Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ranitidine Hydrochloride

COMMENTARY

H. KORTEJA¨ RVI,1 M. YLIPERTTULA,1 J.B. DRESSMAN,2 H.E. JUNGINGER,3 K.K. MIDHA,4 V.P. SHAH,5 D.M. BARENDS6

1Orion Pharma, Research and Development, Espoo, Finland 2Institut fu¨r Pharmazeutische Technologie, Johann Wolfgang Goethe-Universita¨t, Frankfurt am Main, Germany 3Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology, Leiden, The Netherlands 4University of Saskatchewan, Saskatoon, Canada 5U.S. Food and Drug Administration, Center of Drug Evaluation and Research, Rockville, Maryland

6RIVM, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands

Received 8 December 2004; revised 1 April 2005; accepted 7 April 2005 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20392

ABSTRACT: Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classiﬁcation System (BCS), ranitidine hydrochloride should be as- signed to Class III. However, based on its therapeutic and therapeutic index, pharma- cokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1617–1625, 2005 Keywords: absorption; Biopharmaceutics Classiﬁcation System (BCS); ranitidine; permeability; solubility

INTRODUCTION dosage forms. The purpose and scope of these monographs were discussed previously.1 Brieﬂy, A monograph based on literature data is pre- the aims of the present study were to evaluate all sented on ranitidine hydrochloride with respect to pertinent data available from literature sources to its biopharmaceutical properties and the risk of assess the appropriateness of such a biowaiver waiving in vivo bioequivalence testing for the from the biopharmaceutical point of view and also approval of new and reformulated IR solid oral from the perspective of public health risks.

This study reﬂects the scientiﬁc opinion of the authors and not the policies of regulating agencies. EXPERIMENTAL Correspondence to: Dirk M. Barends (Telephone: þ31 30 2744209; Fax: þ31 30 2744462; E-mail: [email protected]) The databases Caplus, Ipa, and Medline were Journal of Pharmaceutical Sciences, Vol. 94, 1617–1625 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association utilized to search using the keyword permeability

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005 1617 1618 KORTEJA¨ RVI ET AL. and Caplus and Ipa using the keywords dissolu- dine hydrochloride with different polymorphic tion, solubility, and degradation. The pharmaco- forms were reported to be bioequivalent.3 kinetic data search was initiated from the Martindale and the Drug Information Fulltext, followed by reviewing the references cited. Partition Coefficient Information with regard to the double-peak LogP (water/n-octanol) was reported to be 0.2.4 phenomenon, site-dependent absorption, first- This value is likely for the ionized form, i.e., logD. pass metabolism, enterohepatic recycling, and LogP (for the neutral molecule) was calculated to bioequivalence studies were reviewed from the be 1.28.5 cited literature obtained from Medline, using the keyword pharmacokinetics. Only literature writ- ten in English and German was included and the pKa searches were not limited to a certain time period. The two pK values reported 8.2 and 2.7 4 are in As the solubility data from literature did not cover a agreement with the values of 8.4 and 3.5, res- the entire physiological pH range, these were pectively, calculated with a structure-fragment- obtained experimentally at Orion Pharma. Tri- based approach.5 plicate determinations were carried out in which the solute was shaken with buffers pH 1, 3, 5, and 7.4 at room temperature for 3 h and the obtain- Indication ed solutions analyzed by high performance liquid chromatography. Ranitidine is a histamine H2-antagonist used in the treatment of gastric and duodenal ulceration with or without Helicobacter pylori infection and for gastro-oesophageal reflux disease.2 Ranitidine RESULTS inhibits gastric acid secretion, which is stimu- lated by pentagastrin, histamine, and normal General Characteristics meals.6 The incidence of adverse drug reactions with H -receptor antagonists are low (<3%) and The INN and World Health Organization (WHO) 2 are usually minor in nature.7 For Zollinger– name for ranitidine, is N-[2-[[[-5-[(dimethylamino) Ellison syndrome doses up to 900 mg daily have methyl]-2-furanyl]methyl]thio]ethyl]-N0-methyl-2- been used without troublesome side effects.6 nitro-1,1-ethenediamine. The WHO recommended dose for ranitidine tablets is 150 mg ranitidine base, given as the hydrochloride salt.8 Strengths currently having a Structure marketing authorization (MA) in Germany (DE)9, See Figure 1. Finland (FI),10 and The Netherlands (NL)11 are the equivalents of 75, 150, and 300 mg ranitidine base. Salt, Esters, Polymorphs Most preparation contain the hydrochloride 2 and Solubility this monograph covers only that salt of ranitidine. The solubility of ranitidine hydrochloride in water Ranitidine hydrochloride exhibits polymorphism.2 is 660 mg/mL and it is reported to be freely soluble Immediate-release (IR) tablets containing raniti- in water.2 The solubility in the pH range 1–7.4 was experimentally found to be over 550 mg/mL. As the highest strength is 300 mg, the dose: solubility ratio is less than 0.55 mL, far below the critical value of 250 mL.12,13 However, these data were obtained at room temperature and the criteria of ‘‘highly soluble’’ according to FDA and EMEA Guidelines are defined at 378C.12,13 But, supposing that the solubility will be higher at 378C than at room temperature, it is reason- Figure 1. Structure of ranitidine. able safe to classify ranitidine hydrochloride as a

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‘‘highly soluble’’ active pharmaceutical ingredient and discussed earlier as these observations can be (API). explained on the basis that tight junctions in the intestinal cell tissues are more permeable than the tight junctions in the Caco-2 monolayers.1 Pharmacokinetics Despite these differences, both permeability tech- Absorption niques demonstrate that the permeability is low. Indeed, ranitidine is recommended as a low per- The oral bioavailability (BA) of ranitidine is 50%– meability internal standard in the FDA guideline 60%. The drug is reported to be rapidly absorbed for Caco-2 permeability studies.12 The Caco-2 per- when administered via the oral route14–18 and meability increases when calcium concentration is absorption after oral administration is linear.19 decreased in the test medium,26 which can be ex- A first peak in plasma concentrations is reached plained on the basis that low calcium concentra- within 0.5–1.5 h and a second peak is observed tions cause opening of the tight junctions of the within 3–4 h after single doses.20,21 The reasons paracellular route or change the membrane integ- for this double-peak phenomenon are unclear. rity by disturbing the phospholipid bilayers. Thus, This is likely not due to biliary excretion, as the main absorption mechanism of ranitidine is biliary excretion is only 0.4% after oral adminis- paracellular passive diffusion. In vitro and non- tration.22 Variations in gastric emptying may also clinical studies have suggested that ranitidine is a not be a satisfactory explanation, since when substrate for P-gp.28,30,32 But it is likely that high ranitidine was administered as a solution directly doses of this highly soluble drug, formulated in to the jejunum, double-peaks were observed even rapidly dissolving tablets, will cause saturation of more often than after administration to the the P-gp efflux protein. stomach.23 In any case, this double-peak phenomenon is not relevant for biowaiver decisions, as Distribution there is no indication that it is formulation- dependent. The apparent volume of the distribution for ter- The BA of ranitidine is significantly lower when minal phase is about 1.16–1.87 L/kg.14,15,21,25,33 administered as a solution directly to the colon Ranitidine has a low protein binding of about instead of stomach, jejunum, or ileum.23,24 Since 15%.15 the tight junctions in the colon are considerably less permeable than those in the small intestine, it Metabolism and Excretion can be hypothesized that ranitidine is absorbed by The urinary excretion of unchanged ranitidine a paracellular mechanism, with the main absorp- following intravenous (i.v.) administration is 70%– tion site in the small intestine. Food in general has 80%,4,17,18,21,25 whereas the renal excretion of no effect on the rate and extent of absorption.25 unchanged drug after oral dosing is 25%– 30%.4,15,17,21 Less than 10% of the dose is metabo- Permeability lized and excreted via the urinary route after Results of permeability measurements are shown either i.v. or oral dosing.15,17 Of orally adminis- in Table 1. tered ranitidine, 26% is excreted with the feces.10 The results of the Caco-2 studies and the human Half-life of elimination phase is 1.7–2.1 h after i.v. intestinal permeability technique show large dif- dose.14,15,19,21 There are no reports that ranitidine ferences. These differences have been reported follows non-linear pharmacokinetics.

Table 1. Permeability of Ranitidine

Concentration Used (mM) Method Papp/Peff (107 cm/s) Reference 0.000142–14.25 Caco-2 1.03 26 0.1–5 Caco-2 18–7.5 27 0.005–5 Caco-2 20–12 28 2.56 Caco-2 3.1a 29 — Caco-2 12.4 30 0.5 Intestinal perfusion 270 31

aFurosemide, atenolol, and propranolol were used as reference compounds.

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Dosage Form Performance stead of the 0.1N HCl as a medium arrived at analogous results.43–45 Excipients Polli45 investigated the association between the The excipients used in the formulations of IR dissolution rate of three ranitidine hydrochloride products having a MA in DE, FI, and NL are IR tablets and their bioequivalence relative to shown in Table 2. In previous monographs, MA’s Zantac1. The dissolution profiles were recorded were taken as indicators that these formulations using the USP27 method. There were difference in had passed in vivo bioequivalence requirements.1 dissolution rate, but all four formulations were However, for ranitidine formulations with a MA found to be bioequivalent in a four-way, single dose in DE, this cannot always be assumed, because in bioequivalence study. The author concluded that 1998 the bioavailability committee of the regula- differences in dissolution rates observed earlier tory authorities of DE classified ranitidine as an than 30 min had negligible consequences in vivo. API for which in vivo bioequivalence testing is not The effect of dissolution rate and gastro-intest- always necessary, in view of its wide therapeutic inal (GI) transit time on the bioequivalence of index and non critical therapeutic use.34 The DE ranitidine has also been studied by computer list was recently withdrawn, but not the MA simulations.46 These simulations also included granted under that provision.35 FI and NL might atenolol (low permeability) and metoprolol (high also have granted MA’s without requiring in vivo permeability). It was concluded that peak plasma bioequivalence studies. concentrations (Cmax) appeared to be more sensi- Studies with specific excipients on the in vitro tive to changes in dissolution and GI transit times permeability of BCS class III drugs have been than area under the curve (AUC). The higher reported, some of which include ranitidine the permeability of the drug substance, the more 36,37 studies. Excipients such as lactose, hydroxy- sensitive Cmax was to the dissolution and gas- propylmethyl-cellulose, docusate sodium, EDTA, tric emptying rates. IR ranitidine hydrochloride propylene glycol, and PEG 400 did not affect the tablets were predicted to be bioequivalent with an Caco-2 permeability. However, other excipients oral solution when dissolution was as slow as 85% such as sodium lauryl sulfate, sodium caprate, in 1.5 h. This observation has also been noted for IR deoxycholate, glycocholate, taurodyhydrofusidate, tablets of metformin, which is also a BCS class III and palmitoylcarnitine increased the Caco-2 per- drug with a paracellular transport mechanism. meability. These latter excipients may open the The IR tablets of metformin had similar in vivo tight junctions and thus may affect absorption via absorption as modified release tablets if their the paracellular route. dissolution rate was as slow as 85% dissolved in Excipients which are osmotically active such as 2h.47,48 sodium acid pyrophosphate and polyethylene glycol 400 have been reported to reduce the BA of ranitidine when present in high concentrations DISCUSSION (1–10 g), likely because these excipients shorten the small intestinal transit time.38–40 Solubility Ranitidine hydrochloride can be expected to be ‘‘highly soluble’’ at 378C over the entire pH-range Dissolution 1–7.4.12,13 The USP 27 dissolution specification for ranitidine hydrochloride tablets is not less than 80% (Q) dissolved in 45 min in 900 mL water, using the Permeability 41 paddle at 50 rpm. Relevant dissolution studies The low BA of ranitidine is in line with its low are presented in Table 3. In the reported study of permeability. Ali et al.,42 about 80% of the studied formulations had trade names that also appear in Table 2. Most formulations showed rapid dissolution in Risks with Respect to Composition the reported medium, however, in most cases and/or Manufacturing Variations the dissolution curves of these ranitidine products did not meet the similarity factor (f2) For the excipients listed in Table 2, it can be con- requirement.12,13 Other studies, using water included that there are little risks to cause clinical

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Table 2. Excipientsa Present in Ranitidine Hydrochloride IR Solid oral Drug Productsb with an Marketing Authorization (MA) in Germany (DE), Finland (FI), and The Netherlands (NL) Basic butylated methacrylate copolymer DE (1–3) NL (4) FI (5,6) Calcium hydrogen phosphate DE (7–13) NL (14) Carmellose sodium NL (15, 16) Carnauba wax DE (17–20) NL (21, 22) Castor oil DE (23–26) NL (27, 28) Cellulose DE (1–3, 7–13, 17–19, 23–26, 29–52) NL (4, 14–16, 21, 22, 27, 28, 53–66) FI (5, 6, 67–74) Copovidone DE (1–3) Croscarmellose sodium DE (17–21, 23–26, 29, 30, 32, 36, 38, 40, 41, 43, 45–47, 49, 52) NL (4, 22, 27, 28, 56, 59, 61, 62, 64) FI (5, 6, 67, 69, 73, 74) Dextran DE (17, 19) Ethylcellulose FI (70) Glucose DE (39, 40, 43) Hydroxypropylcellulose FI (71) Hypromellose DE (1–3, 7–13, 17–20, 23–26, 29–52) NL (4, 14–16, 21, 22, 27, 28, 53–66) FI (5, 6, 67–74) Lactose DE (7–13) NL (14) Macrogol DE (1, 3, 7–13, 17–20, 29, 31–41, 43–47) NL (4, 14, 16, 21, 22, 56–62, 64, 65) FI (5, 6, 67, 69, 70, 73) Magnesium stearate DE (1–3, 7–13, 17–20, 23–26, 29–52) NL (4, 14–16, 21, 22, 27, 28, 53–66) FI (5, 6, 67–74) Maize starch DE (7–13) NL (14) Polydextrose DE (18, 20, 31, 32, 35–38, 41, 44–46) NL (16,21,22,57-61,65) FI (69,73) Polymethacrylate DE (29, 47) NL (56, 62, 64) FI (67) Polymethacrylic acid DE (33) Polymethacrylic acid Copolymer DE (34) Polysorbate FI (70) Povidone DE (33, 34) FI (70) Shellac DE (25) Silica DE (1, 7–13, 18, 19, 23–26, 30, 46) NL (14, 21, 22, 27, 28) FI (73) Silica, hydrophobic DE (17, 41) Simethicone DE (25) Sodium starch glycolate DE (7–13) NL (14) FI (70) Soya-bean oil FI (70) Talc DE (1, 23–26, 29, 33, 34, 47) NL (4, 27, 28, 56, 62, 64) FI (5, 6, 67, 70, 73) Triacetin DE (30, 41, 48–52) NL (15, 53–55) FI (68, 72, 74) Triethyl citrate DE (31, 32, 35–41, 43–46) NL (16, 57–61, 65) FI (69, 73)

Sources of data: DE: www.rote-liste.de; FI: www.nam.fi; NL: www.cbg-meb.nl aPrinting inkt, colorants, and flavors are not included. bExcluded are dosage forms that are swallowed by the patient in liquid form, such as effervescent and dispersible tablets. Chewable tablets are also excluded. 1. Raniberl1 150 mg/-300 mg Filmtabletten. 2. Ranitidoc 300 mg Filmtabletten. 3. Rani-nerton1 150/-300 Filmtabletten. 4. Ranitidine Sandoz 150/300, tabletten 150 mg/300 mg. 5. Ranitidin Alpharma 150 mg/300 mg kalvopaä¨llysteinen tabletti. 6. Ranitidine Biochemie 150 mg/300 mg kalvopaä¨llysteiset tabletti. 7. Ranibeta1 150/-300 Filmtabletten. 8. Raniprotect1 150/-300 Filmtabletten. 9. Ranitic1 75 akut bei Sodbrennen Filmtabletten. 10. Ranitic1 150/-300/-150 akut/-300 akut Filmtabletten. 11. Ranitidin 75-1 A Pharma Filmtabletten. 12. Ranitidin 150/-300-1 A Pharma Filmtabletten. 13. RANITIDIN BASICS 150 mg/-300 mg Filmtabletten. 14. Ranitidine 150 mg/300 mg, tabletten. 15. Zantac 300, tabletten 300 mg. 16. Ranitidine Merck 300 mg, tabletten. 17. Ranitidin PB 150 mg/-300 mg Filmtabletten. 18. Ranitidin Sandoz1 150 mg/-300 mg Filmtabletten. (Continued)

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Table 2. (Continued) 19. Ranitidin STADA1 150 mg/-300 mg Filmtabletten. 20. Ran Lich1 150 mg/-300 mg Filmtabletten. 21. Ranitidine CF 150 mg/300 mg, omhulde tabletten. 22. Ranitidine 150/300 PCH, tabletten 150 mg/300 mg. 23. Ranitab1 75 mg Filmtabletten. 24. Ranitidin-ratiopharm1 75 mg Filmtabletten gegen Sodbrennen. 25. Ranitidin STADA1 75 mg Filmtabletten. 26. ranitidin von ct 75 mg Filmtabletten. 27. Ranitidine 150/300 Ranbaxy, omhulde tabletten 150 mg/300 mg. 28. Ranitidine 75 mg Hexal, tabletten. 29. Junizac1 150 mg/-300 mg Filmtabletten. 30. Rani 150 mg/-300 mg AbZ Filmtabletten. 31. Ranibloc1 150 Filmtabletten. 32. Ranibloc1 300 Filmtabletten. 33. Ranicux1 75 mg Filmtabletten. 34. Ranicux1 150 mg/-300 mg Filmtabletten. 35. Ranidura1 T 150 mg Filmtabletten. 36. Ranidura1 T 300 mg Filmtabletten. 37. Ranimerck1 150 mg Filmtabletten. 38. Ranimerck1 300 mg Filmtabletten. 39. RANI-PUREN1 150 Filmtabletten. 40. RANI-PUREN1 300 Filmtabletten. 41. ranitidin 150/-300 von ct Filmtabletten. 42. Ranitidin acis1 300 mg Filmtabletten. 43. Ranitidin AL 150/-300 Filmtabletten. 44. Ranitidin-ISIS1 150 Filmtabletten. 45. Ranitidin-ISIS1 300 Filmtabletten. 46. Ranitidin-ratiopharm1 150/-300/-150 akut/-300 akut Filmtabletten. 47. Ranitidin-saar1 150 mg/-300 mg Filmtabletten. 48. Sostril1 150 mg Filmtabletten. 49. Sostril1 300 mg Filmtabletten. 50. Zantic1 75 mg Magentabletten Filmtabletten. 51. Zantic1 150 mg Filmtabletten. 52. Zantic1 300 mg Filmtabletten. 53. Zantac 150, tabletten 150 mg. 54. Zantac 75, tabletten 75 mg. 55. Zantac 150, tabletten 150 mg. 56. Ranitidine Dumex 150 mg, tabletten. 57. Ranitidine Merck 150 mg, tabletten. 58. Ranitidine 150 mg Katwijk, tabletten. 59. Ranitidine 300 mg Katwijk, tabletten. 60. Ranitidine CF 150 mg, tabletten. 61. Ranitidine CF 300 mg, tabletten. 62. Ranitidine Gf 150 mg/300 mg, tabletten. 63. Ranitidine 75 mg/150 mg/300 mg, omhulde tabletten (Pharmacin Products). 64. Ranitidine 150 mg/300 mg, omhulde tabletten (Delphi). 65. Ranitidine FLX 75 mg/150 mg/300 mg, filmomhulde tabletten. 66. Ranitidine 75 mg/150 mg/300 mg Katwijk, omhulde tabletten. 67. Ranitidin Pliva 150 mg tabletti, kalvopaä¨llysteinen. 68. ESOFEX1 150 mg-tabletti, kalvopaä¨llysteinen. 69. Ranicur 150 mg/300 mg tabletti, kalvopaä¨llysteinen. 70. Ranil1 150 mg/300 mg kalvopaä¨llysteinen tabletti. 71. Ranimex 150 mg tabletti. 72. Ranimex 75 mg tabletti, kalvopaä¨llysteinen. 73. Ranixal 150 mg/300 mg tabletti, kalvopaä¨llysteinen. 74. Zantac 150 mg/300 mg tabletti. issues as the drug products, in which these ex- only holds when these excipients are present in cipients are formulated, are in therapeutic use. amounts typically used in IR solid oral dosage This observation is supported by Yu et al.,49 forms. For instance, macrogol, i.e., PEG, is listed reporting that commonly used excipients used to in Table 2, but is an osmotically active excipient formulate BSC Class III API’s had no significant and, as discussed above, reduces the BA of rani- effect on their absorption. This risk to cause cli- tidine when administrated in gram amounts. nical issues can be estimated to be even smaller if However, when present in milligram amounts, an excipient is present in a large number of regis- as typically used in the coating of tablets, no effect trated drug products. However, this conclusion on the BA is to be expected.

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Surrogate Techniques for In Vivo Bioequivalence Testing The rate-limiting step in the absorption process of ranitidine is its permeability. So, if there is sufﬁcient evidence that the excipients in the test product have no effect on the permeability or GI transit time, comparative dissolution testing can provide reasonable assurance for bioequivalency

) yes/no Reference of the product. According to the guidances, the 2 test product should be ‘‘rapidly dissolving’’ and also meet the requirement of f2-dissolution curve similarity with the reference product to conclude

Proﬁles (f 12,13 to bioequivalence. Applying the f2 criterion to

Similarity of Dissolution the studies reported in Table 3, most formulations that are bioequivalent to each other, or could be assumed to be therapeutically equivalent, would not pass. In the most cases f2 calculation showed a greater than 10% difference between formulations. However, as long as the two preparations released drug within 30 min, no differences in vivo could be demonstrated. Thus, it appears that applying both criteria, i.e., rapid dissolution and f2 >50 may be unnecessary restrictive for raniti-

Rapidly Dissolving dine products. The too strict nature of the f

85% in 30 min) yes/no 2 > YesYes Fast versus slow: no — 45 44 150 mg: no; 300 mg: yes 150 mg: no; 300 mg: yes 43 ( criterion for ranitidine is further supported by computer simulations, predicting in vivo bioequivalence with an oral solution of IR tablets having dissolution rates as slow as 85% in 1.5 h.46 b b b

Patient’s Risks Associated with Bioinequivalence The unproblematic use of doses six times higher than the recommended dose indicates that ranitidine has a wide therapeutic range. Its IR oral dosage forms are not used for life-threatening Water, paddle 50 rpm Water, paddle 50 rpm indications. These two considerations open the possibility for a biowaiver.

CONCLUSION

a Ranitidine hydrochloride can be classiﬁed as a BCS Class III API. Present regulations describe , fast, medium and

1 the possibility of a biowaiver for BCS Class I API containing drug products only.12,13 However, extensions of the present requirements to BCS Class III API’s have received increasing atten- 49–51

Dissolution of Ranitidine Hydrochloride IR Formulations tion. The data evaluated and discussed in

150 and 300 mg versus BIPI (USP) this study show that it would be reasonably safe to 1 grant biowaivers for IR solid oral dosage forms, The four ranitidine formulations were bioequivalent to one another. Conform to USP 27. a b 150 and 300 mg slow dissolving IR tablets provided that the test product is formulated with Table 3. Formulations Dissolution Method Ranitidine HCl Zantac Generic IR tablet Water, paddle 50 rpm Generic IR products in DEZantac 0.1N HCl, paddle 50 rpmexcipients 47: yes; 2: no shown inTable Most proﬁles: no 2, in amounts 42 typically

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