst drug release under acidic conditions mimicking the stomach and early small intestine environments and showed a sustained release in the colon. The surface charge of ES-PEI-LNPs switched from negative to positive under colonic conditions owing to pH-triggered removal of the ES coating. Bioimaging of the mouse gastrointestinal tract and confocal analysis of colon tissues revealed that ES-PEI-LNPs selectively accumulated in an inflamed colon. Furthermore, ES-PEI-LNPs mitigated experimental colitis in mice. These results suggest that the pH-triggered charge-reversal LNPs could be a promising drug carrier for ulcerative colitis therapy and other colon-targeted treatments.

Process, optimization, and characterization of budesonide-loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease.

The major challenge involved in the treatment of inflammatory bowel disease is targeted delivery of the drug at the site of inflammation. As nanoparticles possess the ability to accumulate at the site of inflammation, present investigation aims at development of Budesonide-loaded nanostructured lipid carrier systems (BDS-NLCs) for the treatment of inflammatory bowel disease. BDS-NLCs were prepared by employing a high pressure homogenization technique. Various preliminary trials were performed for optimization of the NLCs in which different processes, as well as formulation parameters, were studied. The BDS-NLCs was optimized statistically by applying a 3-factor/3-level Box-Behnken design. Drug concentration, surfactant concentration, and emulsifier concentration were selected as independent variables, and % entrapment efficiency and particle size were selected as dependent variables. The best batch comprises of 10%, 7%, and 20% w/w concentration of drug, surfactant, and emulsifier, respectively, with % entrapment efficiency of 92.66 ± 3.42% and particle size of 284.0 ± 4.53 nm. Further, in order to achieve effective delivery of nanoparticulate system to colonic region, the developed BDS-NLCs were encapsulated in Eudragit® S100-coated pellets. The drug release studies of pellets depict intactness of BDS-NLCs during palletization process, with f2 value of 75.879. The in vitro evaluation of enteric-coated pellets revealed that a coating level of 15% weight gain is needed in order to impart lag time of 5 h (transit time to reach colon). The results of the study demonstrate that the developed BDS-NLCs could be used as a promising tool for the treatment of inflammatory bowel disease.

Effect of Relative Humidity on Bipolar Electrostatic Charge Profiles of dry Powder Aerosols.

PURPOSE: This work investigated the effect of relative humidity (RH) on bipolar electrostatic charge profiles of dry powder inhaler aerosols using the Bipolar Charge Analyzer (BOLAR). METHODS: Two commercial products, Pulmicort® (400 µg, budesonide) and Bricanyl® (500 µg, terbutaline sulfate) Turbuhaler®, were used as model dry powder inhalers (DPIs) in this study. Three individual doses from each Turbuhaler® were sampled at 15, 40, 65 and 90% RH. Subsequently, charge and mass profiles were determined for each dispersion. RESULTS: The aerosols from these two Turbuhaler® DPI were bipolarly charged, with larger particles carrying negative charge and smaller particles positive charge. Particles changed polarity around 2.60-4.17 µm and 0.95-2.60 µm for Pulmicort® and Bricanyl®, respectively. The effect of RH on particles differed between DPIs even though the mass output was not significantly affected. The net charge profiles of Pulmicort® were relatively independent of RH, whereas those of Bricanyl® showed a reduction in the charge magnitude with increasing RH. Both positive and negative charge profiles followed a similar trend with the change in RH and individually they had higher magnitudes than the measured net charge. CONCLUSIONS: This study showed drug-specific bipolar charging of the Turbuhaler® DPI aerosols at varied RHs. Bricanyl® was more susceptible to RH and showed decreased bipolar and net charge levels with increasing RH, in comparison to Pulmicort®.

Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy.

PURPOSE: Individualizing gastric-resistant tablets is associated with major challenges for clinical staff in hospitals and healthcare centres. This work aims to fabricate gastric-resistant 3D printed tablets using dual FDM 3D printing. METHODS: The gastric-resistant tablets were engineered by employing a range of shell-core designs using polyvinylpyrrolidone (PVP) and methacrylic acid co-polymer for core and shell structures respectively. Filaments for both core and shell were compounded using a twin-screw hot-melt extruder (HME). CAD software was utilized to design a capsule-shaped core with a complementary shell of increasing thicknesses (0.17, 0.35, 0.52, 0.70 or 0.87 mm). The physical form of the drug and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. RESULTS: A shell thickness ≥0.52 mm was deemed necessary in order to achieve sufficient core protection in the acid medium. The technology proved viable for incorporating different drug candidates; theophylline, budesonide and diclofenac sodium. XRPD indicated the presence of theophylline crystals whilst budesonide and diclofenac sodium remained amorphous in the PVP matrix of the filaments and 3D printed tablets. Fabricated tablets demonstrated gastric resistant properties and a pH responsive drug release pattern in both phosphate and bicarbonate buffers. CONCLUSIONS: Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient's needs.

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery.

OBJECTIVE: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route. SIGNIFICANCE: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. METHODS: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. RESULTS: The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334 ± 0.0178 m2/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension. CONCLUSIONS: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.

Budesonide Loaded PLGA Nanoparticles for Targeting the Inflamed Intestinal Mucosa--Pharmaceutical Characterization and Fluorescence Imaging.

PURPOSE: The purpose of this study was to evaluate the specifically targeted efficiency of budesonide loaded PLGA nanoparticles for the treatment of inflammatory bowel disease (IBD). METHODS: The nanoparticles were prepared by an oil/water (O/W) emulsion evaporation technique. The nanoparticles were characterized for their size, shape and in vitro drug release profile. Solid state characterization was carried out by differential scanning calorimetry (DSC) and X-ray Power diffraction (XPRD). In order to evaluate the targeted efficiency of nanoparticles, a particle localization study in the healthy and in the inflamed colon was determined in vivo. These data were complemented by cryo-sections. RESULTS: Nanoparticles were 200 ± 05 nm in size with a smooth and spherical shape. The encapsulation efficiency was around 85 ± 3.5%, which was find-out by both, direct and indirect methods. Release of budesonide from the nanoparticles showed a biphasic release profile with an initial burst followed by sustained release. XPRD data revealed that the drug in the polymer matrix existed in crystalline state. Nanoparticles accumulation in inflamed tissues was evaluated by in-vivo imaging system and it was found that particles are accumulated in abundance at the site of inflammation when compared to the healthy group. CONCLUSION: The study demonstrates that the budesonide loaded PLGA nanoparticles are an efficient delivery system for targeted drug delivery to the inflamed intestinal mucosa.

Formulation of budesonide mouthwash for the treatment of oral chronic graft-versus-host disease.

Oral involvement is (very) common in chronic graft-versus-host disease and can cause discomfort and impairment of oral function. Budesonide, a highly potent corticosteroid with low systemic activity, can be used as a topical treatment for oral chronic graft-versus-host disease. We describe the development of a formulation of budesonide and sodium bicarbonate for use as mouthwash in patients with oral chronic graft-versus-host disease.

Quality by design approach for development of suspension nasal spray products: a case study on budesonide nasal suspension.

The objective of this study was to provide quality by design (QbD) approach for development of suspension type nasal spray products. Quality target product profile (QTPP) of test product budesonide nasal suspension (B-NS) was defined and critical quality attributes (CQAs) were identified. Critical formulation, process and delivery device variables were recognized. Risk assessment was performed by using failure mode and effect analysis (FMEA) methodology. Selected variables were further assessed using a Plackett Burman screening study. A response surface design consisting of the critical factors was used to study the interactions between the study variables. Formulation variable X2: median particle size of budesonide (D50) (µ) has strikingly influenced dissolution (%) (Y1), while D50 droplet size distribution (µm) (Y2) was significantly impacted by formulation variable X1: Avicel RC 591 (%) and process variable X4: homogenization speed (rpm). A design space plot within which the CQAs remained unchanged was established at lab scale. A comprehensive approach for development of B-NS product based on the QbD methodology has been demonstrated. The accuracy and robustness of the model were confirmed by comparability of the predicted value generated by model with the observed value.

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.