Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (bcs) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol

Biowaiver Monographs for Immediate Release Solid OralDosage Forms Based on Biopharmaceutics ClassificationSystem (BCS) Literature Data: Verapamil Hydrochloride,Propranolol Hydrochloride, and Atenolol H. VOGELPOEL,1* J. WELINK,2* G.L. AMIDON,3 H.E. JUNGINGER,4 K.K. MIDHA,5 H. MO 1RIVM—National Institute for Public Health and the Environment, Center for Quality of Chemical-Pharmaceutical Products,P.O. Box 1, 3720 BA Bilthoven, The Netherlands 2Medicines Evaluation Board in the Netherlands, P.O. Box 16229, 2500 BE The Hague, The Netherlands 3College of Pharmacy, University of Michigan, Ann Arbor, Michigan 4Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology,P.O. Box 9502, 2300 RA Leiden, The Netherlands 5University of Saskatchewan, Saskatoon, Saskatchewan, Canada, S7N 5C9 6Zentrallaboratorium Deutscher Apotheker, Carl-Manich-Strasse 20, 65760 Eschborn, Germany 7Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland Received 11 June 2003; revised 23 October 2003; accepted 1 January 2004 Published online in Wiley InterScience ( DOI 10.1002/jps.20131 ABSTRACT: Literature data related to the Biopharmaceutics Classification System(BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, andatenolol in the form of BCS-monographs. Data on the qualitative composition ofimmediate release (IR) tablets containing these active substances with a MarketingAuthorization (MA) in the Netherlands (NL) are also provided; in view of these MA’s theassumption was made that these tablets were bioequivalent to the innovator product. Thedevelopment of a database with BCS-related data is announced by the InternationalPharmaceutical Federation (FIP). ß 2004 Wiley-Liss, Inc. and the American PharmacistsAssociation J Pharm Sci 93:1945–1956, 2004Keywords: BCS; biowaiver; verapamil; propranolol; atenolol met considerable interest. A biowaiver impliesthat bioequivalence (BE) assessment studies are In recent years the necessity to provide a scientific waived for marketing authorizations (MA) by basis for biowaivers for individual substances has Health Authorities for a new tablet or capsule,or a new formulation of an existing immediate *This article reflects the scientific opinion of the authors release (IR) dosage form, and hence the product is and not the policies of regulating agencies.
considered bioequivalent to its reference product, Correspondence to: Dirk M. Barends (Tel: þ31 30 2744209; without carrying out a BE study. In this case the Fax: þ31 30 2744462; E-mail: [email protected]) comparative in vitro study assures BE of the test Journal of Pharmaceutical Sciences, Vol. 93, 1945–1956 (2004)ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association product. The scientific basis for this work was JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 developed by Amidon et al.1 and is known as the The present article summarizes and discusses Biopharmaceutics Classification System (BCS).
the main features obtained from the literature The BCS states that three major factors govern the rate and extent of drug absorption of IR solidoral dosage forms: dissolution rate, solubility, andintestinal permeability. For IR dosage forms containing active pharmaceutical ingredients(APIs) showing high solubility, high intestinal A literature search was performed in electroni- permeability, and rapid dissolution a waiver from cally available databases. The search performed performing BE studies (biowaiver) can be scien- included information from the Merck Index, the Dictionary of Substances and their Effects, the In the regulatory domain this is adopted by both Hazardous Substances Data Bank, Medline, Tox- line and Embase. Only literature published in the Guidance for Industry: Waiver of In Vivo Bioavail- last 10 years and written in English or German ability (BA) and BE Studies for Immediate-Release was included. When searching for dissolution and Solid Oral Dosage Forms Based on a BCS,2 and the solubility data, two problems occurred. The Note for Guidance on the Investigation of BA and search resulted in a large number of hits so that BE,3 respectively, together referred to as the a detailed study of all references on relevant data Guidances. In particular the FDA document was considered to be too time consuming, and describes in detail the data that are necessary for secondly almost all literature was related to a successful application for a biowaiver.
modified release dosage forms. Therefore, the When a set of BCS-data for an API is established decision was made to use, in general, only data and could be made publicly available in the form obtained form standard reference books like the of a monograph, this monograph could be referred United States Pharmacopeia (USP) and European to by subsequent applicants for biowaivers of other IR oral dosage forms with the same API For data on permeability the literature search without the need for reestablishing the data. Such was performed in the same way as described above, a publicly available BCS-monograph is also of limiting the keywords to permeability and related interest for Official Medicines Control Labora- to permeability, and the drug substance name. The tories (OMCL’s), which want to translate their outcome of the search was satisfactory and dissolution test data into terms of the BA of the sufficient. Relevant literature on all three sub- To explore the scope and the possibilities of It is known that dissolution and permeability of gathering BCS related data from scientific litera- an API can be influenced by excipients in the solid ture, and in order to set up such BCS-monographs, oral dosage forms. In order to gather insight of a literature search was carried out on verapamil possible excipient interactions tablet compositions hydrochloride, propranolol hydrochloride, and of generic formulations registered in NL were examined. The qualitative composition of the IRtablets containing one of the three active sub-stances was obtained from the publicly available Summary of Product Characteristics (SmPC). TheSmPC’s can be obtained from the website of Both chemical–pharmaceutical and pharmacoki- the Medicines Evaluation Board in NL at www.
netic BCS-related information on three sub- Only the excipients used in the tablet stances, verapamil hydrochloride, propranolol cores were considered since we made the assump- hydrochloride, and atenolol, was obtained by tion that the tablet coating for an IR tablet will be means of a literature search. The following data- of very limited influence on the dissolution proper- fields were defined in order to standardize the dataset: indication, solubility, dissolution, poly- The International Pharmaceutical Federation morphism, partition coefficient, pKa, available (FIP) will post these monographs on its website at dose, permeability, stereospecificity, pharmacoki- Additional information will be pub- netic properties. In addition, the qualitative lished and discussed in the form of Addenda to composition of IR tablets having an MA in the these monographs. The corresponding author of this article can be contacted for any contribution.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL Dr. C.A.M. Versantvoort on their comments on a of 8.6,8 and a range 8.6 – 8.9, respectively, The BCS-monographs of each of the three sub- stances are presented and discussed separately.
Strengths currently having an MA in NL: 40, 80, Verapamil hydrochloride is a well-known calciumantagonist. It is used in the treatment of angina The permeability data found for verapamil are After oral administration of a mixture of R- and S- verapamil, plasma concentrations of the R-isomer were substantially higher than those of the S- The Analytical profiles of drug substances, isomer, suggesting stereospecific first-pass meta- (Volume 17)7 contain a profile for verapamil hydrochloride. The solubility of verapamil hydro-chloride as a function of the pH is shown in Table 1.
Oral absorption of labeled 14C-verapamil in man No reference to polymorphic forms was found.
averaged over 90%. The absolute BA is 10–20%,indicating extensive first-pass metabolism.4,16 Peak plasma concentrations are reached within1–2 h after administration of a single dose.17,18 Kasim et al.8 calculated n-octanol/water partition Pharmacokinetics shows a large inter-individual coefficients using different fragmentation meth- ods that were based on atomic contributions to Food intake prolonged the time to peak concen- lipophilicity; for uncharged verapamil, log p values of 4.47 and 5.69 were reported.
area under the curve (AUC) of both isomers.20 The apparent volume of distribution of verapamilis about 2.5 L/kg. Protein binding is moderate (90%),4 not concentration dependent over the range of 10–2000 ng/mL16 and similar for both enantiomers.21 Verapamil binding to red blood Verapamil is extensively metabolized in the liver, primarily by N-dealkylation and O-demethyla- tion. Nor-verapamil is the only active metabolite formed. Further metabolism results in the form- ing of several metabolites that are excreted as inactive conjugates. There is a wide interpatient A 0.1 N NaOH solution and a 0.1 N HCl solution were used variation in verapamil metabolism consistent JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 a95% confidence interval; concentrations are concentrations of the racemate.
with the fact that verapamil undergoes extensive dissolved in 30 min in 900 mL 0.01 N HCl, using first-pass extraction. Urinary and fecal excretion account for about 70 and 15%, respectively, ofverapamil over 5 days. An average of 3% of theparent drug is recovered unchanged in the urine.
The elimination half-life is about 4–5 h, and issimilar for the R- and S-isomer.23 The solubility values observed are critical at a pHat or above 6.76. When the current solubility A number of different excipients are used in the criteria of the Guidances for the highest dose manufacturing of IR verapamil hydrochloride strength (120 mg) in 250 mL or less of aqueous tablets. The excipients used in the formulation media over the pH range of 1–7.52 or 8.0,3 are of the core of the IR tablets having an MA in NL strictly applied, verapamil hydrochloride fails to meet these criteria. At pH 7.32 the solubility isabout equivalent to the minimally required solubility of 0.48 mg/mL (120 mg/250 mL). Athigher pH values the solubility will be below The USP 26 specification for verapamil hydro- the minimal limit of 0.48 mg/mL. However, since chloride tablets is not less than (NLT) 75% (Q) the major fraction of the drug substance will beabsorbed in the upper part of the gastrointestinal (GI) tract where the pH value will normally be below 7.3 the limited solubility at high pH values is considered to be of no concern. This is also supported by a recent proposal to narrow the required pH range for sufficient solubility from Croscarmellose sodiumFurcelleranaGelatine Lactose anhydrate/monohydrateMagnesium stearate The requirements of the USP 26 differ from the stricter and more extensive requirements of the Guidances. They serve however a different pur- pose. The criteria defined by the Guidances aim to assure BE with a reference product, in the context of a regulatory decision, while the USP criteria define the attributes for an acceptable article. In the preface of the USP 2426 the goal of the method aFurcelleran is also known as Danish Agar or Danagar.
was described, which was essentially: to set JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL standards for ‘‘clinically acceptable articles’’ The observed high permeability of verapamil is by defining a dissolution method that is suffi- in line with the reported oral absorption of about ciently discriminating so that both BA and quality 90%. The presence of an absorption window cannot control is covered. This paragraph was deleted be ruled out from the literature data reviewed here starting with the USP 25, but it seems safe to but the postulated mechanism of the permeability assume that the USP 26 still aims at clinically of verapamil, being passive transport, makes such sufficient BA, which is less strict than bioequiva- lent towards a reference product. For verapamil In the IR verapamil hydrochloride tables which hydrochloride tablets the USP 26 prescribes have an MA in NL, and hence are assumed to be 900 mL of 0.01 N HCl as dissolution medium.
bioequivalent to the innovator’s product, a wide Given the limited solubility at higher pH values of range of excipients are used (see Table 3). This this API, testing at a pH of 6.8–7.5 seems more provides evidence that for the usual pharmaceu- discriminative. However, the solubility of this API tical excipients no effect on the extent (and rate) of will not be the limiting factor at this pH-range.
absorption is to be expected. However, it should be The decisive factor for the BA of an IR solid kept in mind that this holds only for excipient dosage form with this API will be the dissolution amounts which are normally used in IR tablet rate. This parameter is suitably controlled by the formulations. In addition, for highly soluble and USP 26 method, which makes it highly likely highly permeable drug substances, formulated that an insufficient dissolution from the for- into IR tablets with known excipients, it has been mulation will be detected. So, the practice to reported that no excipient interaction in the rate carry out the batch to batch dissolution testing and extent of absorption is to be expected.2 according to USP 26 once a formulation has been In conclusion, when the criteria of the Gui- shown to be bioequivalent to the reference dances are strictly applied, verapamil hydrochlor- formulation by a BE study or by comparative ide is a BCS Class II substance and this API can not dissolution studies is supported by the BCS- be considered a candidate for granting a biowaiver.
However, this API is clearly on the borderline, theonly problematic area is the insufficient solubilitybetween pH 7.3 and 8.0. In vivo the limited solubility in this pH interval will not be proble- In the Guidances the term ‘‘highly permeable’’ is matic. This means that the solubility boundaries used for substances whose absorption in humans for this API should be redefined to for instance from an orally administered dose is 90% or more.
1.0–6.8, as is recently suggested in general.25 In a The work of Amidon et al.1 has demonstrated that provisional classification of the WHO Essential the limit for absorption of >90% corresponded Drugs, verapamil was classified to be BCS Class I.8 with a permeability >2.10À4 cm/s (Attachment A So, from a scientific point of view, verapamil hydrochloride is a candidate for granting a bio- On the basis of the data presented in Table 2 waiver when the IR tablets are formulated with verapamil can be considered as a highly permeable well-known excipients, show rapid in vitro dis- solution, and meet the dissolution profile compar- Verapamil is passively transported and is a ison criteria as defined in the Guidances, but with substrate for P-gp. The effect of P-gp on verapamil a redefined upper boundary for the pH of 6.8. The absorption is low, due to the high permeability of USP 26 criteria and method are suitable to assure the drug. At high doses the efflux-mediated mechanism by P-gp becomes saturated and there-fore effective permeability (Peff) increases.11 Nodifference in Peff is observed between R- and S- Permeability values obtained in vivo by the intestinal perfusion technique were comparablewith the Peff obtained by Caco-2 cell line studies.
Propranolol hydrochloride is a well-known non- Permeability values of verapamil, obtained from a selective b-blocker, which is used in the manage- correlation of partition coefficients versus intest- ment of angina pectoris, hypertension myocardial inal permeability, also suggest a high permability JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 The presence of an absorption window cannot be ruled out from the data reviewed here but the Soluble (1 g dissolves in 10–30 mL) in water.5,6 postulated mechanism of the permeability of pro-pranolol: passive transport driven by the strong lipophilic nature of the substance, makes the Propranolol hydrochloride is known to have two existence of such an absorption window unlikely.
Propranolol is rather rapidly distributed over Kasim et al.8 calculated n-octanol/water partition tissues. It is highly lipophilic and moderately coefficients using different fragmentation meth- bound to plasma proteins (80–95%), mainly to a-1 ods that were based on atomic contributions to acid glycoprotein. The distribution volume is lipophilicity; for uncharged propranolol, log p about 4 L/kg. Studies in animals showed that values of 2.75 and 2.65 were reported.
propranolol is distributed into the lungs, liver,kidneys, brain, and the heart.37–39 A pKa range of 9.03–9.09 was reported.9 Propranolol is almost completely metabolized in the liver. Only a small portion of the administereddose is excreted unchanged in urine and feces (1– Strengths currently having a MA in NL: 10, 40, 4%). The main metabolites are naphtoxyl acetic acid (42%), 4-hydroxypropranolol (41%), andpropranolol-O-glucuronide (17%). 4-hydroxy-pro- pranolol is pharmacologically active and is equi- The permeability data found for propranolol are potent to the parent drug. However, due to rapid conjugation, the contribution to the pharmacolo-gical effect is low. The main metabolites are metabolized by cytochrome P450. Propranololand its metabolites are mainly excreted in urine (>90%). The elimination half-life is about Propranolol is almost completely absorbed after oral administration (>90%). Peak plasma concen-trations are reached within 1–2 h after adminis- tration of a single dose. The absolute BA variesbetween 5 and 50%, due to a high pre-systemic The excipients used in the formulation of the core metabolism. As a result, the BA and plasma levels show a large inter-individual variability.36–38 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL Using the Caco-2 cell lines, comparable perme- ability values were found (see Table 4). At a pH of Carboxymethylcellulose sodiumCellulose (microcrystalline) 5.4 permeability decreases at the apical (i.e., the luminal) site,41 but still takes place although the unionized fraction is very small (this is also the case at a pH of 7.2). This is probably due to the fact that the paracellular route represents a relatively small fraction of accessible area of the cell monolayer. Beside this, propranolol is lipo- philic enough to take advantage of the large sur- face area for transcellular permeation.31 Using a different cell line, TC-7 (which is a clone of Caco-2, displaying increased tauro-cholic acid transport) Adding plasma to the basolateral chamber does not influence the Peff of propranolol, due to its highlipophilicity. However, propranolol is avidly boundto plasma protein, and this resulted in a significant decrease of the exsorption (from basolateral toapical) of propranolol.33 The USP 26 specification for dissolution of Permeability values obtained in vivo by the propranolol hydrochloride tablets is NLT 75% intestinal perfusion technique were about 10–20- (Q) dissolved in 30 min in 1000 mL of dilute HCl fold higher than obtained by Caco-2. This differ- using the basket method operated at 100 rpm.
ence is less than observed for atenolol (see further,up to 500-fold). As propranolol is a highly lipophilicdrug, and transported transcellularly, factors influencing permeability in vitro versus in vivowill be less pronounced or even lacking.
The high permeability of propranolol is in line The pKa value of propranolol is about 9.05. At a with the reported high oral absorption of more pH of 7.2, it is reported that propranolol is highly soluble. Therefore, solubility will not be the rate- Given the high permeability of propranolol, it is limiting step in the absorption process of propra- considered unlikely that excipients should have an effect on the permeability and hence have aninfluence on the rate and extent of absorption,provided that rapid and complete dissolution over the physiological pH-range has been demon- The differences in purpose between the dissolu- strated. This is substantiated for the excipients tion tests of the Guidances and the USP were of the IR tablets which have an MA in NL as listed discussed under ‘‘verapamil hydrochloride.’’ For propranolol hydrochloride solubility within the In conclusion, according to the criteria of the physiological pH is not critical, so the dissolution Guidances, propranolol hydrochloride is a BCS rate of the formulation will be the decisive factor Class I substance. In a provisional classification of for BA of this API. The USP 26 dissolution the WHO Essential Drugs, this API was also method, using dilute HCl as dissolution medium, classified to be BCS Class I.8 So, from a scientific can be expected to control insufficient dissolution point of view this API is a candidate for granting a from the formulation. So, the practice to carry out biowaiver when the IR tablets are formulated with the batch to batch dissolution testing according to well-known excipients, show rapid in vitro dis- USP 26 once a formulation has been shown to be solution, and meet the dissolution profile compar- bioequivalent to the reference formulation by a ison criteria as defined in the Guidances. The USP BE study or by comparative dissolution studies is 26 criteria and method are suitable to assure batch supported by the BCS-characteristics of this API.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 The permeability data found for atenolol are Atenolol is a cardio selective b-blocker, widelyused in the management of hypertension, angina pectoris, cardiac arrhythmia’s, and myocardial Following oral administration about 46–62% of aradio-labeled dose is absorbed.4 Peak plasma con- centrations are reached within 2–4 h after admin- Sparingly5 (1 g dissolves in 3–100 mL) to istration of a single dose.4 Atenolol plasma slightly6,42 (1 g dissolves in 100–1000 mL) soluble concentrations increase proportionally to the dose.
In BA studies in healthy subjects in which the AUC after orally and intravenously administration of pH ¼ 1.243 and 2.48 g/100 mL in 0.2 M KH atenolol was compared, an absolute BA of 40–60% was reported. Since only 10% of an intravenousdose, but about 50% of an oral dose is excreted in thefeces, biliary excretion appears to be minimal and the limited BA is thus probably due to incomplete No reference to polymorphic forms was found.
absorption.51–54 Stereoselective oral BA has beenindicated, as it has been observed that the amount excreted unchanged in the urine, the AUC and thepeak concentrations differed between the enantio- Partition coefficients of 0.008 at pH 7.0 and 0.052 mers.55 Food intake significantly shortened the at pH 8.0 (n-octanol/phosphate buffer (0.16 M)) time to peak concentration and also caused a were reported.6,42 Kasim et al.8 calculated n- significant reduction in the AUC values (about octanol/water partition coefficients using differ- 20%), while the elimination half-life remained ent fragmentation methods that were based on atomic contributions to lipophilicity; log p valuesof À0.11 and 0.50 were reported.
Atenolol is relatively widely distributed, with an apparent volume of distribution of 50–75 L.
Protein binding is low and in the range of 6– Strengths currently having an MA in NL: 25, 50, Atenolol is mainly excreted unchanged in urine in man.4 Small amounts of the glucuronide metabo- JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL according to the Guidance for Industry2 is defined as the highest dose dissolvable in 250 mL or less.
Based on the limited information available with regard to atenolol solubility at different pH’s, the Cellulose (microcrystalline)Colloidal anhydrous silica solubility of atenolol is not expected to be the rate- limiting step in the absorption of atenolol from the HypromelloseLactose anhydrate/monohydrate The differences in purpose between the dissolu- tion tests of the Guidances and the USP were discussed under ‘‘verapamil hydrochloride.’’ For atenolol solubility within the physiological pH range is not critical, so the dissolution rate of the Pregelatinized (maize) starchSodium lauryl sulfate formulation will be the decisive factor for BA of this API. The USP 26 dissolution method, using 900 mL acetate buffer pH 4.6 as dissolution medium, can be expected control insufficientdissolution from the formulation. So, the practiceto carry out the batch to batch dissolution testingaccording to USP 26 once a formulation has been lite (ca. 2%) and of the non-conjugated hydro- shown to be bioequivalent to the reference xylated metabolite (2–3% of the 14C-labeled dose formulation by a BE study or by comparative after oral administration and 5.8% after i.v.
dissolution studies is supported by the BCS- administration) have been reported in the urine Excretion is essentially complete after 48 h after administration of a single dose.56 The total bodyclearance of atenolol is about 100 mL/min/1.73 m2 On the basis of the data in Table 6, in accordance and the elimination half-life is 6–9 h.57 with the definition of permeability in the Gui-dances, atenolol can be considered as a lowpermeable drug substance.
The Caco-2 cell drug transport studies showed The excipients used in the formulation of the core comparable permeability values. A value of about of generic IR atenolol tablets marketed in NL are 3.7 Â 10À6 cm/s was found by Rubas et al.47 that was significantly higher than those values re-ported by the other groups. The cause of this highpermeability value is not clear from the report.
Permeability values obtained in vivo by the The USP 26 specification for dissolution of intestinal perfusion technique were up to 500-fold atenolol tablets is NLT 80% (Q) dissolved in 30 higher than those obtained by Caco-2. Factors that min in 900 mL acetate buffer pH 4.6, using the may explain the observed difference are: firstly, atenolol is a hydrophilic drug that is transportedvia the paracellular route through tight junctions.
A higher permeability observed in the intestinalperfusion technique may be due to a lower paracellular transport and/or a larger area avail-able for absorption in vivo in humans, as it is assumed that the absorption of hydrophilic com- Atenolol with a pKa value of 9.6 is expected to be pounds is so slow that a larger surface area of the sufficiently soluble under physiological condi- intervillous space is exposed.48,49 Secondly, the tions. The highest tablet strength dissolves in intestine has mucus producing goblet cells, which about 25 mL of water at pH 7.4. ‘‘Highly soluble’’ influence the tight junctions. When Caco-2 cells JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 are mixed with mucus producing cells (HT29- MTX), permeability of atenolol increased.30 Whenmucus-producing cells were used instead of Caco- 1. Amidon GL, Lennerna¨s H, Shah VP, Crison JR.
2, permeability increased up to 30-fold.45 Thirdly, 1995. A theoretical basis for a Biopharmaceutics differences in extracellular Caþþ-concentrations Drug Classification: The correlation of in vitro drug can lead to a change in the integrity of the cell product dissolution and in vivo bioavailability.
structures, thereby causing a change in the paracellular permeability of atenolol. It has been 2. U.S. Department of Health and Human Services reported that by lowering the (free) extracellular Food and Drug Administration Center for Drug Caþþ-concentration, the permeability of atenolol Evaluation and Research (CDER). 2000. Guidance increased about 7-fold.27 Finally, cell tissue of for industry: Waiver of in vivo bioavailability and intestine has a transepithelial electrical resistance bioequivalence studies for immediate-release solid (TEER) of 50–100 OÁcm2.46 Caco-2 cell lines have a oral dosage forms based on a Biopharmaceutics TEER of >200–300 OÁcm2. Atenolol, having a low 3. Committee for Proprietary Medicinal Products permeability and being paracellularly trans- (CPMP). 2001. Note for guidance on the investiga- ported, the higher TEER of Caco-2 cells may tion of bioavailability and bioequivalence.
contribute to the lower permeability when com- 4. Martindale. The extra pharmacopoeia, 31st edn.
Royal Pharmaceutical Society, London, UK: Royal The data obtained with the intestinal perfusion technique are in reasonable agreement. On the 5. European Directorate for the Quality of Medicines.
average, a value of 2.10À5 cm/s is found, demon- European pharmacopoeia, 4th edn. Strasbourg, strating that the permeability of atenolol is low.
France: European Directorate for the Quality of The low permeability of atenolol is in line with Medicines, Council of Europe, Strasbourg, France.
the reported moderate oral absorption of about 6. Merck Index CD-ROM version 12:1, Merck & Co.
7. Chang ZL. In: Florey—Analytical profiles of drug In the IR atenolol tables which have an MA in substances, Vol. 17. London, UK: Academic Press.
NL, and hence are bioequivalent to the innovator’s 8. Kasim NA, Whitehouse M, Ramachandran C, product, a wide range of excipients is used (see Bermejo M, Lennerna¨s H, Hussain AS, Junginger Table 7). This provides evidence that for the usual HE, Stavchansky SA, Midha KK, Shah VP, Amidon pharmaceutical excipients no effect on the extent GL. 2004. Molecular properties of WHO essential (and rate) of absorption is to be expected. However, drugs and provisional Biopharmaceutical Classifi- it should be kept in mind that this holds only for excipient amounts which are normally used in IR 9. Hagers Handbuch der pharmazeutischen Praxis— tablet formulations. Probably for atenolol the Hrsg F von Bruchhausen.-5., vollst. neubearb.
low permeability is not so critical with regard to Aufl.—Berlin; Heidelberg; New York; London; Paris; Tokyo; Hong Kong; Barcelona; Budapest: Springer.
10. Doppenschmitt S, Spahn-Langguth H, Regardh In conclusion, the Guidances only describe the CG, Langguth P. 1999. Role of P-glycoprotein- possibility of a biowaiver for Class I substances.
mediated secretion in absorptive drug permeabil- From the data obtained, atenolol is indicated as a ity: An approach using passive membrane perme- BCS Class III substance. In a provisional classifi- ability and affinity to P-glycoprotein. J Pharm Sci cation of the WHO Essential Drugs, this API was also classified to be BCS Class III.8 However, we 11. Sandstro¨m R, Karlsson A, Knutson L, Lennerna¨s conclude that atenolol might be a candidate for a H. 1998. Jejunal absorption and metabolism of R/S- biowaiver, as excipient interaction appeared not verapamil in humans. Pharm Res 15:856–862.
to be critical with regard to the absorption of 12. Winniwarter S, Bonham NM, Ax F, Hallberg A, atenolol, provided that tablets are formulated Lennerna¨s H, Karlen A. 1998. Correlation of with well-known excipients as listed in Table 7, human jejunal permeability (in vivo) of drugs withexperimental show rapid in vitro dissolution, and meet the meters. A multivariate data analysis approach.
dissolution profile comparison criteria as defined in the Guidances. Class III substances have also 13. Sandstro¨m R, Knutson TW, Knutson L, Jansson B, been reported as candidates for biowaivers by Lennerna¨s H. 1999. The effect of ketoconazole on other authors.25,58 The USP 26 criteria and the jejunal permeability and CYP3A metabolism of method can be used to assure batch to batch (R/S)-verapamil in humans. J Clin Pharmacol 48: JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL 14. Lennerna¨s H, Knutson L, Hussain A, Lesko L, monolayers of intestinal (Caco-2) cells. J Pharm Sci jejunal Peff-value for each enantiomet of (R,S)- 28. Artursson P. 1990. Epithelial transport of drugs in cell culture. I: A model for studying the passive 15. Wright MR, Jamali F. 1993. Bioequivalence: diffusion of drugs over intestinal absorptive (Caco- Stereochemical considerations. Clin Res Reg Aff 2) cells. J Pharm Sci 79(6):476–482.
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