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Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets*
Journal of Pharmaceutical Sciences xxx (2018) 1-6
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org
Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets* Zongming Gao 1, *, Cindy Ngo 1, Wei Ye 1, Jason D. Rodriguez 1, David Keire 1, Dajun Sun 2, Hong Wen 2, Wenlei Jiang 2 1
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, St. Louis, Missouri 63110 Office of Research and Standards, Office of Generic Drugs, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland 20993 2
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 July 2018 Revised 17 September 2018 Accepted 11 October 2018
In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products. Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Keywords: dissolution controlled release osmotic pump(s) gastrointestinal tract US Pharmacopeia (USP) polymeric drug delivery system(s) physiological model(s) pH oral drug delivery in vitro model(s)
Introduction Drug absorption from a solid dosage form after oral administration depends on drug release from the formulation, the physical state of the drug molecules under physiological conditions, and drug permeation across the gastrointestinal membranes.1,2 The dissolution of a drug in the gastrointestinal (GI) tract is critical for the drug’s absorption into the systemic circulation. In vitro dissolution testing is an important technique for evaluating drug release from the pharmaceutical products in the development pipeline as well as during commercial scale up manufacturing. During pharmaceutical product development, dissolution testing is primarily used for measuring the rate of drug release, assessing the stability
*This article reflects the views of the authors and should not be construed to represent FDA’s views or policies. * Correspondence to: Zongming Gao (Telephone: þ1-314-539-3817). E-mail address: [email protected] (Z. Gao).
of the formulations, monitoring product consistency, evaluating formulation changes, and establishing in vitroein vivo relationships or correlations. For a commercial product, dissolution testing is primarily used for confirming product lot-to-lot quality consistency, evaluating the quality of the product during its shelf-life and assessing postapproval changes and the need for bridging bioequivalence studies.3,4 For the purpose of quality control, compendial dissolution methods based on United States Pharmacopeia (USP) are relatively simplified models meant to cover a broad range of formulations and contain limited or no consideration of dissolution dynamics caused by GI physiology and transition through the digestive tract. As a result, the in vitro dissolution data based on USP methods may not be correlated to in vivo drug release, although the compendial dissolution tests may work well for ensuring the batchto-batch consistency. One of the areas where dissolution dynamics may play a key role is in products that feature different release mechanisms, specifically polymer matrix-based versus osmotic pump-based products. One example is nifedipine, which was first introduced in the mid-
https://doi.org/10.1016/j.xphs.2018.10.014 0022-3549/Published by Elsevier Inc. on behalf of the American Pharmacists Association.
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1970s for the prevention of angina symptoms and later for the treatment of hypertension. A number of studies have been conducted on in vitro and in vivo behaviors of nifedipine products.5-9 Oral administration of the nifedipine immediate-release capsules was associated with profound reflex increases in heart rate associated with activation of the sympathetic nervous system. The development of the extended-release (ER) formulation aimed to delay and flatten the attainment of the peak plasma concentrations of nifedipine in the pharmacokinetic profiles and result in a smooth, more gradual onset of the antihypertensive effect, which can be sustained throughout 24 h without discernible cardio acceleration.7,8 As the rate of delivery of nifedipine into the systemic circulation is a direct determinant of the rate of onset of the vasodilator effect, there will be some potential risks to the patients if ER formulations fail their controlled slow release functionality under the actual GI conditions. Gastric pH modification commonly occurs in patients who have achlorhydria or take over-the-counter proton pump inhibitors. In particular, some nifedipine ER products, which utilize a polymer matrix-based formulation design, may show an increased dissolution rate at a higher pH in comparison with osmotic pump-based products.8 In addition, a significant dose-dumping effect in vivo was observed in fed conditions after administration of polymer-based nifedipine ER tablet products approved and marketed in Europe with conclusions that pHdependent in vitro release may partly contribute to the observed dose-dumping phenomenon, but the in vitro USP dissolution results of the tested polymer matrix-based formulations could not completely explain the observed in vivo phenomenon.8-11 Pollak et al.12 also reported therapeutic differences in pharmacodynamics endpoints when switching between two 60 mg once-daily nifedipine ER products using different drug delivery technologies that were deemed bioequivalent in Canada. When passing through the stomach and small intestine, oral dosage forms are normally subjected to physical shear and grinding forces as well as pressure exerted by peristaltic movements. The complex physical forces exerted by the GI tract are not well simulated by a USP dissolution method in a stirred medium. pHdependent or alcohol-induced in vitro dose-dumping effects are popular fields of research studies, and alcohol dose-dumping studies are sometimes recommended for developing highly dosed, modified-released oral dosage forms. Contraction-induced dose-dumping could also impact product in vivo performance but has not received consideration because of a lack of clinical data and of the capacity of existing in vitro dissolution-testing devices to mimic these forces. Scientists have developed some none compendial dissolution methods to explore the impact of contractile forces during transit along the GI tract.13-15 These methods examined the mechanical robustness of the drug product and its ability to withstand forces similar to those measured in the GI tract and passage through the pylorus junction. However, the studies were unable either to monitor the force applied to the samples or measure sample deformation during the test. Recently, a modified dissolution-testing apparatus that applies external force and medium environment was assembled and explored for gelatin capsule formulations.16 The device assembled was called the “in-house” apparatus in this article. The objective of this study focuses on studying the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media and the potential impacts that media pHs and simulated GI contractions have on drug release. The USP paddle apparatus was used to measure drug release of nifedipine ER tablets from polymer matrix and osmotic pump formulations in pH 1.2, 4.5, or 6.8 dissolution media. The in-house dissolution apparatus was used to apply compression forces on test sample during dissolution testing. The compression force could be adjusted
based on published in vivo physiological data to simulate GI contraction. Experimental Materials Two nifedipine strengths (30 and 60 mg) of each osmotic pump (Product A) and polymer matrix-based extended-release tablets (Product B) were purchased from the U.S. market. According to the insert of product B, the drug product contains methacrylic acid and methyl methacrylate copolymer as inactive ingredients. Nifedipine reference standard was purchased from USP (lot #: LOJ059, Purity: 99.7%). All chemicals were either analytical or high-performance liquid chromatography grades. Medium Preparation Dissolution media of pH 1.2 HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were prepared following the USP method (USP40eNF35, page 5354). All dissolution media were added 1% sodium lauryl sulfate. Testing Procedure Dissolution testing using USP apparatus 2 was performed for each dosage strength at 37 C with a paddle speed at 50 rpm in 900 mL dissolution medium under each of the above pH conditions for 24 h. The sample aliquot at predetermined time points was taken, and the amount of drug release was measured based on the calibration curve using online ultravioletevisible (UV/vis) (Agilent8453, quartz cuvette with 2 mm path length) at 238 nm. Each condition with the USP 2 apparatus was repeated twice with 12 tablets. The description of the in-house dissolution testing apparatus has been previously reported.16 In brief, a test sample was placed on a stainless steel plate, which was held on a sample holder and placed in a 500 mL jacketed glass beaker. A magnetic stir bar under the plate was used to agitate 350 mL dissolution media. The dissolution testing was conducted in various buffer media at 37 C. The Texture Analyzer (TA.XT Plus) applied a preprogrammed compression to the sample during dissolution testing through a probe, and both compression force and probe displacement were recorded. The Texture Analyzer equipped with a 500 gram load cell with 0.02 gram increments (#139125; Stable Micro System) was calibrated using a Low Force Loadcell Kit (Texture Instrument) before starting of the project. The distance traveled by the probe during the test was recorded as the displacement. The displacement is defined as the distance between the reference position, just touching the sample at the beginning of the test, and its position measured subsequently in contact with the sample at the specified force. The resulting displacement curve caused by sample deformation or geometric change characterizes the mechanical properties of the sample over time. A displacement curve with a positive slope indicates that the sample’s resistance to the applied force is diminishing, reflecting sample softening, shrinking, or disintegrating. By contrast, a displacement curve with negative slope indicates that the sample’s resistance to the applied force is increasing, reflecting sample hardening, swelling, or expanding. The sample aliquot at predetermined time points was taken through a sample cannula and using UV (Agilent-8453) detection at 238 nm to measure the amount of drug release based on the standard solution. All tests with the in-house apparatus were conducted in triplicate. Since nifedipine is light sensitive, we covered the USP 2 and in-house apparatuses with aluminum foil during the test to prevent light-induced degradation.
Z. Gao et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-6
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Figure 1. Comparison of dissolution profiles of 30 and 60 mg product A (osmotic pump formulation) in 3 different pH media using USP paddle apparatus.
Results and Discussion Modified-release dosage forms are normally developed to reduce the dosing frequency for better therapeutic compliance in chronic treatment and to attenuate maximum peak plasma levels in the case of concentration-related side effects. For nifedipine ER products, osmotic pump and polymer matrix-based delivery systems are 2 types of formulation designs, which are commonly used to control drug release. The osmotic pump-based formulation applies push-pull osmotic technology using an osmotically active but pharmacologically inert polymer surrounded by a semipermeable membrane.17 After the tablet enters the GI tract on oral ingestion, as the polymer expands and the osmotic pressure increases, the drug substance is extruded through the precision-drilled orifice at a controlled rate over 24 h. The osmotic delivery system is designed to deliver drug substance into the GI system and hence into the systemic circulation at a constant (zero-order) rate until the formulation is exhausted. For polymer matrix-based systems, the drug dissolution and diffusion through the polymer/coating are critical in controlling the release characteristics of the formulation.6,18 Figures 1 and 2 show dissolution profiles of the 2 different formulations (osmotic pump or matrix-based formulations) in dissolution media at pH 1.2, 4.5, and 6.8. Table 1 summarizes the similarity factor (f2 calculated based on FDA guidance19) of dissolution profiles of products A (osmotic pump) and B (matrix-based) nifedipine ER tablets across 3 pH levels. Both drug products had
minimal drug release (<10%) during the first 2 h of tests under all 3 pH conditions. For the osmotic pump formulation (Fig. 1), both dosage strengths exhibit similar dissolution behaviors at all 3 pH conditions. The osmotic pump formulation releases drug through an orifice on one side of the tablet at a constant (zero-order) rate that is independent of the pH and hydrodynamics of the dissolution medium. After 24 h in dissolution media, the shape and the size of the osmotic pump tablet remained unchanged based on visual inspection. By contrast, for the matrix-based formulation (Fig. 2), the pH of the media impacted the dissolution profiles, and drug was released faster with increasing pH values. The trend of pHdependent dissolution behaviors for the matrix-based formulation may be a result of faster dissolution of polymeric carrier at a higher pH. The dissolution results showed that the osmotic pump-based formulation is robust toward pH changes of dissolution media comparing to polymer matrix-based product. Similar dissolution results had been reported in another publication.9 The similar results are not unexpected because both studies focused on a similar nifedipine ER formulation, which was design to release drug in a certain way. However, in Grabacz et al. and the work performed here, the sources of tested drug products were different. The drug products in Grabacz et al. were from European manufacturers, whereas the drug products in this work were made in the US. Moreover, this study developed a different approach to explain observed dissolution results with more precise control of the compression forces. Thus, in the present study, product
Figure 2. Comparison of dissolution profiles of 30 and 60 mg product B (polymer matrix formulation) in 3 different pH media using USP paddle apparatus.
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Table 1 Similarity Factor (f2) of Dissolution Profiles Across pH 1.2 (0.1 N HCl), 4.5, and 6.8 for Products A (Osmotic Pump) and B (Matrix-Based) Nifedipine ER Tablets at Different Strengths f2 Product Product Product Product
A 30 mg A 60 mg B 30 mg B 60 mg
pH 1.2/4.5
pH 4.5/6.8
pH 6.8/1.2
97 81 67 55
93 71 47 52
90 85 41 40
deformation in dissolution medium can make a direct link to changes of nifedipine drug release from different formulations under various pHs and applied compression forces. To get a better understanding of the observed pH effect on drug release from nifedipine ER formulations, the mechanical properties of the ER tablets during dissolution testing were measured by an inhouse dissolution apparatus with capability of monitoring product mechanical response during dissolution testing. The responses to the applied force or geometric changes of dosage form such as disintegration, softening, shrinking, and swelling in the dissolution medium could directly impact the drug release mechanism. Based on above results (Figs. 1 and 2) from the USP method in 3 pH dissolution media, there was no significant dissolution difference between the 2 strengths of each product. Therefore, available 60 mg product A and 30 mg product B were further tested in the pH 1.2 and pH 6.8 dissolution media, respectively, using the in-house apparatus. Figure 3 shows displacement profiles for tablet mechanical responses of 2 different formulations during dissolution testing in the pH 1.2 and 6.8 media. The results show a significant difference in mechanical response for matrix-based product B in the phosphate buffer at pH 6.8 comparing that in pH 1.2 HCl medium. In the phosphate buffer at pH 6.8, product B swelled less (only a 15% increase of the tablet original height was observed), was relatively faster to reach the highest swelling point (in 3 h), and lost mechanical resistance quicker in 5 h compared to those in pH 1.2 HCl. However, the mechanical response showed no difference for osmotic pump product A in both media because the tablets remain rigidly intact throughout dissolution testing. These data indicated that the polymer matrix-based formulation was mechanically weak in pH 6.8 phosphate buffer after 3 h. Because product B features a polymer matrix-based formulation, it was vulnerable to pH changes and had weak mechanical properties at pH 6.8. Further research focused on the possible impacts of compression force on drug release in pH 6.8 dissolution medium. Usually, the pH 1.2 dissolution medium is used to simulate
Figure 4. Applied various compression forces on product A and B tablets in pH 6.8 buffer. Green line: constant 0.1g force; Blue line: 4 stage compressions including (1) 0.1g force for 2 h, (2) 10g force for 1 h, (3) dynamic 400g force for 10 min, and (4) 5g force for the rest of dissolution testing.
gastric condition during early dissolution time periods (1-2 h). As shown in Figures 1 and 2, pH values of the dissolution media have a minor impact on drug release before 2 h; pH 6.8 buffer was applied as dissolution medium throughout dissolution testing for ease of operating the test. The human gastrointestinal tract consists of distinct compartments of differing shapes, sizes, and orientations. These compartments should be considered when designing a realistic dynamic model. There are many reports on values attributed to the forces involved in human GI motility and contractility, but the results vary significantly. The parameters used in this study to simulate GI contraction were selected based on published results.18,20-22 One limitation of compression forces applied in this study is that the applied forces may not accurately reflect the in vivo GI motility and contractility. The simulated parameters could be adjusted in the future depending on clinical studies with quantitative measurements of contraction force and frequency during the physiological phases of GI digestion. Figure 4 shows a constant (0.1 gram force in green) and 4 stage compression forces (in blue) that were applied to samples during the dissolution testing in pH 6.8 phosphate buffer. Four stage compression forces were programmed to simulate various GI contractions. At the first stage, a constant 0.1g force was applied
Figure 3. The displacement of product A (1) and B (2) during dissolution testing in 2 different media.
Z. Gao et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-6
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Figure 5. Displacement profiles of product A (1) and B (2) in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
Figure 6. Dissolution profiles of product A (1) and B (2) in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
Figure 7. The dissolution rate (%/hr) of product A (1) and B (2) during dissolution testing in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
for 2 h to simulate storage period in the stomach. At the second stage, a 10 g constant force for 1 h was simulated for stomach mixing period. At the third stage, a dynamic compression force for 10 min was applied. As shown in Figure 4, the dynamic force keeps 400 g for 10 s duration every 15 s to simulate 4 contractions per minute. At the fourth stage, a 5 g constant force was applied.
The displacement changes of tested sample under various simulated compression forces are shown in Figure 5. For product A, the 400 gram compression decreased the tablet height (original tablet height ¼ 5.90 ± 0.01 mm) when it was applied on to the tablet in pH 6.8 phosphate buffer but with less than 10% change (in blue) when compared with results with 0.1 gram contact force (in green). For product B, the 400 gram contraction dramatically
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decreased more than 60% (in blue) of the tablet height (original tablet height ¼ 4.25 ± 0.10 mm) in pH 6.8 phosphate buffer when compared with results with 0.1 gram contact force (in green). Figure 6 shows dissolution profiles of product A and B tablets in pH 6.8 phosphate buffer measured with different compression forces. The results showed that product B (polymer matrix-based) had different dissolution performance under simulated GI contraction. The drug release increased right after the simulated contraction was applied. However, the results from product A (osmotic pump) showed that the compressions had no impact on drug dissolution performance. This difference in dissolution performance between polymer matrix and osmotic pump-based products was also observed in drug release rates (Fig. 7). For the osmotic pump formulation, there was only a little fluctuation of dissolution rates during the period of applied compression forces. Under the 400 gram simulated contraction force, the polymer matrix-based formulation showed an abrupt increase (i.e., more than double) in dissolution rate that caused dose-dumping after contraction. For nifedipine extended-release drug products approved and marketed in Europe, the pharmacokinetics of some once-daily nifedipine extended-release formulations based on nonosmotic pump formulations (e.g., erosive matrices, monolayer matrices, or capsules with mini tablets) is more sensitive to concomitant food intake than nifedipine ER formulation based on osmotic pumps.8,10,11,23 A significant dose-dumping effect was also observed in vivo after fed administration of polymer matrix-based tablet, resulting in rising nifedipine plasma concentrations, nearly 3-to 4fold, in 11 of 24 volunteers.6 These reports concluded that the pHdependent in vitro release may partly contribute to the observed in vivo dose-dumping phenomenon, for matrix-based nifedipine ER dosage forms under fed conditions where the ingested oral formulations may experience a longer duration of gastric contraction because of a greater gastric emptying time in comparison to the fasting conditions. This study demonstrated a direct connection between applied compression and drug release rate by analyzing tablet geometric/mechanical response data. The observed in vitro contraction-induced dose-dumping may be used to explain the clinical PK results of abnormal high plasma concentrations in some patients after taking polymer-based nifedipine ER products. Conclusions If an ER formulation fails to control release under GI contraction or altered pH condition, the patient would not get the intended dose profile for the drug. A modified dissolution testing apparatus was assembled and characterized drug dissolution profiles with or without mechanical compression. Product mechanical property changes during dissolution testing may be used as an indicator during product development and for quality assurance of oral drug products. With respect to the designed therapeutic use of ER nifedipine tablets, the findings indicate that the in vitro performance of the osmotic pump was robust toward concomitant medium pH changes and mechanical compression, whereas the polymer matrix-based formulation was sensitive to these physiological factors. The contraction-induced drug dose-dumping may contribute to the reported differences in pharmacokinetics for nifedipine ER formulations, and further investigation of the in vivo relevance of the in vitro observations may be warranted.
References 1. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413-420. 2. Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1988;15: 11-22. 3. Vangani S, Li X, Zhou P, et al. Dissolution of poorly water-soluble drugs in biphasic media using USP 4 and fiber optic system. Clin Res Regul Aff. 2009;26(1e2):8-19. 4. Dokoumetzidis A, Macheras P. A century of dissolution research: from noyes and whitney to the biopharmaceutics classification system. Int J Pharm. 2006;321:1-11. 5. Abrahamsson B, Alpsten M, Bake B, Jonsson UE, Eriksson-Lepkowsk M, Larsson A. Drug absorption from nifedipine hydrophilic matrix extendedrelease (ER) tablet-comparison with an osmotic pump tablet and effect of food. J Control Release. 1998;52:301-310. 6. Schug BS, Brendel E, Wolf D, Wonnemann M, Wargenau M, Blume HH. Formulation-dependent food effects demonstrated for nifedipine modifiedrelease preparations marketed in the European Union. Eur J Pharm Sci. 2002;15:279-285. 7. Ilic M, Kovacevic I, Parojcic J. Deciphering nifedipine in vivo delivery from modified release dosage forms: identification of food effect. Acta Pharm. 2015;65:427-441. 8. Meredith PA, Elliott HL. A review of the gastrointestinal therapeutic system (GITS) formulation and its effectiveness in the delivery of antihypertensive drug treatment (focus on nifedipine GITS). Integr Blood Press Control. 2013;6: 79-87. 9. Garbacz G, Golkea B, Wedemeyer R, et al. Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses. Eur J Pharm Sci. 2009;38:147-155. 10. Schug BS, Brendel E, Wonnemann M, et al. Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast. Eur J Clin Pharmacol. 2002;58(2):119-125. 11. Schug B, Brendel E, Chantraine E, et al. The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast. Br J Clin Pharmacol. 2002;53(6):582-588. 12. Pollak PT, Herman RJ, Feldman RD. Therapeutic differences in 24-h ambulatory blood pressures in patients switched between bioequivalent nifedipine osmotic systems with differing delivery technologies. Clin Transl Sci. 2017;10: 217-224. 13. Vardakou M, Mercuri A, Barker SA, Craig DQM, Faulks RM, Wickham MSJ. Achieving antral grinding forces in biorelevant in vitro models: comparing the USP dissolution apparatus II and the dynamic gastric model with human in vivo data. AAPS PharmSciTech. 2011;12:2. 14. Burke DM, Maheshwari RC, Zimmerman OB. Pharmaceutical analysis apparatus and method, US Patent, US 8,043,270 B2, 10/25/2011. 15. Garbacz G, Wedemeyer RS, Nagel S, et al. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. Eur J Pharm Biopharm. 2008;70(2):421-428. 16. Gao Z. In vitro dissolution testing of gelatin capsules with applied mechanical compression-a technical note. AAPS PharmSciTech. 2017;18:231. 17. Malaterre V, Ogorka J, Loggia N, Gurny R. Evaluation of the tablet core factors influencing the release kinetics and the loadability of pushepull osmotic systems influence of ppos core formulation on the drug delivery. Drug Dev Ind Pharm. 2008;12:1-7. 18. Borgquist P, Komer A, Piculell L, Larsson A, Axelsson A. A model for the drug release from a polymer matrix tablet-effects of swelling and dissolution. J Control Release. 2006;113:216-225. 19. U.S. Food and Drug Administration. Guidance for Industry. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Silver Spring, MD: FDA, Center for Drug Evaluation and Research; 2017. 20. Laulicht B, Tripathi A, Schlageter V, Kucera P, Mathiowitz E. Understanding gastric forces calculated from high-resolution pill tracking. Proc Natl Acad Sci U S A. 2010;107(18):8201-8206. 21. Abeele JVD, Rubbens J, Brouwers J, Augustijns P. The dynamic gastric environment and its impact on drug and formulation behavior. Eur J Pharm Sci. 2017;96:207-231. 22. Collins PJ, Houghton LA, Read NW, et al. Role of the proximal and distal stomach in mixed solid and liquid meal emptying. Gut. 1991;32:615-619. 23. Wonnemann M, Schug B, Schmücker K, Brendel E, van Zwieten PA, Blume H. Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union. Int J Clin Pharmacol Ther. 2006;44(1):38-48.
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org
Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets* Zongming Gao 1, *, Cindy Ngo 1, Wei Ye 1, Jason D. Rodriguez 1, David Keire 1, Dajun Sun 2, Hong Wen 2, Wenlei Jiang 2 1
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, St. Louis, Missouri 63110 Office of Research and Standards, Office of Generic Drugs, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland 20993 2
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 July 2018 Revised 17 September 2018 Accepted 11 October 2018
In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products. Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Keywords: dissolution controlled release osmotic pump(s) gastrointestinal tract US Pharmacopeia (USP) polymeric drug delivery system(s) physiological model(s) pH oral drug delivery in vitro model(s)
Introduction Drug absorption from a solid dosage form after oral administration depends on drug release from the formulation, the physical state of the drug molecules under physiological conditions, and drug permeation across the gastrointestinal membranes.1,2 The dissolution of a drug in the gastrointestinal (GI) tract is critical for the drug’s absorption into the systemic circulation. In vitro dissolution testing is an important technique for evaluating drug release from the pharmaceutical products in the development pipeline as well as during commercial scale up manufacturing. During pharmaceutical product development, dissolution testing is primarily used for measuring the rate of drug release, assessing the stability
*This article reflects the views of the authors and should not be construed to represent FDA’s views or policies. * Correspondence to: Zongming Gao (Telephone: þ1-314-539-3817). E-mail address: [email protected] (Z. Gao).
of the formulations, monitoring product consistency, evaluating formulation changes, and establishing in vitroein vivo relationships or correlations. For a commercial product, dissolution testing is primarily used for confirming product lot-to-lot quality consistency, evaluating the quality of the product during its shelf-life and assessing postapproval changes and the need for bridging bioequivalence studies.3,4 For the purpose of quality control, compendial dissolution methods based on United States Pharmacopeia (USP) are relatively simplified models meant to cover a broad range of formulations and contain limited or no consideration of dissolution dynamics caused by GI physiology and transition through the digestive tract. As a result, the in vitro dissolution data based on USP methods may not be correlated to in vivo drug release, although the compendial dissolution tests may work well for ensuring the batchto-batch consistency. One of the areas where dissolution dynamics may play a key role is in products that feature different release mechanisms, specifically polymer matrix-based versus osmotic pump-based products. One example is nifedipine, which was first introduced in the mid-
https://doi.org/10.1016/j.xphs.2018.10.014 0022-3549/Published by Elsevier Inc. on behalf of the American Pharmacists Association.
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1970s for the prevention of angina symptoms and later for the treatment of hypertension. A number of studies have been conducted on in vitro and in vivo behaviors of nifedipine products.5-9 Oral administration of the nifedipine immediate-release capsules was associated with profound reflex increases in heart rate associated with activation of the sympathetic nervous system. The development of the extended-release (ER) formulation aimed to delay and flatten the attainment of the peak plasma concentrations of nifedipine in the pharmacokinetic profiles and result in a smooth, more gradual onset of the antihypertensive effect, which can be sustained throughout 24 h without discernible cardio acceleration.7,8 As the rate of delivery of nifedipine into the systemic circulation is a direct determinant of the rate of onset of the vasodilator effect, there will be some potential risks to the patients if ER formulations fail their controlled slow release functionality under the actual GI conditions. Gastric pH modification commonly occurs in patients who have achlorhydria or take over-the-counter proton pump inhibitors. In particular, some nifedipine ER products, which utilize a polymer matrix-based formulation design, may show an increased dissolution rate at a higher pH in comparison with osmotic pump-based products.8 In addition, a significant dose-dumping effect in vivo was observed in fed conditions after administration of polymer-based nifedipine ER tablet products approved and marketed in Europe with conclusions that pHdependent in vitro release may partly contribute to the observed dose-dumping phenomenon, but the in vitro USP dissolution results of the tested polymer matrix-based formulations could not completely explain the observed in vivo phenomenon.8-11 Pollak et al.12 also reported therapeutic differences in pharmacodynamics endpoints when switching between two 60 mg once-daily nifedipine ER products using different drug delivery technologies that were deemed bioequivalent in Canada. When passing through the stomach and small intestine, oral dosage forms are normally subjected to physical shear and grinding forces as well as pressure exerted by peristaltic movements. The complex physical forces exerted by the GI tract are not well simulated by a USP dissolution method in a stirred medium. pHdependent or alcohol-induced in vitro dose-dumping effects are popular fields of research studies, and alcohol dose-dumping studies are sometimes recommended for developing highly dosed, modified-released oral dosage forms. Contraction-induced dose-dumping could also impact product in vivo performance but has not received consideration because of a lack of clinical data and of the capacity of existing in vitro dissolution-testing devices to mimic these forces. Scientists have developed some none compendial dissolution methods to explore the impact of contractile forces during transit along the GI tract.13-15 These methods examined the mechanical robustness of the drug product and its ability to withstand forces similar to those measured in the GI tract and passage through the pylorus junction. However, the studies were unable either to monitor the force applied to the samples or measure sample deformation during the test. Recently, a modified dissolution-testing apparatus that applies external force and medium environment was assembled and explored for gelatin capsule formulations.16 The device assembled was called the “in-house” apparatus in this article. The objective of this study focuses on studying the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media and the potential impacts that media pHs and simulated GI contractions have on drug release. The USP paddle apparatus was used to measure drug release of nifedipine ER tablets from polymer matrix and osmotic pump formulations in pH 1.2, 4.5, or 6.8 dissolution media. The in-house dissolution apparatus was used to apply compression forces on test sample during dissolution testing. The compression force could be adjusted
based on published in vivo physiological data to simulate GI contraction. Experimental Materials Two nifedipine strengths (30 and 60 mg) of each osmotic pump (Product A) and polymer matrix-based extended-release tablets (Product B) were purchased from the U.S. market. According to the insert of product B, the drug product contains methacrylic acid and methyl methacrylate copolymer as inactive ingredients. Nifedipine reference standard was purchased from USP (lot #: LOJ059, Purity: 99.7%). All chemicals were either analytical or high-performance liquid chromatography grades. Medium Preparation Dissolution media of pH 1.2 HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were prepared following the USP method (USP40eNF35, page 5354). All dissolution media were added 1% sodium lauryl sulfate. Testing Procedure Dissolution testing using USP apparatus 2 was performed for each dosage strength at 37 C with a paddle speed at 50 rpm in 900 mL dissolution medium under each of the above pH conditions for 24 h. The sample aliquot at predetermined time points was taken, and the amount of drug release was measured based on the calibration curve using online ultravioletevisible (UV/vis) (Agilent8453, quartz cuvette with 2 mm path length) at 238 nm. Each condition with the USP 2 apparatus was repeated twice with 12 tablets. The description of the in-house dissolution testing apparatus has been previously reported.16 In brief, a test sample was placed on a stainless steel plate, which was held on a sample holder and placed in a 500 mL jacketed glass beaker. A magnetic stir bar under the plate was used to agitate 350 mL dissolution media. The dissolution testing was conducted in various buffer media at 37 C. The Texture Analyzer (TA.XT Plus) applied a preprogrammed compression to the sample during dissolution testing through a probe, and both compression force and probe displacement were recorded. The Texture Analyzer equipped with a 500 gram load cell with 0.02 gram increments (#139125; Stable Micro System) was calibrated using a Low Force Loadcell Kit (Texture Instrument) before starting of the project. The distance traveled by the probe during the test was recorded as the displacement. The displacement is defined as the distance between the reference position, just touching the sample at the beginning of the test, and its position measured subsequently in contact with the sample at the specified force. The resulting displacement curve caused by sample deformation or geometric change characterizes the mechanical properties of the sample over time. A displacement curve with a positive slope indicates that the sample’s resistance to the applied force is diminishing, reflecting sample softening, shrinking, or disintegrating. By contrast, a displacement curve with negative slope indicates that the sample’s resistance to the applied force is increasing, reflecting sample hardening, swelling, or expanding. The sample aliquot at predetermined time points was taken through a sample cannula and using UV (Agilent-8453) detection at 238 nm to measure the amount of drug release based on the standard solution. All tests with the in-house apparatus were conducted in triplicate. Since nifedipine is light sensitive, we covered the USP 2 and in-house apparatuses with aluminum foil during the test to prevent light-induced degradation.
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Figure 1. Comparison of dissolution profiles of 30 and 60 mg product A (osmotic pump formulation) in 3 different pH media using USP paddle apparatus.
Results and Discussion Modified-release dosage forms are normally developed to reduce the dosing frequency for better therapeutic compliance in chronic treatment and to attenuate maximum peak plasma levels in the case of concentration-related side effects. For nifedipine ER products, osmotic pump and polymer matrix-based delivery systems are 2 types of formulation designs, which are commonly used to control drug release. The osmotic pump-based formulation applies push-pull osmotic technology using an osmotically active but pharmacologically inert polymer surrounded by a semipermeable membrane.17 After the tablet enters the GI tract on oral ingestion, as the polymer expands and the osmotic pressure increases, the drug substance is extruded through the precision-drilled orifice at a controlled rate over 24 h. The osmotic delivery system is designed to deliver drug substance into the GI system and hence into the systemic circulation at a constant (zero-order) rate until the formulation is exhausted. For polymer matrix-based systems, the drug dissolution and diffusion through the polymer/coating are critical in controlling the release characteristics of the formulation.6,18 Figures 1 and 2 show dissolution profiles of the 2 different formulations (osmotic pump or matrix-based formulations) in dissolution media at pH 1.2, 4.5, and 6.8. Table 1 summarizes the similarity factor (f2 calculated based on FDA guidance19) of dissolution profiles of products A (osmotic pump) and B (matrix-based) nifedipine ER tablets across 3 pH levels. Both drug products had
minimal drug release (<10%) during the first 2 h of tests under all 3 pH conditions. For the osmotic pump formulation (Fig. 1), both dosage strengths exhibit similar dissolution behaviors at all 3 pH conditions. The osmotic pump formulation releases drug through an orifice on one side of the tablet at a constant (zero-order) rate that is independent of the pH and hydrodynamics of the dissolution medium. After 24 h in dissolution media, the shape and the size of the osmotic pump tablet remained unchanged based on visual inspection. By contrast, for the matrix-based formulation (Fig. 2), the pH of the media impacted the dissolution profiles, and drug was released faster with increasing pH values. The trend of pHdependent dissolution behaviors for the matrix-based formulation may be a result of faster dissolution of polymeric carrier at a higher pH. The dissolution results showed that the osmotic pump-based formulation is robust toward pH changes of dissolution media comparing to polymer matrix-based product. Similar dissolution results had been reported in another publication.9 The similar results are not unexpected because both studies focused on a similar nifedipine ER formulation, which was design to release drug in a certain way. However, in Grabacz et al. and the work performed here, the sources of tested drug products were different. The drug products in Grabacz et al. were from European manufacturers, whereas the drug products in this work were made in the US. Moreover, this study developed a different approach to explain observed dissolution results with more precise control of the compression forces. Thus, in the present study, product
Figure 2. Comparison of dissolution profiles of 30 and 60 mg product B (polymer matrix formulation) in 3 different pH media using USP paddle apparatus.
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Table 1 Similarity Factor (f2) of Dissolution Profiles Across pH 1.2 (0.1 N HCl), 4.5, and 6.8 for Products A (Osmotic Pump) and B (Matrix-Based) Nifedipine ER Tablets at Different Strengths f2 Product Product Product Product
A 30 mg A 60 mg B 30 mg B 60 mg
pH 1.2/4.5
pH 4.5/6.8
pH 6.8/1.2
97 81 67 55
93 71 47 52
90 85 41 40
deformation in dissolution medium can make a direct link to changes of nifedipine drug release from different formulations under various pHs and applied compression forces. To get a better understanding of the observed pH effect on drug release from nifedipine ER formulations, the mechanical properties of the ER tablets during dissolution testing were measured by an inhouse dissolution apparatus with capability of monitoring product mechanical response during dissolution testing. The responses to the applied force or geometric changes of dosage form such as disintegration, softening, shrinking, and swelling in the dissolution medium could directly impact the drug release mechanism. Based on above results (Figs. 1 and 2) from the USP method in 3 pH dissolution media, there was no significant dissolution difference between the 2 strengths of each product. Therefore, available 60 mg product A and 30 mg product B were further tested in the pH 1.2 and pH 6.8 dissolution media, respectively, using the in-house apparatus. Figure 3 shows displacement profiles for tablet mechanical responses of 2 different formulations during dissolution testing in the pH 1.2 and 6.8 media. The results show a significant difference in mechanical response for matrix-based product B in the phosphate buffer at pH 6.8 comparing that in pH 1.2 HCl medium. In the phosphate buffer at pH 6.8, product B swelled less (only a 15% increase of the tablet original height was observed), was relatively faster to reach the highest swelling point (in 3 h), and lost mechanical resistance quicker in 5 h compared to those in pH 1.2 HCl. However, the mechanical response showed no difference for osmotic pump product A in both media because the tablets remain rigidly intact throughout dissolution testing. These data indicated that the polymer matrix-based formulation was mechanically weak in pH 6.8 phosphate buffer after 3 h. Because product B features a polymer matrix-based formulation, it was vulnerable to pH changes and had weak mechanical properties at pH 6.8. Further research focused on the possible impacts of compression force on drug release in pH 6.8 dissolution medium. Usually, the pH 1.2 dissolution medium is used to simulate
Figure 4. Applied various compression forces on product A and B tablets in pH 6.8 buffer. Green line: constant 0.1g force; Blue line: 4 stage compressions including (1) 0.1g force for 2 h, (2) 10g force for 1 h, (3) dynamic 400g force for 10 min, and (4) 5g force for the rest of dissolution testing.
gastric condition during early dissolution time periods (1-2 h). As shown in Figures 1 and 2, pH values of the dissolution media have a minor impact on drug release before 2 h; pH 6.8 buffer was applied as dissolution medium throughout dissolution testing for ease of operating the test. The human gastrointestinal tract consists of distinct compartments of differing shapes, sizes, and orientations. These compartments should be considered when designing a realistic dynamic model. There are many reports on values attributed to the forces involved in human GI motility and contractility, but the results vary significantly. The parameters used in this study to simulate GI contraction were selected based on published results.18,20-22 One limitation of compression forces applied in this study is that the applied forces may not accurately reflect the in vivo GI motility and contractility. The simulated parameters could be adjusted in the future depending on clinical studies with quantitative measurements of contraction force and frequency during the physiological phases of GI digestion. Figure 4 shows a constant (0.1 gram force in green) and 4 stage compression forces (in blue) that were applied to samples during the dissolution testing in pH 6.8 phosphate buffer. Four stage compression forces were programmed to simulate various GI contractions. At the first stage, a constant 0.1g force was applied
Figure 3. The displacement of product A (1) and B (2) during dissolution testing in 2 different media.
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Figure 5. Displacement profiles of product A (1) and B (2) in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
Figure 6. Dissolution profiles of product A (1) and B (2) in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
Figure 7. The dissolution rate (%/hr) of product A (1) and B (2) during dissolution testing in pH 6.8 phosphate buffer under different compression forces; Green line: under constant 0.1g force; Blue line: under 4 stages force with applied 400 g dynamic force in the third stage.
for 2 h to simulate storage period in the stomach. At the second stage, a 10 g constant force for 1 h was simulated for stomach mixing period. At the third stage, a dynamic compression force for 10 min was applied. As shown in Figure 4, the dynamic force keeps 400 g for 10 s duration every 15 s to simulate 4 contractions per minute. At the fourth stage, a 5 g constant force was applied.
The displacement changes of tested sample under various simulated compression forces are shown in Figure 5. For product A, the 400 gram compression decreased the tablet height (original tablet height ¼ 5.90 ± 0.01 mm) when it was applied on to the tablet in pH 6.8 phosphate buffer but with less than 10% change (in blue) when compared with results with 0.1 gram contact force (in green). For product B, the 400 gram contraction dramatically
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decreased more than 60% (in blue) of the tablet height (original tablet height ¼ 4.25 ± 0.10 mm) in pH 6.8 phosphate buffer when compared with results with 0.1 gram contact force (in green). Figure 6 shows dissolution profiles of product A and B tablets in pH 6.8 phosphate buffer measured with different compression forces. The results showed that product B (polymer matrix-based) had different dissolution performance under simulated GI contraction. The drug release increased right after the simulated contraction was applied. However, the results from product A (osmotic pump) showed that the compressions had no impact on drug dissolution performance. This difference in dissolution performance between polymer matrix and osmotic pump-based products was also observed in drug release rates (Fig. 7). For the osmotic pump formulation, there was only a little fluctuation of dissolution rates during the period of applied compression forces. Under the 400 gram simulated contraction force, the polymer matrix-based formulation showed an abrupt increase (i.e., more than double) in dissolution rate that caused dose-dumping after contraction. For nifedipine extended-release drug products approved and marketed in Europe, the pharmacokinetics of some once-daily nifedipine extended-release formulations based on nonosmotic pump formulations (e.g., erosive matrices, monolayer matrices, or capsules with mini tablets) is more sensitive to concomitant food intake than nifedipine ER formulation based on osmotic pumps.8,10,11,23 A significant dose-dumping effect was also observed in vivo after fed administration of polymer matrix-based tablet, resulting in rising nifedipine plasma concentrations, nearly 3-to 4fold, in 11 of 24 volunteers.6 These reports concluded that the pHdependent in vitro release may partly contribute to the observed in vivo dose-dumping phenomenon, for matrix-based nifedipine ER dosage forms under fed conditions where the ingested oral formulations may experience a longer duration of gastric contraction because of a greater gastric emptying time in comparison to the fasting conditions. This study demonstrated a direct connection between applied compression and drug release rate by analyzing tablet geometric/mechanical response data. The observed in vitro contraction-induced dose-dumping may be used to explain the clinical PK results of abnormal high plasma concentrations in some patients after taking polymer-based nifedipine ER products. Conclusions If an ER formulation fails to control release under GI contraction or altered pH condition, the patient would not get the intended dose profile for the drug. A modified dissolution testing apparatus was assembled and characterized drug dissolution profiles with or without mechanical compression. Product mechanical property changes during dissolution testing may be used as an indicator during product development and for quality assurance of oral drug products. With respect to the designed therapeutic use of ER nifedipine tablets, the findings indicate that the in vitro performance of the osmotic pump was robust toward concomitant medium pH changes and mechanical compression, whereas the polymer matrix-based formulation was sensitive to these physiological factors. The contraction-induced drug dose-dumping may contribute to the reported differences in pharmacokinetics for nifedipine ER formulations, and further investigation of the in vivo relevance of the in vitro observations may be warranted.
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