Synthesis of budesonide conjugates and their anti-inflammatory effects: a preliminary study.

PURPOSE: Budesonide (Bud) is a nonhalogenated glucocorticoid with high anti-inflammatory potency and low systemic side effects. However, the poor water solubility of Bud affects its dissolution and release behavior, thus influencing its anti-inflammatory effect. This study was aimed at synthesizing and evaluating novel conjugates of Bud, hoping to increase the anti-inflammatory activity of Bud by improving its water solubility. MATERIALS AND METHODS: Seven novel Bud conjugates (3a-3g) were designed and synthesized in this study. Besides, the equilibrium solubility, cell viability, in vitro and in vivo anti-inflammatory activity, and the hydrolysis behavior of the conjugates in different pH solutions, rat and human plasma, and rat lung homogenate were studied in detail. RESULTS: As compared to Bud, the equilibrium solubility of 3a, 3c, and 3e was significantly increased; 3a, 3b, and 3c significantly inhibited the interleukin-6 production in lipopolysaccharide-induced A549 cells; 3a and 3e could significantly decrease the xylene-induced ear edema; and 3a and 3c were gradually and slowly hydrolyzed into Bud in the alveolar fluid and lung homogenate and broken down quickly in plasma. CONCLUSION: The amino acid ester compounds budesonide-21-glycine ester (3a) and budesonide-21-alanine ester (3c) were selected as potential conjugates of Bud. This study would provide a theoretical and an experimental basis for the in vivo process of glucocorticoids and the treatment of inflammatory diseases.

Preparation and characterization of pH-sensitive nanoparticles of budesonide for the treatment of ulcerative colitis.

OBJECTIVE: The aim of this study was to develop pH sensitive nanoparticles of budesonide for the treatment of ulcerative colitis. METHODS: The NPs system was characterized by the transmission electron microscopy (TEM), particle size, drug loading and encapsulation efficiency. In addition, in vitro drug release prop-erties and pharmacokinetics were also investigated in detail. The optimized formulation was examined for its in-vivo targeting potential using 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in a rat model. RESULTS: Dynamic light-scattering results showed that the particle size of budesonide-Eudragit S100/poly(lactic-co-glycolic acid) nanoparticles was around 110.5 nm, with a polydispersity index of 0.098. Transmission electron microscopy images showed that BUD-ES100/PLGA NPs were spherical with uniform size and relatively smooth surfaces. In vitro release showed that BUD-ES100/PLGA NPs required minimal release of drugs during its transit in the stomach and the upper small intestine to ensure that a maximum dose reached the colon. After the pharma-codynamic treatment, the myeloperoxidase value of BUD-ES100/PLGA NPs was close to the normal group. The histopathological examination of rectum showed that no sign of damages such as epithelial necrosis and sloughing epithelial cells was detected. CONCLUSION: Our findings suggested that BUD-ES100/PLGA NPs were a promising alternative to single pH-dependent systems for colitis therapy.

Acoustically enhanced microfluidic mixer to synthesize highly uniform nanodrugs without the addition of stabilizers.

BACKGROUND: This article presents an acoustically enhanced microfluidic mixer to generate highly uniform and ultra-fine nanoparticles, offering significant advantages over conventional liquid antisolvent techniques. METHODS: The method employed a 3D microfluidic geometry whereby two different phases - solvent and antisolvent - were introduced at either side of a 1 µm thick resonating membrane, which contained a through-hole. The vibration of the membrane rapidly and efficiently mixed the two phases, at the location of the hole, leading to the formation of nanoparticles. RESULTS: The versatility of the device was demonstrated by synthesizing budesonide (a common asthma drug) with a mean diameter of 135.7 nm and a polydispersity index of 0.044. CONCLUSION: The method offers a 40-fold reduction in the size of synthesized particles combined with a substantial improvement in uniformity, achieved without the need of stabilizers.

Engineering of budesonide-loaded lipid-polymer hybrid nanoparticles using a quality-by-design approach.

Chronic obstructive pulmonary disease (COPD) is a complex disease, characterized by persistent airflow limitation and chronic inflammation. The purpose of this study was to design lipid-polymer hybrid nanoparticles (LPNs) loaded with the corticosteroid, budesonide, which could potentially be combined with small interfering RNA (siRNA) for COPD management. Here, we prepared LPNs based on the biodegradable polymer poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid dioleyltrimethylammonium propane (DOTAP) using a double emulsion solvent evaporation method. A quality-by-design (QbD) approach was adopted to define the optimal formulation parameters. The quality target product profile (QTPP) of the LPNs was identified based on risk assessment. Two critical formulation parameters (CFPs) were identified, including the theoretical budesonide loading and the theoretical DOTAP loading. The CFPs were linked to critical quality attributes (CQAs), which included the intensity-based hydrodynamic particle diameter (z-average), the polydispersity index (PDI), the zeta-potential, the budesonide encapsulation efficiency, the actual budesonide loading and the DOTAP encapsulation efficiency. A response surface methodology (RSM) was applied for the experimental design to evaluate the influence of the CFPs on the CQAs, and to identify the optimal operation space (OOS). All nanoparticle dispersions displayed monodisperse size distributions (PDI<0.2) with z-averages of approximately 150nm, suggesting that the size is not dependent on the investigated CFPs. In contrast, the zeta-potential was highly dependent on the theoretical DOTAP loading. Upon increased DOTAP loading, the zeta-potential reached a maximal point, after which it remained stable at the maximum value. This suggests that the LPN surface is covered by DOTAP, and that the DOTAP loading is saturable. The actual budesonide loading of the LPNs was mainly dependent on the initial amount of budesonide, and a clear positive effect was observed, which shows that the interaction between drug and PLGA increases when increasing the initial amount of budesonide. The OOS was modeled by applying the QTPP. The OOS had a budesonide encapsulation efficiency higher than 30%, a budesonide loading above 15µg budesonide/mg PLGA, a zeta-potential higher than 35mV and a DOTAP encapsulation efficiency above 50%. This study shows the importance of systematic formulation design for understanding the effect of formulation parameters on the characteristics of LPNs, eventually resulting in the identification of an OOS.

Processing of pharmaceutical materials by electrospraying under reduced pressure.

CONTEXT: Electrospraying was used in drug particle production. OBJECTIVE: The aim of the research was to evaluate the possibilities to produce drug particles with desired pharmaceutical properties by electrospraying. In particular, the effect of drying pressure on particle properties was studied. MATERIALS AND METHODS: A poorly water soluble model drug (budesonide) was dissolved in chloroform, and the solution was atomized by electrospraying. Following this, the charged droplets were neutralized and dried in a drying chamber. The pressure in the drying chamber was varied. The dried particles were collected and analyzed. RESULTS: The pressure reduction had a slight impact on particle size distribution. The particles produced in reduced pressure turned out to be notably more porous than the particles produced in atmospheric pressure. The pressure reduction also affects the degree of crystallinity of the product. The dissolution of the particles produced in reduced pressures was faster to a certain extent than that of the particles produced in atmospheric pressure. DISCUSSION AND CONCLUSIONS: A setup for electrospraying materials in a reduced pressure was presented. The pressure reduction had a notable impact on particle morphology. The possibilities to tailor the particle properties during electrospraying were studied.

Synthesis and evaluation of dextran-budesonide conjugates as colon specific prodrugs for treatment of ulcerative colitis.

Budesonide is a potent glucocorticoid with high affinity for the glucocorticoid receptor, which is now used for the treatment of inflammatory bowel diseases. Current oral formulations of budesonide present low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. The objective of this study was to develop a colon specific delivery system for budesonide to increase the efficacy in the treatment of ulcerative colitis. Dextran-budesonide conjugates were prepared with different molecular weights (MW) of dextran (10,000, 70,000 and 500,000) in the presence of dimethylaminopyridine (DMAP) using succinate spacer. The conjugates were characterized by (1)H NMR and IR spectroscopy and elemental analysis. The degree of substitution, aqueous solubility and chemical stability of conjugates in HCl 0.1N, phosphate buffer solutions pH 6.8 and 7.4 were studied. Drug release characteristics of the conjugates were also studied in the presence of the luminal contents of different segments of the rat gastrointestinal tract. Degree of substitution (DS) was dependent on the polymer MW and was 19.33, 14.29 and 11.60 mg/100 mg conjugate for MW 10,000, 70,000 and 500,000, respectively. Solubility of the drug in conjugates of MW 10,000 and 70,000 was increased with respect to the free drug and was dependent on DS. The three conjugates were found to be stable in HCl 0.1N, phosphate buffer solutions pH 6.8 and 7.4 incubated at 37 degrees C within 6 h and the rate constants for degradation of conjugates to budesonide and budesonide hemisuccinate were less than 0.006 h(-1). Less than 10% of the drug was released in contents of the stomach and small intestine, while about two-fold increase was observed after incubating the conjugates with colonic luminal contents. Conjugate prepared by dextran 70,000 showed the most desirable solubility, stability and release properties and could therefore be evaluated in vivo, for potential clinical use in the treatment of ulcerative colitis.

Pulmonary deposition of a budesonide/gamma-cyclodextrin complex in vitro.

Cyclodextrins (CDs) may be potential excipients in inhalation powders; e.g., to increase drug stability, dissolution rate and bioavailability, or to decrease local irritation of an inhaled drug. The aim of this study was to investigate the effect of CD complexation on the pulmonary deposition of drugs. Studies were performed by using novel Taifun multi-dose dry powder inhalers and budesonide as a model compound. A precipitation method was developed to prepare solid budesonide/gamma-CD complexes. Inhalation powders containing either budesonide/gamma-CD complexes (15 microg/dose; complex:carrier ratio 1:15) or budesonide (10 microg/dose and 100 microg/dose; drug:carrier ratio 1:159 and 1:15, respectively) with a lactose carrier, were prepared by dry mixing. The in vitro pulmonary depositions of budesonide and budesonide/gamma-CD complexes were determined initially and after 1 month's storage (40 degrees C, 75% RH) using an Andersen cascade impactor. The respirable fraction (RF) of the budesonide/gamma-CD complex was 35% initially and 31% after storage. The RF of budesonide was 35% (10 microg/dose) and 45% (100 microg/dose) initially, and 31% (10 microg/dose) and 51% (100 microg/dose) after storage, respectively. In conclusion, CDs may be used in inhalation powders to improve pharmaceutical and biopharmaceutical properties of drugs without lowering their pulmonary deposition.