Salicylic Acid (SA) Bioaccessibility from SA-Based ... - ACS Publications

The bioaccessibility of salicylic acid (SA) can be effectively modified by incorporating the pharmacological compound directly into polymers such as ...
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Salicylic Acid (SA) Bioaccessibility from SA-Based Poly(anhydrideester) Michael A. Rogers,*,†,‡ Yim-Fan Yan,‡ Karen Ben-Elazar,‡ Yaqi Lan,‡ Jonathan Faig,§ Kervin Smith,§ and Kathryn E. Uhrich§ ‡

Department of Food Science and †New Jersey Institute of Food, Nutrition and Health, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08901, United States § Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States

ABSTRACT: The bioaccessibility of salicylic acid (SA) can be effectively modified by incorporating the pharmacological compound directly into polymers such as poly(anhydride-esters). After simulated digestion conditions, the bioaccessibility of SA 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 polymer precursor (SADG), and 21.2 ± 3.1% for SADG-P (polymer). The release rates followed a zero-order release rate that was dependent on several factors, including (1) solubilization rate, (2) macroscopic erosion of the powdered polymer, (3) hydrolytic cleavage of the anhydride bonds, and (4) subsequent hydrolysis of the polymer precursor (SADG) to SA and diglycolic acid.

behavior and low solubility.9,14−16 Furthermore, PAEs do not display the burst release typically observed in conventional delivery systems, which has been associated with toxicity concerns. While the PAEs do not demonstrate burst release behavior, a disadvantage of the PAEs could be the observed lag time.3,5,14 With some PAEs, drug release could be delayed by days, a behavior that may not be desirable if immediate pain relief, for example, is required. The lag time can be overcome by several approaches, such as admixing small molecules,17 increasing the hydrophilicity of the linker molecule,7,11,13 preparing copolymers7,9 and altering the pH of the degradation environment.3 Overall, PAEs offer an effective means of delivering drug moieties such as SA for applications requiring both short- and long-term drug release.18 As numerous variables influence the polymer degradation rate, including temperature, pH, water content, and mixing, it is important to understand how these polymeric systems behave in the alimentary track to ensure pharmacopeial efficacy. The influence of biological and formulation variables makes it essential to characterize the “release” profile from the delivery vehicle into the luminal fluids, which is termed bioaccessibility, defined here as the cumulative percent of SA released in the jejunum and ileum (Figure 1, TIM-1 sections 5c and 5d, respectively). It is not necessary to probe the bioavailability

INTRODUCTION Salicylic acid (SA), an active metabolite of aspirin (acetylsalicylic acid; ASA), is useful due to its anti-inflammatory, antipyretic, keratolyic and analgesic properties.1,2 While SA has been used since the fifth century to relieve pain, recent advances describe a new delivery system that directly incorporates SA into a poly(anhydride-ester) (PAE) to overcome issues associated with ASA.3−6 The polymeric version of SA offers many advantages over the small molecule of ASA; the first is the ability to formulate into various geometries, including powders,7 disks,8 fibers,9 and microspheres.10 Second, PAEs allow high SA loadings, typically between 60 and 80%, because of the direct incorporation of SA into the polymeric backbone.3 Third, PAEs enable sustained release of SA; as small molecules, SA rapidly diffuses, whereas the polymeric version delivers a sustained, controlled release of SA over time.5,11 Thus, PAEs have great potential in various biomedical applications, as they have been found to be nontoxic in both in vitro12 and in vivo studies.8 In designing SA-based PAEs, both the drug release rate and drug loading capacity can be modified by altering the chemical composition of the linker molecule, enabling a tunable drug release profile for diverse applications.5,11,13 Upon exposure to water, PAEs undergo hydrolytic degradation; the SA release rate is dependent upon the solution conditions (i.e., pH, temperature, etc.) and polymer composition.5 PAE’s typically exhibit a sustained, near zero-order rate of drug release, owing to their rate-limiting step being governed by its surface-eroding © 2014 American Chemical Society

Received: June 25, 2014 Revised: July 31, 2014 Published: July 31, 2014 3406 | Biomacromolecules 2014, 15, 3406−3411



Figure 1. Schematic diagram of the in vitro gastrointestinal model, TIM-1: (1) food inlet, (2) jejunum filtrate, (3) ileum filtrate, (4) ileal colorectal valve, (5a) gastric compartment, (5b) duodenal compartment, (5c) jejunum compartment, (5d) ileal compartment, (6a) hollow fiber membrane from jejunum, (6b) hollow fiber membrane from ileum, (7a) and (7b) secretion pumps. Reprinted with permission from ref 20. Copyright 2013 American Chemical Society. Thermogravimetric analysis (TGA) was used to acquire the decomposition temperature (Td) of polymer samples. TGA analysis was performed using a PerkinElmer TGA7 analyzer with TAC7/DX controller equipped with a Dell OptiPlex Gx 110 computer running PerkinElmer Pyris software (PerkinElmer, Waltham, MA). Polymer samples (10 mg) were heated under nitrogen at a rate of 10 °C/min from 25 to 400 °C. Td was defined as the onset of decomposition, represented by the beginning of a sharp slope on the thermogram. Simulated Digestion. Pancreatin was obtained from SigmaAldrich. Fresh pig bile was obtained from Farm-to-Pharm (Warren, NJ, U.S.A.). The bile was collected, standardized from a slaughterhouse, and pooled together before an aliquot for individual TIM experiments was taken and stored at −20 °C until use. Rhizopus lipase (150000 units/mg F-AP-15) was obtained from Amano Enzyme Inc. (Nagoya, Japan). Trypsin from bovine pancreas (7500 N-α-benzoyl-Larginine ethyl ester (BAEE) units/mg, T9201) was obtained from Sigma-Aldrich. TNO Intestinal Model (TIM-1). A dynamic, in vitro gastrointestinal (GI) model, TIM-1, developed by TNO (Zeist, The Netherlands), was utilized to simulate digestion. The TIM-1 system models the human digestive tract utilizing four compartments mimicking the stomach, duodenum, jejunum and ileum, peristaltic movements, nutrient/drug and water absorption, gastric emptying, and transit time, as would be observed in vivo (Figure 1). Compartments are infused with formulated gastric secretions, bile, and pancreatic secretions to modify pH and reproduce digestive conditions, respective of a fed or fasted state. In the fasted state, the pH of the gastric compartment is 2.2 upon administration of the pharmacological agent and decreases to 1.5 over 90 min, and the gastric emptying rate has a half-life of 20 min. A 1.4% pancreatin solution (Pepsin from porcine gastric mucosa, lyophilized powder, >2500 units/mg protein, Sigma-Aldrich) and small intestinal electrolyte solution (SIES: NaCl 5 g/L, KCl 0.6 g/L, CaCl2 0.25 g/L) were prepared. Duodenal start residue (60 g; 15 g SIES, 30 g diluted fresh porcine bile (20% bile), 2 mg trypsin solution, 15 g pancreatin solution), jejunal start residue (160 g: 40 g SIES, 80 g fresh porcine bile, 40 g pancreatin solution), and ileal start residue (160 g SIES) were injected into respective compartments prior to heating the system to physiological temperature (37 °C) in preparation for feeding.

because absorption and circulation will be only affected by the rate of SA release, as it is the free SA that is absorbed. The purpose of this study is to observe how the chemical structures of SA precursors and polymers influence SA release (from SADG and SADG-P, respectively) as compared to the smaller molecules (SA) in a dynamic simulated TNO-intestinal model (TIM-1) and to determine if SA release is targeted to different intestinal segments.


Materials. All chemicals, solvents, and reagents were used as received, unless otherwise indicated, and purchased from SigmaAldrich (Milwaukee, WI). SA (Sigma-Aldrich) was used as a control and the polymer precursor (SADG) and polymer (SADG-P) were synthesized according to a previously published protocol.4,5,7,13,19 Molecular Weight Analysis. Gel permeation chromatography (GPC) was used to determine the molecular weight (Mw) and polydispersity index (PDI) of the polymer samples. A Waters system consisting of a 1515 isocratic high pressure liquid chromatography (HPLC) pump, a 717plus autosampler, and a 2414 refractive index (RI) detector was used. Waters Breeze 2 software running on an IBM ThinkCentre CPU was used for data collection and analysis. Samples were dissolved in dichloromethane (DCM; 10 mg/mL) and filtered through 0.45 μm polytetrafluoroethylene syringe filters (VWR, Bridgeport, NJ). A 10 μL aliquot was injected and resolved on a Jordi divinylbenzene mixed-bed GPC column (7.8 × 300 mm, Alltech Associates, Deerfield, IL) at 25 °C, with DCM as the mobile phase at a flow rate of 1.0 mL/min. Molecular weights were calibrated relative to broad polystyrene standards (Polymer Source Inc., Dorval, Canada). Thermal Analysis. Thermal analysis was accomplished using differential scanning calorimetry (DSC) to acquire the glass transition (Tg) temperature. DSC was performed utilizing a Thermal Advantage (TA, New Castle, DE) DSC Q200 running on an IBM ThinkCentre computer equipped with TA Universal Analysis software for data acquisition and processing. Samples (4−6 mg) were heated under nitrogen from −10 to 200 °C at a rate of 10 °C/min. A minimum of two heating/cooling cycles was used for each sample set. TA Instruments Universal Analysis 2000 software, version 4.5A, was used to analyze the data. 3407 | Biomacromolecules 2014, 15, 3406−3411



Figure 2. SA release from free SA powder, SADG, and SADG-P at 30, 60, 90, 120, 180, 240, and 300 min in the jejunum (A), ileum (B), jejunum + ileum (C), and at the ileum efflux (D). HPLC-Evaporative Light Scattering Detector (ELSD) Analysis. Separations were carried out by using Waters e2695 Alliance HPLC system (Waters, Milford, MA, U.S.A.) equipped with a free fatty acid HP column (4 μm, 3.9 × 150 mm; Waters, Milford, MA, U.S.A.) set at 30 °C. The injection volume was 50 μL, the flow rate was 0.5 mg/min, and run time was 6 min. The isocratic eluting system consisted of 50% water and 50% tetrahydrofuran (THF). The effluent was monitored with Waters 2424 Evaporative Light Scattering Detector (ELSD; Waters, Milford, MA, U.S.A.) with the following settings: drift tube temperature for ELSD set at 65 °C and nebulizer for nitrogen gas adjusted to 40 psi. Comparing the retention time with the reference compound identified the chromatographic peaks. The corresponding retention times are 2.4 for SA and 1.8 min for SADG. A total of 10 concentrations of SA (≥99.0%; Sigma-Aldrich, St. Louis, MO, U.S.A.) solutions were injected in triplicate to generate the calibration curve constructed by plotting the peak areas versus the concentration of the SA. Quantification was carried out from the integrated peak area and corresponding calibration curve.

Different formulations were tested during 5 h experiments in the TIM-1 model, simulating fasted-state physiological conditions following ingestion of SA, SADG, or SADG-P. The test sample was placed in a mesh teabag located in between the two glass compartments of the gastric unit, so that the formulation was exposed to physiologically relevant waves of peristalsis mixing, but not to direct pressure forces. To simulate the initial amount of gastric juice, 5 g gastric enzyme (NaCl 4.8 g/L, KCl 2.2 g/L, CaCl2 0.22 g/L, and) was added to the gastric compartment. Formulations were standardized so a total of 249.3 mg of SA could be hydrolytically generated and each formulation was prepared as a fine powder, loaded into a tea bag and suspended in the gastric compartment. Then, 45 g gastric electrolyte solution, 100 g of water, and 2.5 mg amylase were immediately added into the gastric compartment, followed by a 50 g of water rinse. Secretion of HCl (1 M) into the gastric compartment during digestion was controlled to follow a preprogrammed computer protocol, which regulates gastric emptying (half-life = 20 min), intestinal transit times, pH (pH 2.2 to 1.5), and secretion fluid amounts.21 Secretion of digestive fluids were setup based on the following: duodenal secretion consisting of fresh porcine bile at a flow rate of 0.5 mL/min, a 1.4% pancreatin solution at 0.25 mL/min, and SIES at 3.2 mL/min. Jejunal secretion consisting of SIES and fresh porcine bile were introduced at a flow rate of 3.2 mL/min. Ileal secretion consisting of SIES was pumped at a flow rate of 3.0 mL/min. Secretion of HCl (1 M) into the gastric compartment during digestion was monitored via a preprogrammed computer protocol that regulates gastric emptying, intestinal transit times, pH values, and secretion fluid amounts. The pH of duodenal, jejunal, and ileal compartments was maintained at 6.5, 6.8, and 7.2, respectively, by controlled secretion of sodium bicarbonate solution (1 M). The available SA fraction was observed by collection and analysis of dialysate fluids, which were passed through semipermeable capillary membranes (Spectrum Milikros modules M80S-300−01P, Irving, TX) with 0.05 μm pores at the ileal and jejunal compartments. Jejunal and ileal filtrates as well as ileal efflux were cooled on ice to reduce residual enzyme activity once the samples passed through the capillary membranes. Samples were gathered at 30, 60, 90, 120, 180, 240, and 300 min and immediately analyzed on an HPLC (see parameters below). This process allows the individual compartments of the upper GI to have their isolated effects on hydrolytic release of SA. Residues were not collected for analysis following experiment termination at 300 min. SA bioaccessibility was evaluated for each formulation in triplicate and each run was analyzed in duplicate, providing three sample triplicates and two technical duplicates for each variable.

RESULTS AND DISCUSSION SADG and SADG-P were successfully synthesized according to published procedures.4,5,7,13,19 Following SADG-P isolation, Mw and PDI were determined to be 16.0 kDa and 1.4, respectively. Furthermore, thermal properties were assessed to ensure the polymer morphology would not be altered during the course of the study conducted at 37 °C. SADG-P was found to possess favorable thermal properties with a Tg of 72 °C and Td of 330 °C. In vitro evaluation of SA, SADG, and SADG-P was performed using the TIM-1 model under fasted conditions. The TIM-1 system was chosen as the simulated digestion model because of the dynamic nature of the apparatus and because it has been previously reported to have strong in vitro/ in vivo correlation (IVIVC) for orally administered drugs in the human GI tract.22−24 Previous research demonstrated that the hydrolytic degradation of a similar PAE, using sebacic acid rather than diglycolic acid was pH-dependent.3 As shown for polyanhydrides, in general, the relative rates of anhydride bond hydrolysis increases when subjected to more basic conditions.3,25−27 This data suggests that SA-derived PAEs might be an effective delivery system for releasing SA into the lower intestine.3 As the SA release rate is a direct result of the 3408 | Biomacromolecules 2014, 15, 3406−3411



Scheme 1. Hydrolytic Degradation of SA-Based Polymers (SADG-P): Anhydride Linkages are First Hydrolyzed to Form the Intermediate (SADG) and Then the Ester Bonds Further Hydrolyze to Yield SA and DG

Figure 3. Cumulative SA release from free SA, SADG and SADG-P concentrations in jejunal filtrate (A), ileal filtrate (B), combined jejunal and ileal filtrates (C), and ileal efflux (D).

120 min after which there is a 2-fold increase in the release per unit time (Figure 2A). SA bioaccessibility is not only limited by the solubility, but also by the rate of surface erosion of the powder or rate of dispersion. As expected, the SA concentration released by SA was the highest (138 mg), followed by SADG (78 mg) and SADG-P (53 mg), respectively. Although no initial lag phase was observed for any drug formulation, differences in the total SA released by the SA, SADG, and SADG-P indicate a delay in the hydrolytic degradation of the SADG and SADG-P. This divergence became even more pronounced between 90 and 120 min (Figure 2A−C). Further, the amount of SA released by SADGP was lower compared to SADG. This difference is attributed to the fact that SADG-P must first hydrolyze to SADG via anhydride bond cleavage, and then SADG undergoes hydrolysis further to the SA and diglycolic acid (DG) via ester bond cleavage (Scheme 1). As in the jejunum, a slower hydrolysis rate was observed with the SADG and SADG-P in the ileum (Figure 2B). Overall, the fraction of SA available in the ileum, section 5d in Figure 1, was lower than the fraction available in

hydrolytic cleavage of the PAE anhydride and ester bonds, it is possible to determine the SA release rate from the SADG and SADG-P and subsequently infer SA bioaccessibility from each formulation in the different intestinal segments (Figure 2). Very little SA is released during the first 60 min of digestion (Figure 2). This result is consistent with the cyclic interdigestive pattern, also known as the migrating motility/ myoelectricity complex (MMC), for the fasted state. MMC consists of three phases: a resting period of approximately 60− 70 min, a phase of 20−30 min during which the frequency of muscular contractions increases, and a final phase of approximately 5−10 min of forceful contractions.28 Given the known lag time for polyanhydrides and PAEs, we anticipated that SA release from the polymer formulation would be delayed. Yet, for all test samples (SA, SADG, and SADG-P), SA concentrations increased with transit time between 180 and 240 min and declined after 240 min. The sharpest increase in concentrations was observed between the 60−120 min and 120−180 min time intervals. In the jejunum, section 5c in Figure 1, SA bioaccessibility increases linearly during the first 3409 | Biomacromolecules 2014, 15, 3406−3411



Table 1. SA Release Rates Calculated As Zeroth-Order Rate from the Combined Ileum and Jejunum Bioaccessible Fractions jejunum


jejunum + ileum



release rate (mg/min)


release rate (mg/min)


release rate (mg/min)


release rate (mg/min)



0.29 0.21 0.16

0.96 0.94 0.96

0.16 0.06 0.04

0.99 0.92 0.96

0.42 0.27 0.19

0.98 0.95 0.93

0.03 0.02 0.02

0.51 0.26 0.33

Figure 4. Total SA bioaccessibility (i.e., combined jejunal and ileal filtrate concentrations) after 5 h of simulated digestion. Letters denote significant differences based on triplicate digestions using a two-way ANOVA and Tukey’s multiple comparison test (p < 0.0001).

SADG-P. For SA to be released from the polymer, several steps must occur: the polymer surface is hydrolyzed, the anhydride bonds are cleaved, then both ester bonds must be hydrolyzed before the SA is solubilized (Scheme 1). Interestingly, the majority of ASA was released in the jejunum compared to either the ileum or the efflux (Figures 2 and 3). Since the powder was partially confined in the stomach, only the soluble/ dispersed fraction reaches the jejunum, and upon reaching the jejunum, the pH changes from 1.5 to 6.5, which facilitates the hydrolytic cleavage of the ASA monomers. After 5 h of simulated digestion, the bioaccessibility of SA was observed to be 55.5 ± 2.0% for free SA, 31.2 ± 2.4% for SADG, and 21.2 ± 3.1% for SADG-P (Figure 4). The statistically significant (p < 0.001) differences in SA bioaccessibility correlate with the differences in drug formulation/composition. A polymeric version of SA ultimately translates to decreased SA bioaccessibility throughout the entire GI tract.

the jejunum, indicating that the majority of hydrolysis occurred in the jejunum. This trend was also observed at the ileal efflux (Figure 2D, section 4 in Figure 1), which represents the SA delivered to the colon. Although the hydrolysis of ASA is a second-order reaction, dependent upon the initial ASA concentration and pH, it is often assumed to be a near zero-order reaction when the pH is constant.29 Using the absolute concentrations obtained from Figure 2, a cumulative bioaccessible concentration was obtained and plotted as a function of time (Figure 3A−C) to facilitate the calculation of the rate kinetics. The zeroth-order reaction rate becomes prevalent when the total SA bioaccessibility is observed as a function of time; as all test samples (SA, SADG and SADG-P) display near zero-order release profiles. It is plausible that the near zero-order release of SADG-P is due to predominantly surface eroding characteristics, as this is common in PAE systems.14 The cumulative release rates of SA were determined to be 0.42 mg/min (R2 = 0.98) for SA, 0.28 mg/min (R2 = 0.95) for SADG, and 0.19 mg/min (R2 = 0.93) for the SADG-P (Table 1). As expected, free SA had a consistently higher release rate in each of the intestinal segments compared to SADG and SADGP. The bioaccessibility of free SA appears to be dependent only on the solubilization rate and power erosion. Very little SA was detected in the ileal efflux (i.e., delivered to the colon), suggesting that very little of the drug would be metabolized by the gut microflora. The SA release rate from the SADG was 1/3 more slow than the SA, illustrating that SADG is not only affected by the solubilization rate but must also undergo hydrolysis to dissociate into the SA and diglycolic acid. As expected, the SA release rate was slowest for the polymer,


The bioaccessibility of SA, found to be a zero-order hydrolysis reaction, can effectively be modified by incorporating SA into a PAE backbone. After simulated digestion using the TIM-1, the SA bioaccessibility was 55.5 ± 2.0% for SA, 31.2 ± 2.4% for SADG, and 21.2 ± 3.1% for SADG-P. The SA release rates were dependent on (1) solubilization rate, (2) macroscopic erosion of the powder, (3) hydrolytic cleavage of the polymer’s anhydride bonds, and (4) hydrolytic cleavage of the ester bonds to SA and diglycolic acid. 3410 | Biomacromolecules 2014, 15, 3406−3411



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Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS We would like to acknowledge the technical support from TNO and TNO Triskelion and Susann Bellmann on the operation and technical support for the TIM-1 GI model. M.A.R. and K.E.U. also gratefully acknowledge support for this project supplied from the New Jersey Institute of Food, Nutrition and Health (IFNH) seed grant program.


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