Budesonide

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Budesonide (BDS) is a structural analog of the naturally occurring mineralocorticoid, cortisone, produced by the adrenal glands. The chemical structure of budesonide is depicted in Figure 1. This drug was determined not to have the undesirable side effects of water retention, high blood pressure, and muscle weakness associated with other glucocorticoids like cortisone. Budesonide is most often given by oral, topical, and pulmonary administration.

Budesonide has been used to treat a number of autoimmune and autoinflammatory diseases, including those diseases which affect the digestive tract. Orally dosed budesonide has shown effectiveness against Crohn's disease, ulcerative colitis (UC), and IBD, all of which are believed to have an autoimmune component as part of their etiology (20). Drug delivery systems containing budesonide have been used to effectively target the drug to the site of action, avoiding the side effects that could accompany systemic delivery of the drug. One study evaluated the colon specific delivery of budesonide in an enteric formulation (21). This drug delivery system is a microparticulate formulation consisting of hydrophobic budesonide-containing cores of cellulose acetate butyrate (CAB) which are enterically coated with Eudragit® S. Scanning electron micrographs of this formulation are shown in Figure 4. Drug release profiles of the formulation showed no release of budesonide in the acid phase, with sustained release of the drug occurring after the buffer stage. Figure 5 shows the in vitro release profiles of the formulation. These formulations were then tested with rats in vivo to determine the degree of inflammation that the microparticulate budesonide formulation could inhibit. These experiments were designed to mimic the inflammation that occurs with ulcerative colitis using 2,4,6-trinitrobenzene-sulfonic acid (TNBS) to induce inflammation. Histological evaluations of the intestinal tissue of rats showed substantially decreased inflammation,

Uptodate Budesonide Microscopic Colitis

Figure 4 SEM of a cross-section of Eudragit S microparticles containing budesonide-loa-ded cellulose acetate butyrate cores. Source: From Ref. 21.

Figure 4 SEM of a cross-section of Eudragit S microparticles containing budesonide-loa-ded cellulose acetate butyrate cores. Source: From Ref. 21.

resulting in lower microscopic histological damage scores. Micrographs of rat intestinal mucosa showed much lower degrees of inflammation when the budesonide CAB microparticles were used (Fig. 6). This colonic delivery system improved the efficacy, at the site of action, of budesonide in the healing of induced colitis in rats, demonstrating that the effects of budesonide were generally improved compared to those obtained with budesonide enteric microparticles for upper intestinal drug release.

Based on previous research, development of the Entocort EC capsule for delivery of budesonide to the site of action for Crohn's disease patients has been reported by AstraZeneca Pharmaceuticals (22). Entocort EC has a pH- and time-dependent release profile for budesonide, developed to

Figure 5 In vitro release profiles obtained from Eudragit S microparticles containing budesonide (BDS) directly encapsulated (BDS/MCP) or included in CAB cores (BDS-CAB/MCP). Data are mean — standard deviation n = 4. Source: From Ref. 21.
Eudragit Microparticles

Figure 6 Optical micrographs of the colon of (A) a TNBS-treated rat after oral administration of blank microparticles, showing mucosa with severe inflammatory infiltrate (a) extensive areas of necrosis (b). This colon was given a damage score of 6; and (B) optical micrograph of colon of a TNBS-treated rat after oral administration of Eudragit S microparticles containing budesonide loaded CAB cores, showing mucosa with mild inflammatory infiltrate (a), vascular congestion (b), and well-conserved mucosa (c). This colon was given a tissue damage score of 2. Source: From Ref. 21.

Figure 6 Optical micrographs of the colon of (A) a TNBS-treated rat after oral administration of blank microparticles, showing mucosa with severe inflammatory infiltrate (a) extensive areas of necrosis (b). This colon was given a damage score of 6; and (B) optical micrograph of colon of a TNBS-treated rat after oral administration of Eudragit S microparticles containing budesonide loaded CAB cores, showing mucosa with mild inflammatory infiltrate (a), vascular congestion (b), and well-conserved mucosa (c). This colon was given a tissue damage score of 2. Source: From Ref. 21.

optimize drug delivery to the ileum, the site of inflamed tissue in Crohn's patients. The dosage form is a capsule with beads consisting of a sugar core, coated first with a layer containing budesonide, ethylcellulose and surfactants, followed by an enteric polymer coating (Eudragit L). This formulation design allows for both the pH- and time-dependent release of the drug. pH-dependent release of the drug was shown to be caused by the Eudragit-L enteric coating, while time-release of the drug was caused by the ethylcellulose/surfactant coating layer. Since ethylcellulose is water-insoluble, the presence of the surfactantants in this layer allowed for partial dissolution and pore-formation in this coating allowing for the time-dependent release of the drug. Scintigraphic methods confirmed that the Entocort® formulation delays absorption and prolongs the rate of elimination, while maintaining complete absorption. This study evaluated the regional deposition and uptake of budesonide in the Entocort capsules and the immediate release capsules (22). Delivery of budesonide from Entocort capsules was evaluated when the formulation was given both before and after a meal to determine absorption with varying intestinal transit times (23). The time-to-peak (tmax) plasma concentration was significantly increased with controlled-release budesonide when compared to the immediate release formulation (before breakfast 4.5 vs. 1.8 h; after breakfast 5.2 vs. 2.9 h). When given after breakfast, the controlled release formulation was associated with a mean residence time 1.6 h longer than seen with the immediate release formulation (23). The rate of absorption of budesonide from standard and controlled-release capsules taken before and after breakfast evaluated in this study. The proportions of the budesonide dose absorbed from immediate release and controlled-release capsules in the upper and lower gastrointestinal tract are shown to vary according to the dose delivery system. Controlled-release budesonide, therefore, effectively delivers most of the budesonide dose to the ileum and colon, the regions that are most often affected by IBD. In addition, the time of food intake had little effect on the site of absorption or the bioavailability of the controlled-release formulation (23).

Pulmonary formulations of budesonide have also been reported for use in other chronic inflammatory conditions such as asthma. Waldrep et al. reported inclusion of various types of immunosuppressants in liposomal formulations for aerosol delivery to the lungs (24,25). Liposomal formulations of cyclosporin, beclomethasone, and budesonide were prepared using different types of phospholipids with varying drug to phospholipid ratios. Aerosol particle size analysis demonstrated that the mass median aerodynamic diameter (MMAD) of aerosolized liposomal formulations of these drugs increased minimally with higher liposome concentrations, remaining in the desirable respirable fraction for pulmonary formulations (2-5 mm in diameter) (24). Lobo et al. from Nektar Therapeutics has reported budesonide dry powder formulations for inhalation (26). The powders were manufactured by dissolving the drug in acetone before processing via the SEDS technique (26). These SEDS processed powders were characterized by their low density and a MMAD (2.4 mm average) within the respirable size range. The performance of the budesonide powders were evaluated in a Turbospin® and Eclipse® dry powder inhaler (DPI) device. The capsules of the inhaler devices were filled with powder, and their emitted doses (ED), defined as the relative amount of powder loaded in the capsule that leaves the device, were studied. The SEDS processed powders dispersed well in the DPI devices, exhibiting high ED's (70-80%) and relatively low variability (RSD 8-13%). Regardless of the device, the SEDS processed powders outperformed both the micronized drug and the commercial powder while showing good batch-to-batch reproducibility (RSD <5%) (26). Both of these formulation techniques offer more effective dosing options for the treatment of asthma. Clinical trials of these formulations are on-going, but preliminary results showed that SEDS powders formulated into DPI devices, using the Turbospin and Eclipse DPI's deposit drug in the deep lung, leading to enhanced treatment of asthmatic conditions.

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