Pharmacokinetics of a Taste-Masked Prednisone Oral Microsphere Powder

Many active pharmaceutical ingredients (APIs) face the challenge of palatability when administered orally. Tastemasking technologies often utilize coatings to help palatability but these coatings or agglomerations can negatively impact bioavailability. Orbis Biosciences, Inc. (Orbis) has developed a novel taste-masking technology that has previously been demonstrated to have virtually complete taste-masking of the extremely bitter API, prednisone. The next facet of development was to assess the pharmacokinetics (PK) and relative bioequivalence (BE) of prednisone from this new formulation. Presented here is a randomized, open-label, two products, two period and crossover study in fasted adults comparing 10 mg prednisone taste-masked microspheres to a 10 mg prednisone tablet. Fourteen (14) post-dose plasma concentrations obtained over a 12 h period were analyzed for prednisone and its metabolite, prednisolone, using a validated HPLC/MS/MS method. Bioavailability was assessed according to current United States’ Food and Drug Administration (FDA) criteria. Results indicated that for both Cmax (90% CI; 0.81-1.10) and AUCtotal (0.94-1.18), the microsphere formulation met bioavailability criteria for prednisone. For prednisolone, only AUCtotal met criteria for bioavailability. Cmax was lower (90% confidence interval of 0.647-0.938 for log transformed data) and time of Cmax (Tmax) was delayed (2.9 ± 0.5 vs. 1.8 ± 1.0 h, p=0.02) in the microsphere relative to the tablet formulation. In conclusion, the relative bioavailability of the novel microsphere formulation of prednisone was evident as compared to a commercially available tableted formulation of the drug. for the ersatz compounder. Thus, a pressing need exists to develop new formulation technology that would enable the creation of drug products with favourable organoleptic and physicochemical properties (e.g., stability, retention of potency) that permit accurate weight-based dosing in a novel dosage form. An API commonly cited as extremely bitter and difficult to mask is prednisone [10,11]. This corticosteroid is used in paediatrics and adults for a plethora of indications including respiratory conditions, dermatologic diseases and allergic response. Crushing adult solid dosage forms to facilitate weight-based dosing of prednisone in paediatric patients or individuals with swallowing difficulties further exacerbates problems with palatability and acceptability (e.g., taste and mouth feel) Liquid formulations may overcome some of these issues, but often the API’s inherent bitter taste is apparent, especially for children whose bitter taste receptors are more discriminating as compared to adults [12]. Recent research shows that children more genetically sensitive to bitter tastes are less likely to accept liquid drug formats as compared to *Corresponding author: Nathan H Dormer, PhD, Vice President, Research & Development, Orbis Biosciences, Inc., Lenexa, KS 66214, USA, Tel: 913-544-1199; Ext: 204; E-mail: [email protected] Received August 15, 2017; Accepted October 10, 2017; Published October 20, 2017 Citation: Shoults CC, Kearns GL, Meyer AR, Moran J, D’Ann P, et al. (2017) Pharmacokinetics of a Taste-Masked Prednisone Oral Microsphere Powder. J Bioequiv Availab 9: 547-554. doi: 10.4172/jbb.1000360 Copyright: © 2017 Shoults CC, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Shoults CC, Kearns GL, Meyer AR, Moran J, D’Ann P, et al. (2017) Pharmacokinetics of a Taste-Masked Prednisone Oral Microsphere Powder. J Bioequiv Availab 9: 547-554. doi: 10.4172/jbb.1000360 J Bioequiv Availab, an open access journal ISSN: 0975-0851 Volume 9(6): 547-554 (2017) 548 their peers and that, overall, children report issues with taking liquid formulations due to taste [13]. Orbis Biosciences, Inc. (Orbis), produces taste-masked microspheres, utilizing an innovative manufacturing platform [1416]. which precisely controls size distributions to match the release of existing formulations. This precision particle fabrication technology was utilized to formulate a novel prednisone microsphere that has been previously demonstrated to produce effective and virtually complete taste-masking of the drug [17]. These microspheres could be utilized as a drug product intermediate with a liquid suspension final product or alone as a powder. The first human trial of relative bioavailability of this novel taste-masked prednisone powder formulation is reported here. Materials and Methods Investigational product The test formulation was produced in accordance with U.S. FDA current Good Manufacturing Practices (cGMP) 21 Code of Federal Regulations Parts 210/211 under cGMP conditions at Orbis’ facility in Lenexa, KS. The proprietary process involved mixing prednisone with a lipid excipient base co-melted with a reverse-enteric polymer, then processing said mixture through an acoustically-excited nozzle with coaxial nitrogen stream into a containment system. The resulting product was a free-flowing taste-masked prednisone-containing microsphere powder. The microsphere formulation for this study was developed to provide taste-masking without extended-release behaviour. Following manufacture, the microsphere product was tested to ensure conformity against the drug product’s specifications and acceptance criteria before release and shipping to the clinical site. USP dissolution: According to the FDA draft guidance recommended January of 2016, prednisone tablets can now utilize comparative dissolution testing on 12 dosage units of all strengths of the tablet in order to demonstrate bioequivalence [18]. This guidance is not applicable to the microsphere prednisone tested in this study due to dissolution method changes necessary to allow for the proper study of the microsphere. Specifically, the current FDA dissolution media is comprised solely of water, which is not ideal for the hydrophobic lipids utilized in the microsphere formulation. Testing dissolution with water media alone results in the microspheres floating on the surface of the dissolution bath. Additionally, the microsphere formulation incorporates a pH-responsive excipient, requiring that the dissolution media be closer to gastric pH levels for drug release. Because of these two formulation characteristics, the final dissolution media had a low pH and contained surfactant. Reagents and chemicals: All chemicals were at the least reagent grade and unless otherwise noted, were provided by Sigma-Aldrich (St. Louis, MO) and Fisher Scientific (Fairlawn, NJ). Equipment: Dissolution was executed using a Vankel VK7000 Dissolution System (Santa Clara, CA), equipped with paddles. Samples were analysed using an Agilent 1100 liquid chromatography system, equipped with a variable wavelength detector (Santa Clara, CA). Instrument control and data acquisition and analysis was handled through Chromeleon (VER 7.2.2.6394). Analytical standard preparation: United States Pharmacopoeia (USP) reference standard materials were used to prepare all analytical standards and quality control samples as per the USP Prednisone Tablet Monograph. All analytical standard solutions were stored at 5 degrees Centigrade (°C) until needed. Dissolution: The dissolution method from the USP Monograph for Prednisone Tablets was modified to more accurately display the release of the microsphere’s drug product. 0.1% SLS (sodium dodecyl sulfate) and 0.1 one normal solution of hydrochloric acid (N HCl) were added to the dissolution media, with a paddle stir speed of 75 revolutions per min (rpm). Sample volumes of 3 milliliters (mL) were withdrawn from each vessel at 10, 20, 30, 45, 60 and 120 min and filtered for high performance liquid chromatography (HPLC) analysis. This modified dissolution test method was validated. Liquid chromatography: HPLC analysis was performed as outlined in the USP Monograph for Prednisone Tablets. Briefly, the method utilized 10 microliters (μL) injections on a C-18 (L1) column (Thermo ODS Hypersil C18, 4.6 × 150 mm, 5 μm) with ambient column and sample temperatures. The mobile phase comprised of HPLC grade tetrahydrofuran:methanol:water (250:62:688 v/v/v) at a flow rate of 1.0 milliliters per min (mL/min) (isocratic) and analytes were detected using a detector wavelength of 254 nanometer (nm).