1 Salicylic Acid (SA) Bioaccessibility from SA-Based Poly(anhydride- 2 ester) 3 Michael A. Rogers,* ,†,‡ Yim-Fan Yan, ‡ Karen Ben-Elazar, ‡ Yaqi Lan, ‡ Jonathan Faig, § Kervin Smith, § 4 and Kathryn E. Uhrich § 5 ‡ Department of Food Science and † New Jersey Institute of Food, Nutrition and Health, Rutgers University, The State University of 6 New Jersey, New Brunswick, New Jersey 08901, United States 7 § Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States 8 ABSTRACT: The bioaccessibility of salicylic acid (SA) can be effectively modified by incorporating the pharmacological 9 compound directly into polymers such as poly(anhydride-esters). After simulated digestion conditions, the bioaccessibility of SA 10 was observed to be statistically different (p < 0.0001) in each sample: 55.5 ± 2.0% for free SA, 31.2 ± 2.4% the SA-diglycolic acid 11 polymer precursor (SADG), and 21.2 ± 3.1% for SADG-P (polymer). The release rates followed a zero-order release rate that 12 was dependent on several factors, including (1) solubilization rate, (2) macroscopic erosion of the powdered polymer, (3) 13 hydrolytic cleavage of the anhydride bonds, and (4) subsequent hydrolysis of the polymer precursor (SADG) to SA and 14 diglycolic acid. 15 ■ INTRODUCTION 16 Salicylic acid (SA), an active metabolite of aspirin (acetylsali- 17 cylic acid; ASA), is useful due to its anti-inflammatory, 18 antipyretic, keratolyic and analgesic properties. 1,2 While SA 19 has been used since the fifth century to relieve pain, recent 20 advances describe a new delivery system that directly 21 incorporates SA into a poly(anhydride-ester) (PAE) to 22 overcome issues associated with ASA. 3-6 The polymeric 23 version of SA offers many advantages over the small molecule 24 of ASA; the first is the ability to formulate into various 25 geometries, including powders, 7 disks, 8 fibers, 9 and micro- 26 spheres. 10 Second, PAEs allow high SA loadings, typically 27 between 60 and 80%, because of the direct incorporation of SA 28 into the polymeric backbone. 3 Third, PAEs enable sustained 29 release of SA; as small molecules, SA rapidly diffuses, whereas 30 the polymeric version delivers a sustained, controlled release of 31 SA over time. 5,11 Thus, PAEs have great potential in various 32 biomedical applications, as they have been found to be nontoxic 33 in both in vitro 12 and in vivo studies. 8 34 In designing SA-based PAEs, both the drug release rate and 35 drug loading capacity can be modified by altering the chemical 36 composition of the linker molecule, enabling a tunable drug 37 release profile for diverse applications. 5,11,13 Upon exposure to 38 water, PAEs undergo hydrolytic degradation; the SA release 39 rate is dependent upon the solution conditions (i.e., pH, 40 temperature, etc.) and polymer composition. 5 PAE’s typically 41 exhibit a sustained, near zero-order rate of drug release, owing 42 to their rate-limiting step being governed by its surface-eroding 43 behavior and low solubility. 9,14-16 Furthermore, PAEs do not 44 display the burst release typically observed in conventional 45 delivery systems, which has been associated with toxicity 46 concerns. While the PAEs do not demonstrate burst release 47 behavior, a disadvantage of the PAEs could be the observed lag 48 time. 3,5,14 With some PAEs, drug release could be delayed by 49 days, a behavior that may not be desirable if immediate pain 50 relief, for example, is required. The lag time can be overcome 51 by several approaches, such as admixing small molecules, 17 52 increasing the hydrophilicity of the linker molecule, 7,11,13 53 preparing copolymers 7,9 and altering the pH of the degradation 54 environment. 3 Overall, PAEs offer an effective means of 55 delivering drug moieties such as SA for applications requiring 56 both short- and long-term drug release. 18 57 As numerous variables influence the polymer degradation 58 rate, including temperature, pH, water content, and mixing, it is 59 important to understand how these polymeric systems behave 60 in the alimentary track to ensure pharmacopeial efficacy. The 61 influence of biological and formulation variables makes it 62 essential to characterize the “release” profile from the delivery 63 vehicle into the luminal fluids, which is termed bioaccessibility, 64 defined here as the cumulative percent of SA released in the 65 f1 jejunum and ileum (Figure 1, TIM-1 sections 5c and 5d, 66 respectively). It is not necessary to probe the bioavailability Received: June 25, 2014 Revised: July 31, 2014 Article pubs.acs.org/Biomac © XXXX American Chemical Society A dx.doi.org/10.1021/bm500927r | Biomacromolecules XXXX, XXX, XXX-XXX lhc00 | ACSJCA | JCA10.0.1465/W Unicode | research.3f (R3.6.i5 HF03:4230 | 2.0 alpha 39) 2014/07/15 09:23:00 | PROD-JCAVA | rq_3802100 | 8/06/2014 11:29:28 | 6 | JCA-DEFAULT