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Comparison of Dissolution Properties of 2 Enteric-Coated Formulations Containing Mycophenolate Sodium: Myfortic vs Femulan
Comparison of Dissolution Properties of 2 Enteric-Coated Formulations Containing Mycophenolate Sodium: Myfortic vs Femulan A. Esquivel, R. González-Ramírez, J. Alberú, C. Gracida, M. Medeiros, and G. Castañeda-Hernández ABSTRACT Enteric-coated tablets containing mycophenolate sodium have been developed to reduce gastric toxicity. The objective of this study was to compare 2 enteric-coated formulations containing 360 mg of mycophenolate sodium: the innovator product, Myfortic, and an agent that recently became available in Mexico, Femulan. For both formulations, mycophenolate sodium content was within the 90% to 110% range of the label claimed dose, and no impurities were present as determined at high-performance liquid chromatography. Mycophenolate sodium release was assayed by applying the US Pharmacopeia apparatus 2 dissolution test at 2 different pH values (1.2 and 6.8) to mimic conditions in the stomach and the small intestine, respectively. At pH 1.2, mycophenolate sodium release was less than 2%, with respect to the label claimed dose, for both formulations. At pH 6.8, mean (range) mycophenolate sodium release with Myfortic was 104.9% (104.0%– 105.6%), and with femulan was 62.3% (51.3%– 67.7%); the difference between formulations achieved statistical significance (P ⫽ .04). Moreover, intratablet variability with the generic formulation was unacceptable. Variation between the highest and lowest drug release was 32.0% for Femulan, and 1.02% for Myfortic. Thus, it is likely that Femulan results in insufficient and irreproducible absorption of mycophenolate sodium in the small intestine, leading to inadequate immunosuppressive efficacy. It is concluded that Femulan and myfortic are not equivalent formulations. Furthermore, Femulan is not a suitable formulation for clinical use in organ transplantation because it does not meet pharmaceutical quality standards. YCOPHENOLIC ACID is an effective immunosuppressive agent. Its use, however, is limited by gastric toxicity. Two strategies are presently used to reduce gastric damage1: (1) administration of the inactive prodrug mycophenolate mofetil, which is absorbed and then cleaved to the active moiety by first-pass biotransformation, avoiding direct contact of mycophenolic acid with the gastric mucosa; and (2) administration of an enteric-coated tablet containing mycophenolate sodium.1,2 The enteric coating is acid-resistant but labile at neutral pH. Therefore, the formulation remains unaltered in the stomach, avoiding drug direct contact with the gastric mucosa. Once in the small intestine, the coating disintegrates and the tablet releases mycophenolate sodium, which is readily absorbed in the jejunum and results in adequate bioavailability.1,2 The innovator product insofar as an enteric-coated tablet containing mycophenolate sodium is Myfortic (Novartis AG, Basel, Switzerland).2 Recently, another formulation, Femulan (Landsteiner Scientific SA de CV, Toluca, Mex-
M
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 42, 353–356 (2010)
ico) became available in Mexico. Although generic drug products are widely used worldwide, there is concern about From Departamento de Farmacologia, Centro de Investigación y de Estudios Avanzados el Instituto Politécnico Nacional (A.E., R.G.-R., G.C.-H.), Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y de la Nutrición (J.A.), Unidad de Trasplantes, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (C.G.), and Laboratorio de Investigación en Nefrologia y Metabolismo Mineral, Hospital Infantil de México Federico Gómez (M.M.), Mexico City, Mexico. This study was supported by CINVESTAV-IPN and Novartis Farmacéutica SA, Mexico City. Drs Esquivel and GonzálezRamírez are fellows of CONACYT, Mexico. Address reprint requests to Gilberto Castañeda-Hernández, Centro de Investigación y de Estudios Avanzados el Instituto Politécnico Nacional, Av Instituto Politécnico Nacional 2508, Col San Pedro Zacatenco, Mexico City, Mexico 07360. E-mail: [email protected] 0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2009.11.015 353
354
immunosuppressant agents.3–5 These drugs have a narrow therapeutic index. Therefore, quality standards must be more stringent with respect to other pharmaceutical products.6 Moreover, there is evidence that, even meeting regulatory bioequivalence criteria, some generic immunosuppressive agents are therapeutically inferior to the corresponding innovator products.3,4,7 It has been recently reported that tacrolimus generic formulations presently commercially available in Mexico do not meet pharmaceutical quality criteria.5 Hence, we compared the content uniformity and dissolution profiles of Myfortic and Femulan. Differential dissolution is a critical feature of entericcoated tablets.2 Tablets were assayed at 2 different pH values, 1.2 and 6.8, to mimic the conditions of the stomach and the small intestine, respectively.1 MATERIALS AND METHODS Reagents and Formulations Two brands of enteric-coated tablets with a label claimed dose of 360 mg were studied. The reference formulation was the innovator product Myfortic (Novartis AG; batch S0298). The test formulation was Femulan (Landstainer Scientific; batch LPTISO9D010). Pure mycophenolate sodium standard was a gift from Novartis Farmacéutica SA (Mexico City). Acetonitrile, chromatographic grade, was purchased from Merck (Darmstadt, Germany). Ultrapure deioniged water was obtained using a Milli Q Reagent Water System (Continental Water Systems, El Paso, Texas). All other reagents were of analytical grade.
ESQUIVEL, GONZÁLEZ-RAMÍREZ, ALBERÚ ET AL in a total volume of 990 mL, and stirred at 50 rpm at a temperature of 37°C (0.5°C) to mimic the conditions of the small intestine. After 60 minutes, 10-mL samples were drawn. Because the dissolutor has 12 vessels, 6 tablets of Myfortic and 6 tablets of Femulan were assayed simultaneously.10 Mycophenolate sodium concentration in the samples from media at pH 1.2 and 6.8 was determined by UV detection at 250 nm using a DR-800 spectrophotometer (Beckman Coulter, Fullerton, California) coupled to the dissolutor. Calibration curves were constructed using a pure mycophenolate sodium standard. Formulations were compared using the t test. Differences were considered statistically significant at P ⬍ .05.
RESULTS
Typical chromatograms observed with the high-performance liquid chromatography assay of pure mycophenolate sodium, Myfortic, and Femulan are shown in Fig 1. In the 3 cases, a single peak appeared at 6.0 minutes, corresponding to the elution of mycophenolate sodium. Six tablets of each formulation were assayed. In all cases, the mycophenolate sodium content was within the 90% to 110% range of the
Content Uniformity Tablets were placed in flasks containing 1000 mL of a 0.2 M sodium phosphate solution, pH 6.8, and maintained under fast magnetic stirring until complete disintegration. After filtration using a 1-m nylon filter, 10 L aliquots were assayed for mycophenolate sodium using high-performance liquid chromatography with an 010 automated chromatographic system (Dionex Corp, Sunnyvale, California). Analyses were performed on a Nucleosil C8 250 ⫻ 4.6 (inner diameter)–mm column of 5-m particle size (Sorbent Technologies, Atlanta, Georgia) eluted with a mixture of acetonitrilewater-citrate buffer, (40:45:15), pH 3, at a flow rate of 1 mL/min and a temperature of 40°C. The effluent from the column was monitored using UV detection at 251 nm. Calibration curves were constructed using a pure mycophenolate sodium standard. The acceptance range for mycophenolate sodium content uniformity was fixed at 90% to 110% of the label claimed dose because this is a narrow therapeutic index drug.6
Dissolution Assay Mycophenolate sodium release from Myfortic and Femulan was determined using the apparatus 2 dissolution test described in the US Pharmacopeia.8 Because these formulations are enteric-coated tablets, the assay was carried out at 2 pH values, 1.2 and pH 6.8.1,2,8,9 A paddle dissolutor (Hanson Research SR-8, Chatswoth, California) was used. Initially, tablets were placed in vessels containing 750 mL of hydrochloric acid, 0.1 M, pH 1.2, and submitted to paddle agitation at 50 rpm at a mean (SD) temperature of 37°C (0.5°C) to mimic the conditions of the stomach. After 120 minutes, 10-mL samples were drawn. Then, 250 mL of 0.2 M phosphate solution was added to each vessel to achieve a pH of 6.8
Fig 1. Analysis of mycophenolate sodium using highperformance liquid chromatography. Typical chromatograms correspond to pure mycophenolate sodium standard (A) and 2 mycophenolate sodium enteric-coated formulations with a label claimed dose of 360 mg: Myfortic (B) and Femulan (C).
COMPARISON OF 2 FORMULATIONS OF MYCOPHENOLATE SODIUM
label claimed dose of 360 mg. No impurities were detected in any formulation. Dissolution test results are given in Table 1 At pH 1.2 for 120 minutes, for both formulations, the amount of mycophenolate sodium released was less than 2%, with regard to the label claimed dose. At pH 6.8 for 60 minutes, mycophenolate sodium release with Myfortic ranged from 104.0% to 105.6%, and with Femulan ranged from 51.3% to 67.7% of the label claimed dose. The difference in drug release at pH 6.8 between formulations achieved statistical significance (P ⫽ .04). Furthermore, with Myfortic, mycophenolate sodium release was highly reproducible, the difference between the tablets with highest and lowest values being 1.01%. On the other hand, results with Femulan were considerably more variable. The difference between tablets with highest and lowest release was 32%. DISCUSSION
Generic drug products are extensively used worldwide. There is evidence that many generic agents commercially available in Mexico meet bioequivalence criteria. Our group, as well as other investigators, reported that this is not always the case. Among the generic products available in Mexico that do not meet accepted quality standards are oxcarbazepine,10 thalidomide,11 naproxen,12 and tacrolimus.5 Tacrolimus is of particular concern because immunosuppressant drugs have a narrow therapeutic index and, thus, require more stringent controls.4 –7 Therefore, we examined a recently introduced Mexican generic of entericcoated tablets containing mycophenolate sodium, Femulan, which is claimed to be interchangeable with the innovator product, Myfortic. For content uniformity, a 15% variation can be considered acceptable.5 However, we preferred to use a reduced range of 90% to 110% with regard to the label claimed dose because it has been recommended for drugs with a narrow therapeutic index.6 Mycophenolate sodium content was within this acceptance range for all the assayed tablets of Myfortic and Femulan. Moreover, no impurities were detected. Therefore, it seems that Femulan exhibits a better Table 1. Amount of Mycophenolate Sodium Released From 2 Pharmaceutical Formulations With a Label Claimed Dose of 360 mg at 2 Different pH Values* Dissolution at pH 1.2
Dissolution at pH 6.8
Tablet
Myfortic
Femulan
Myfortic
Femulan
1 2 3 4 5 6 Mean SD
1.98 0.45 0.10 0.68 0.32 0.05 0.60 0.72
0.52 ⫺0.14 ⫺0.10 ⫺0.13 ⫺0.14 ⫺0.09 ⫺0.01 0.26
105.6 105.5 104.8 104.0 104.4 104.9 104.9 0.62
62.7 65.4 66.9 59.9 67.6 51.2 62.3† 6.13
*Data are expressed as percentage of the label claimed dose. † Indicates a statistically significant difference (P ⬍ .05) with regard to Myfortic at pH 6.8.
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quality profile compared with the tacrolimus formulations studied by Petan et al.5 Notwithstanding, it should be considered that content uniformity is only one of the features of a pharmaceutical product. Additional criteria must be met, particularly for enteric-coated oral formulations.1,2,8,9 A critical property of enteric-coated formulations is differential dissolution.2,9 That is, the coating must be acid-resistant but readily disintegrate at neutral pH. If these features are met, the tablet remains unchanged in the acid milieu of stomach, sparing the gastric mucosa from direct contact with mycophenolate and, thus, reducing gastric damage.2 Once in the small intestine, at neutral pH conditions, the coating disintegrates, and the tablet releases its content. Inasmuch as mycophenolate sodium is a highly soluble salt, it readily dissolves and is rapidly absorbed.1,2 It has been demonstrated that the innovator formulation, Myfortic, yields an adequate bioavailability comparable to that of mycophenolate mofetil.1 Therefore, the 2 assayed mycophenolate sodium enteric-coated formulations were compared by assaying drug release using a pharmacopeial dissolution test performed at 2 pH values, 1.2 and 6.8, for 120 and 60 minutes, respectively, as required by current regulatory criteria.9 At pH 1.2, drug release was less than 2% for Myfortic and Femulan. This indicates that both formulations exhibit a coating that meets regulatory criteria for acid resistance.2,9 However, at neutral pH, Myfortic released its full mycophenolate sodium content in 60 minutes. The amount of drug dissolved was within the 90% to 110% range of total content in the tablets. This was not the case for Femulan. After 60 minutes at pH 6.8, this formulation released only 51.3% to 67.7% despite a total content of 90% to 100% with regard to the label claimed dose. The difference between formulations achieved statistical significance. Drug release at neutral pH with Femulan was not only low, but was also considerably more variable compared with Myfortic. The maximal variation with the innovator product was 1.02%, and was as high as 32% for the generic. This variability is unacceptable considering that mycophenolate sodium has a narrow therapeutic index, and, thus, variations should not exceed 15%.6 Inasmuch as it has been demonstrated that an adequate rate of drug release and dissolution at neutral pH is critical for adequate mycophenolate sodium bioavailabilty,1,2 it is likely that Femulan results in an insufficient and irreproducible immunosuppressive response. It is, therefore, concluded that Femulan is not interchangeable with Myfortic. Furthermore, Femulan is not an adequate formulation for clinical use as an immunosuppressive agent in organ transplantation because it does not meet current pharmaceutical specifications and recommendations for drugs with a narrow therapeutic index.3–7 Our results provide further evidence for the commercialization of some drug products of questionable quality in Mexico,10 –12 including immunosuppressive agents.5 Health authorities are
356
urged to take the necessary regulatory actions to protect patient integrity and quality of life. REFERENCES 1. Arns W, Breuer S, Choudhury S, et al: Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 19:199, 2005 2. United States Patent No. 6,306,900 B1. Enteric coated pharmaceutical compositions. October 23, 2001. http://www.google. com.mx/patents?id⫽DA8IAAAAEBAJ&printsec⫽claims&zoom⫽ 4#v⫽onepage&q⫽&f⫽false. Accessed September 21, 2009 3. Alloway RR, Isaacs R, Lake K, et al: Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant 3:1211, 2003 4. Kahan BD: Considerations concerning generic formulations of immunosuppressive drugs. Transplant Proc 31:1635, 1999 5. Petan JA, Undre N, First MR, et al: Physiochemical properties of generic formulations of tacrolimus in Mexico. Transplant Proc 40:1439, 2008 6. Palylyk-Colwell E, Jamali F, Dryden W, et al: Bioequivalence and interchangeability of narrow therapeutic range drugs: Canadian Society for Pharmaceutical Sciences discussion. J Pharm Pham Sci 1:2, 1998
ESQUIVEL, GONZÁLEZ-RAMÍREZ, ALBERÚ ET AL 7. Buist L: Cyclosporine brands: are they all the same? Br J Renal Med 9:S3, 2004 8. United States Pharmacopeia, chapter 711, Dissolution. http:// www.usp.org/pdf/EN/USPNF/chapter711.pdf Accessed September 21, 2009 9. Ministerio de Salud, Gobierno de Costa Rica: Guía técnica para la presentación y evaluación de los estudios de perfiles de disolución comparativos. http://www.ministeriodesalud.go.cr/ bioequivalencia/guiadisolucioncomparativos221008.pdf. Accessed: September 21, 2009 10. Castañeda-Hernández G, Cruz-Antonio L: Differences in the dissolution profile, suggesting a lower oral bioavailability, of a novel formulation of oxcarbazepine (Actinium) compared to the innovator product (Trileptal). Proc West Pharmacol Soc 49:83, 2006 11. Fujita Y, Yamamoto K, Aomori T, et al: Comparison of dissolution profile and plasma concentration–time profile of the thalidomide formulations made by Japanese, Mexican and British companies. Yakugaku Zasshi 128:1449, 2008 12. Hernández-Abad V, Castañeda-Hernández G, GarcíaJiménez S, et al: Evaluation of the quality of four Mexican drug products containing sodium naproxen. J Clin Pharm Ther 33:237, 2008
M
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 42, 353–356 (2010)
ico) became available in Mexico. Although generic drug products are widely used worldwide, there is concern about From Departamento de Farmacologia, Centro de Investigación y de Estudios Avanzados el Instituto Politécnico Nacional (A.E., R.G.-R., G.C.-H.), Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y de la Nutrición (J.A.), Unidad de Trasplantes, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (C.G.), and Laboratorio de Investigación en Nefrologia y Metabolismo Mineral, Hospital Infantil de México Federico Gómez (M.M.), Mexico City, Mexico. This study was supported by CINVESTAV-IPN and Novartis Farmacéutica SA, Mexico City. Drs Esquivel and GonzálezRamírez are fellows of CONACYT, Mexico. Address reprint requests to Gilberto Castañeda-Hernández, Centro de Investigación y de Estudios Avanzados el Instituto Politécnico Nacional, Av Instituto Politécnico Nacional 2508, Col San Pedro Zacatenco, Mexico City, Mexico 07360. E-mail: [email protected] 0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2009.11.015 353
354
immunosuppressant agents.3–5 These drugs have a narrow therapeutic index. Therefore, quality standards must be more stringent with respect to other pharmaceutical products.6 Moreover, there is evidence that, even meeting regulatory bioequivalence criteria, some generic immunosuppressive agents are therapeutically inferior to the corresponding innovator products.3,4,7 It has been recently reported that tacrolimus generic formulations presently commercially available in Mexico do not meet pharmaceutical quality criteria.5 Hence, we compared the content uniformity and dissolution profiles of Myfortic and Femulan. Differential dissolution is a critical feature of entericcoated tablets.2 Tablets were assayed at 2 different pH values, 1.2 and 6.8, to mimic the conditions of the stomach and the small intestine, respectively.1 MATERIALS AND METHODS Reagents and Formulations Two brands of enteric-coated tablets with a label claimed dose of 360 mg were studied. The reference formulation was the innovator product Myfortic (Novartis AG; batch S0298). The test formulation was Femulan (Landstainer Scientific; batch LPTISO9D010). Pure mycophenolate sodium standard was a gift from Novartis Farmacéutica SA (Mexico City). Acetonitrile, chromatographic grade, was purchased from Merck (Darmstadt, Germany). Ultrapure deioniged water was obtained using a Milli Q Reagent Water System (Continental Water Systems, El Paso, Texas). All other reagents were of analytical grade.
ESQUIVEL, GONZÁLEZ-RAMÍREZ, ALBERÚ ET AL in a total volume of 990 mL, and stirred at 50 rpm at a temperature of 37°C (0.5°C) to mimic the conditions of the small intestine. After 60 minutes, 10-mL samples were drawn. Because the dissolutor has 12 vessels, 6 tablets of Myfortic and 6 tablets of Femulan were assayed simultaneously.10 Mycophenolate sodium concentration in the samples from media at pH 1.2 and 6.8 was determined by UV detection at 250 nm using a DR-800 spectrophotometer (Beckman Coulter, Fullerton, California) coupled to the dissolutor. Calibration curves were constructed using a pure mycophenolate sodium standard. Formulations were compared using the t test. Differences were considered statistically significant at P ⬍ .05.
RESULTS
Typical chromatograms observed with the high-performance liquid chromatography assay of pure mycophenolate sodium, Myfortic, and Femulan are shown in Fig 1. In the 3 cases, a single peak appeared at 6.0 minutes, corresponding to the elution of mycophenolate sodium. Six tablets of each formulation were assayed. In all cases, the mycophenolate sodium content was within the 90% to 110% range of the
Content Uniformity Tablets were placed in flasks containing 1000 mL of a 0.2 M sodium phosphate solution, pH 6.8, and maintained under fast magnetic stirring until complete disintegration. After filtration using a 1-m nylon filter, 10 L aliquots were assayed for mycophenolate sodium using high-performance liquid chromatography with an 010 automated chromatographic system (Dionex Corp, Sunnyvale, California). Analyses were performed on a Nucleosil C8 250 ⫻ 4.6 (inner diameter)–mm column of 5-m particle size (Sorbent Technologies, Atlanta, Georgia) eluted with a mixture of acetonitrilewater-citrate buffer, (40:45:15), pH 3, at a flow rate of 1 mL/min and a temperature of 40°C. The effluent from the column was monitored using UV detection at 251 nm. Calibration curves were constructed using a pure mycophenolate sodium standard. The acceptance range for mycophenolate sodium content uniformity was fixed at 90% to 110% of the label claimed dose because this is a narrow therapeutic index drug.6
Dissolution Assay Mycophenolate sodium release from Myfortic and Femulan was determined using the apparatus 2 dissolution test described in the US Pharmacopeia.8 Because these formulations are enteric-coated tablets, the assay was carried out at 2 pH values, 1.2 and pH 6.8.1,2,8,9 A paddle dissolutor (Hanson Research SR-8, Chatswoth, California) was used. Initially, tablets were placed in vessels containing 750 mL of hydrochloric acid, 0.1 M, pH 1.2, and submitted to paddle agitation at 50 rpm at a mean (SD) temperature of 37°C (0.5°C) to mimic the conditions of the stomach. After 120 minutes, 10-mL samples were drawn. Then, 250 mL of 0.2 M phosphate solution was added to each vessel to achieve a pH of 6.8
Fig 1. Analysis of mycophenolate sodium using highperformance liquid chromatography. Typical chromatograms correspond to pure mycophenolate sodium standard (A) and 2 mycophenolate sodium enteric-coated formulations with a label claimed dose of 360 mg: Myfortic (B) and Femulan (C).
COMPARISON OF 2 FORMULATIONS OF MYCOPHENOLATE SODIUM
label claimed dose of 360 mg. No impurities were detected in any formulation. Dissolution test results are given in Table 1 At pH 1.2 for 120 minutes, for both formulations, the amount of mycophenolate sodium released was less than 2%, with regard to the label claimed dose. At pH 6.8 for 60 minutes, mycophenolate sodium release with Myfortic ranged from 104.0% to 105.6%, and with Femulan ranged from 51.3% to 67.7% of the label claimed dose. The difference in drug release at pH 6.8 between formulations achieved statistical significance (P ⫽ .04). Furthermore, with Myfortic, mycophenolate sodium release was highly reproducible, the difference between the tablets with highest and lowest values being 1.01%. On the other hand, results with Femulan were considerably more variable. The difference between tablets with highest and lowest release was 32%. DISCUSSION
Generic drug products are extensively used worldwide. There is evidence that many generic agents commercially available in Mexico meet bioequivalence criteria. Our group, as well as other investigators, reported that this is not always the case. Among the generic products available in Mexico that do not meet accepted quality standards are oxcarbazepine,10 thalidomide,11 naproxen,12 and tacrolimus.5 Tacrolimus is of particular concern because immunosuppressant drugs have a narrow therapeutic index and, thus, require more stringent controls.4 –7 Therefore, we examined a recently introduced Mexican generic of entericcoated tablets containing mycophenolate sodium, Femulan, which is claimed to be interchangeable with the innovator product, Myfortic. For content uniformity, a 15% variation can be considered acceptable.5 However, we preferred to use a reduced range of 90% to 110% with regard to the label claimed dose because it has been recommended for drugs with a narrow therapeutic index.6 Mycophenolate sodium content was within this acceptance range for all the assayed tablets of Myfortic and Femulan. Moreover, no impurities were detected. Therefore, it seems that Femulan exhibits a better Table 1. Amount of Mycophenolate Sodium Released From 2 Pharmaceutical Formulations With a Label Claimed Dose of 360 mg at 2 Different pH Values* Dissolution at pH 1.2
Dissolution at pH 6.8
Tablet
Myfortic
Femulan
Myfortic
Femulan
1 2 3 4 5 6 Mean SD
1.98 0.45 0.10 0.68 0.32 0.05 0.60 0.72
0.52 ⫺0.14 ⫺0.10 ⫺0.13 ⫺0.14 ⫺0.09 ⫺0.01 0.26
105.6 105.5 104.8 104.0 104.4 104.9 104.9 0.62
62.7 65.4 66.9 59.9 67.6 51.2 62.3† 6.13
*Data are expressed as percentage of the label claimed dose. † Indicates a statistically significant difference (P ⬍ .05) with regard to Myfortic at pH 6.8.
355
quality profile compared with the tacrolimus formulations studied by Petan et al.5 Notwithstanding, it should be considered that content uniformity is only one of the features of a pharmaceutical product. Additional criteria must be met, particularly for enteric-coated oral formulations.1,2,8,9 A critical property of enteric-coated formulations is differential dissolution.2,9 That is, the coating must be acid-resistant but readily disintegrate at neutral pH. If these features are met, the tablet remains unchanged in the acid milieu of stomach, sparing the gastric mucosa from direct contact with mycophenolate and, thus, reducing gastric damage.2 Once in the small intestine, at neutral pH conditions, the coating disintegrates, and the tablet releases its content. Inasmuch as mycophenolate sodium is a highly soluble salt, it readily dissolves and is rapidly absorbed.1,2 It has been demonstrated that the innovator formulation, Myfortic, yields an adequate bioavailability comparable to that of mycophenolate mofetil.1 Therefore, the 2 assayed mycophenolate sodium enteric-coated formulations were compared by assaying drug release using a pharmacopeial dissolution test performed at 2 pH values, 1.2 and 6.8, for 120 and 60 minutes, respectively, as required by current regulatory criteria.9 At pH 1.2, drug release was less than 2% for Myfortic and Femulan. This indicates that both formulations exhibit a coating that meets regulatory criteria for acid resistance.2,9 However, at neutral pH, Myfortic released its full mycophenolate sodium content in 60 minutes. The amount of drug dissolved was within the 90% to 110% range of total content in the tablets. This was not the case for Femulan. After 60 minutes at pH 6.8, this formulation released only 51.3% to 67.7% despite a total content of 90% to 100% with regard to the label claimed dose. The difference between formulations achieved statistical significance. Drug release at neutral pH with Femulan was not only low, but was also considerably more variable compared with Myfortic. The maximal variation with the innovator product was 1.02%, and was as high as 32% for the generic. This variability is unacceptable considering that mycophenolate sodium has a narrow therapeutic index, and, thus, variations should not exceed 15%.6 Inasmuch as it has been demonstrated that an adequate rate of drug release and dissolution at neutral pH is critical for adequate mycophenolate sodium bioavailabilty,1,2 it is likely that Femulan results in an insufficient and irreproducible immunosuppressive response. It is, therefore, concluded that Femulan is not interchangeable with Myfortic. Furthermore, Femulan is not an adequate formulation for clinical use as an immunosuppressive agent in organ transplantation because it does not meet current pharmaceutical specifications and recommendations for drugs with a narrow therapeutic index.3–7 Our results provide further evidence for the commercialization of some drug products of questionable quality in Mexico,10 –12 including immunosuppressive agents.5 Health authorities are
356
urged to take the necessary regulatory actions to protect patient integrity and quality of life. REFERENCES 1. Arns W, Breuer S, Choudhury S, et al: Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 19:199, 2005 2. United States Patent No. 6,306,900 B1. Enteric coated pharmaceutical compositions. October 23, 2001. http://www.google. com.mx/patents?id⫽DA8IAAAAEBAJ&printsec⫽claims&zoom⫽ 4#v⫽onepage&q⫽&f⫽false. Accessed September 21, 2009 3. Alloway RR, Isaacs R, Lake K, et al: Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant 3:1211, 2003 4. Kahan BD: Considerations concerning generic formulations of immunosuppressive drugs. Transplant Proc 31:1635, 1999 5. Petan JA, Undre N, First MR, et al: Physiochemical properties of generic formulations of tacrolimus in Mexico. Transplant Proc 40:1439, 2008 6. Palylyk-Colwell E, Jamali F, Dryden W, et al: Bioequivalence and interchangeability of narrow therapeutic range drugs: Canadian Society for Pharmaceutical Sciences discussion. J Pharm Pham Sci 1:2, 1998
ESQUIVEL, GONZÁLEZ-RAMÍREZ, ALBERÚ ET AL 7. Buist L: Cyclosporine brands: are they all the same? Br J Renal Med 9:S3, 2004 8. United States Pharmacopeia, chapter 711, Dissolution. http:// www.usp.org/pdf/EN/USPNF/chapter711.pdf Accessed September 21, 2009 9. Ministerio de Salud, Gobierno de Costa Rica: Guía técnica para la presentación y evaluación de los estudios de perfiles de disolución comparativos. http://www.ministeriodesalud.go.cr/ bioequivalencia/guiadisolucioncomparativos221008.pdf. Accessed: September 21, 2009 10. Castañeda-Hernández G, Cruz-Antonio L: Differences in the dissolution profile, suggesting a lower oral bioavailability, of a novel formulation of oxcarbazepine (Actinium) compared to the innovator product (Trileptal). Proc West Pharmacol Soc 49:83, 2006 11. Fujita Y, Yamamoto K, Aomori T, et al: Comparison of dissolution profile and plasma concentration–time profile of the thalidomide formulations made by Japanese, Mexican and British companies. Yakugaku Zasshi 128:1449, 2008 12. Hernández-Abad V, Castañeda-Hernández G, GarcíaJiménez S, et al: Evaluation of the quality of four Mexican drug products containing sodium naproxen. J Clin Pharm Ther 33:237, 2008