FLuconazole Anhydrate Form

COMMENTARY
Biowaiver Monograph for Immediate-Release Solid Oral Dosage

Forms: Bisoprolol Fumarate
NASEEM A. CHAROO,1 AREEG A. A. SHAMSHER,2 LAI Y. LIAN,1 BERTIL ABRAHAMSSON,3 RODRIGO CRISTOFOLETTI,4
D. W. GROOT,5 SABINE KOPP,6 PETER LANGGUTH,7 JAMES POLLI,8 VINOD P. SHAH,9 JENNIFER DRESSMAN10
1
Xepa—Soul Pattinson (M) Sdn Bhd, Melaka, Malaysia
2
RAK Medical and Health Sciences University, Ras Al Khaima, UAE
3
AstraZeneca R&D, Mölndal, Sweden
4
Brazilian Health Surveillance Agency (Anvisa), Division of Bioequivalence, Brasilia, Brazil
5
RIVM—National Institute for Public Health and the Environment, Bilthoven, The Netherlands
6
World Health Organization, Geneva, Switzerland
7
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg-University, Mainz, Germany
8
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland
9
International Pharmaceutical Federation FIP, The Hague, The Netherlands
10
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany
Received 9 October 2013; revised 20 November 2013; accepted 20 November 2013

Published online 30 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23817
ABSTRACT: Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-
release (IR) solid oral dosage forms containing bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol
is classified as a Class I API according to the current Biopharmaceutics Classification System (BCS). In addition to the BCS class, its
therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability
problems are taken into consideration. Qualitative compositions of IR tablet dosage forms of bisoprolol with a marketing authorization
(MA) in ICH (International Conference on Harmonisation) countries are tabulated. It was inferred that these tablets had been demonstrated
to be bioequivalent to the innovator product. No reports of failure to meet BE standards have been made in the open literature. On the
basis of all these pieces of evidence, a biowaiver can currently be recommended for bisoprolol fumarate IR dosage forms if (1) the test
product contains only excipients that are well known, and used in normal amounts, for example, those tabulated for products with MA
in ICH countries and (2) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving with similarity of
the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8.
C 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J
Pharm Sci 103:378–391, 2014

Keywords: bioequivalence; dissolution; bisoprolol; biopharmaceutics classification system (BCS); permeability; solubility; absorption
INTRODUCTION vitro study results rather than in vivo results, and additionally
to assess the risks associated with such a biowaiver. Risk for
The International Pharmaceutical Federation (FIP) Biowaiver
this purpose is defined as both the probability of arriving at an
Monographs series is a project of the Biopharmaceutics Clas-
incorrect biowaiver decision and an assessment of the conse-
sification System (BCS) and Biowaiver Focus Group of FIP,
quences of such an incorrect decision on public health and the
and monographs for over 35 APIs have already been published
individual patient.
in the Journal of Pharmaceutical Sciences (JPS). These mono-
Biowaiver monographs for several cardiovascular drugs,
graphs are also available online at www.fip.org/bcs.
such as verapamil, propranolol, and atenolol, have already been
In this work, a monograph based on literature data is pre-
published.1 The widespread use of bisoprolol justifies its in-
sented for bisoprolol, with respect to its biopharmaceutical
clusion in the series. In fact, the 18th Expert Committee on
properties and the possibility of waiving in vivo bioequivalence
the Selection and Use of Essential Medicines recommended
(BE) testing in the approval of new immediate-release (IR) solid
that bisoprolol should be added to the World Health Organiza-
oral dosage forms containing bisoprolol as the sole active phar-
tion (WHO) Model List of Essential Medicines for heart failure
maceutical ingredient (API), including both reformulated prod-
and suggested changing the representative beta blocker from
ucts and new multisource products. The purpose and scope of
atenolol to bisoprolol.2
these monographs have been discussed previously.1
All the relevant data available from the literature were re-
viewed to assess the feasibility of making a biowaiver decision, METHODS
that is, assessing interchangeability of products based on in
Literature data were obtained from PubMed, Micromedex, and
Web of Science databases up to August 2013. The keywords
Correspondence to: Jennifer Dressman (Telephone: +49 69 7982 9680;
Fax: +49 69 7982 9724; E-mail: dressman@em.uni-frankfurt.de) used for searching were bisoprolol, intestinal absorption, linear
Journal of Pharmaceutical Sciences, Vol. 103, 378–391 (2014) pharmacokinetics (PK), absolute bioavailability (BA), BE, log P,

C 2013 Wiley Periodicals, Inc. and the American Pharmacists Association solubility, permeability, mass balance, and radiolabeled studies.
378 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

COMMENTARY 379
angiotensin converting enzyme inhibitors, diuretics and option-

ally, cardiac glycosides.5,6 It is also indicated in the suppression
of atrial fibrillation5,7,8 and has antihypertensive efficacy.9–12
Therapeutic Index and Toxicity
Preclinical studies including conventional safety pharmacology,
repeated dose toxicity, genotoxicity, or carcinogenicity have not
revealed any special hazard to humans. Like other $- blockers,
the common side effects observed after its use include low blood
pressure, vomiting, diarrhoea, tiredness, weakness, headache,
and breathlessness.13 In general $-blockers are safe and well
Figure 1. Structure of bisoprolol fumarate. tolerated with a wide therapeutic index.14–16 The tolerability
of bisoprolol 5 and 10 mg tablets per day was investigated
in an open multicenter clinical study involving 2012 hyper-
Additional solubility studies of bisoprolol in various pH me- tensive patients and it was rated as “good” by 96.3% of the
dia were performed at Xepa-Soul Pattinson (Melaka, Malaysia) patients.17
Sdn. Bhd (Melaka, Malaysia). In the first series of studies, the The therapeutic concentration range of 10–50 ng/mL can
solubility of bisoprolol fumarate API over the pH range 1.2–7.5 be achieved with 10 mg bisoprolol tablets. Within this concen-
was determined in triplicate according to the WHO guidelines3 tration range, the heart rate decreases linearly with plasma
using a mechanical shaker (Promax 2020; Heidolph Instru- concentration.18 Doses as low as 5 mg are effective in caus-
ments, Schwabach, Germany) at 37 ± 0.5◦ C. Approximately ing long-lasting reduction in blood pressure and heart rate in
20.0 g of bisoprolol fumarate was weighed into 10 mL volumet- angina pectoris patients with a history of heart disease. Higher
ric flasks and adjusted to volume with the appropriate buffer doses (>30 mg) can cause incipient impairment of bronchomo-
solution. The flasks were then shaken efficiently for 24 h and tor function.18–22
samples were subsequently filtered through a Whatman filter
(Grade 41; 20 :m; GE Healthcare Sdn Bhd., Kuala Lumpur,
Malaysia). The filtrate was further diluted with corresponding PHYSICOCHEMICAL PROPERTIES
buffer solutions and analyzed for dissolved bisoprolol fumarate Salts, Esters, Polymorphs, and Hydrates
using HPLC.4
After these preliminary solubility experiments, additional Bisoprolol is formulated as the fumarate salt. It contains one
solubility studies were performed in pH 1.2 and 4.5 media, as asymmetric carbon atom.23 Bisoprolol is produced as a racemic
in the first series there was a pH shift during the solubility de- mixture.23 References to polymorphic forms were not found in
termination. In the second set of experiments, approximately the literature.
300 mg of bisoprolol fumarate was weighed into 50 mL volumet-
Solubility
ric flasks and the volume was adjusted with the corresponding
buffers. The amount of API was selected such that pH after the Bisoprolol fumarate is soluble in water.23 The USP (United
addition of API did not change more than 0.5 units from its ini- States Pharmacopoeia) categorizes this API to be “very solu-
tial value and the pH values were recorded initially and after ble in water.”24 Experimentally determined values of solubility
24 h of shaking. The flasks were shaken for 24 h and analyzed in different pH media at 37◦ C were not found in the literature.
for dissolved drug by HPLC.4 Though it can be assigned an aqueous solubility of at least 1000
The HPLC system consisted of an Agilent 1100 series sys- mg/mL based on the USP definition of “very soluble in water,”
tem (Agilent Technologies Singapore Pte Ltd., Yishun Avenue, other authors had used a more conservative approach in catego-
Singapore) operated in isocratic mode, an automatic injector rizing it as “soluble” and had assigned it an aqueous solubility
fitted with a 50-:L loop (G1313 A) and an Agilent diode array of 33 mg/mL.25 By contrast, the free base form of bisoprolol
detector (Agilent G1315 B). The HPLC was performed on a C18 has low aqueous solubility and its water solubility at 25◦ C was
column (4.6 × 150 mm2 , i.d. 5 :m; Zorbax Eclipse XDB, Agilent reported as 2.24 mg/mL.26
Technologies Singapore Pte Ltd.). The mobile phase consisted The experimentally determined solubilities and correspond-
of 1 L of water–acetonitrile (65:35, %, v/v), 5 mL of diethylamine ing dose-solubility ratios of bisoprolol over the pH range 1.2–7.5
and 2.5 mL of formic acid pumped at 1.0 mL/min. The detection are shown in Tables 1 and 2.
was performed at 273 nm.4
Partition Coefficient
The partition coefficient (log P) of bisoprolol fumarate in n-
GENERAL CHARACTERISTICS octanol/water, determined by the shake flask method at 32◦ C,
Name and Structure is reported to be −1.1.27 A log P value of 2.15 has also been re-
ported in the literature.28 The log P calculated from the struc-
INN: Bisoprolol fumarate.2 Its chemical name is ( ± ) -1- {[a- (2- ture by using online interactive LOGKOW program of the En-
isopropoxyethoxy)- p-tolyl]oxy}-3- (isopropylamino)-2- propanol vironmental Science Centre of Syracuse Research Corporation
fumarate (2:1) and the structure is shown in Figure 1. was 1.84.29
The log P values are generally similar to the log P value of
Therapeutic Indication
1.72 of the highly permeable marker drug metoprolol.25
Bisopolol is indicated in the treatment of stable chronic heart Distribution coefficients in n-octanol/phosphate buffer (at pH
failure with reduced systolic ventricular function in addition to 7.4, 37◦ C) and n-octanol/universal buffer (pH 7.4, 37◦ C) are
DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

380 COMMENTARY
Table 1. Saturation Solubility Values of Bisoprolol Fumarate in Different Buffered Media Maintained at 37◦ C
Medium pH of the Medium pH After API Addition Final pH After 24 h Shaking Amount Dissolved (mg/mL) ( ± SD)
Hydrochloric acid (0.1N) 1.2 6.1 6.2 795 ± 15

Acetate buffer 4.5 6.2 6.2 1260 ± 25
Phosphate buffer 6.8 6.7 6.6 831 ± 4
Table 2. Concentrations of Bisoprolol Fumarate Attained by Adding Approximately 300 mg Bisoprolol Furmate to 50 mL pH 1.2 or 4.5
Medium at 37◦ C
Medium pH of the Medium pH After API Addition Final pH After 24 h Amount Dissolved in 50 mL*(± SD)
Hydrochloric acid (0.1N) 1.2 1.4 1.4 310 ± 5

Acetate buffer 4.5 4.9 4.8 327 ± 3
*These values do not represent the thermodynamic solubility, instead approximately 300 mg bisoprolol fumarate was added to 50 mL buffer. This ensured that
the pH of the buffer did not change by more than 0.5 units during the determination.
reported to be 4.8 and 2.5, respectively.18,30 The lipophilicity of 14

C-labeled bisoprolol excreted in urine and 1.4% in the
commonly used ß-blockers can be rank ordered as propranolol feces.18,19 Concomitant food intake did not influence its BA,19
> bisoprolol > atenolol and some authors have considered biso- thus it can be taken regardless of the food intake.13,35,36
prolol to have an ideal PK profile as a result of its balanced The peak plasma concentration is reached within 1–3 h after
lipophilic and hydrophilic characteristics.22,23 oral administration.23 The PK of bisoprolol is linear, indepen-
dent of age and sex, and exhibits low inter- and intraindividual
pK a variability.13,18,37 At 2 h after oral administration of 10 and
The pKa of the bisoprolol base reported in the literature is 9.57 20 mg bisoprolol to eight coronary patients, the interindivid-
at 25◦ C.28 ual variability of plasma concentration was 10.3% and 11.2%,
respectively.37
Dosage Strengths Available In a Caco-2 cell model, bisoprolol permeability was
demonstrated to be 20.00 × 10−6 and 67.01 × 10−6 cm/s
The highest dose strength of bisoprolol recommended in the from apical-to-basolateral and basolateral-to-apical directions,
18th edition of the WHO Model List of Essential Medicine is respectively.38 It was not indicated whether a reference stan-
10 mg for coated tablets. Strengths with a marketing authoriza- dard was used in the study. Using verapamil as a transport
tion from the US FDA (United States Food and Drug Admin- inhibitor, it was concluded that bisoprolol is not a substrate for
istration) and the MHRA (Medicines and Healthcare Products P-glycoproteins.38
Regulatory Agency) include 1.25, 2.5, 3.75, 5, 7.5, and 10 mg Similar to the human results, bisoprolol was found to be
film-coated tablets (Table 3). Bisoprolol 2.5, 5.0, and 10.0 mg 91.4% orally bioavailable following oral and i.v. administration
are also available as uncoated tablets in these markets. It is of bisoprolol to 12 healthy adult beagles.39
marketed as a racemic mixture.
Stereospecificity
Distribution, Metabolism, and Excretion
The pharmacological activity of bisoprolol is predominantly be-
cause of the S(−) enantiomer.31–33 The $ adrenergic receptor The apparent volume of distribution of bisoprolol is 3.5 L/kg
blocking activity of S(−) enantiomer is 30–80 times greater and approximately 30% is protein bound.23,40 This binding
than the R(+) enantiomer.34 Both the R(+) and S(−) enan- is pharmacologically insignificant. The PK of bisoprolol is
tiomers of bisoprolol exhibit similar plasma concentration– not affected by pathophysiological changes in the plasma
time profiles after 5, 10, 20, and 40 mg oral administration,34 proteins.23
although a slight but insignificant difference in area under Bisoprolol was found to be primarily metabolized via
the curve (AUC) and elimination half-life of bisoprolol enan- CYP3A4 in in vitro studies in human liver microsomes. Cy-
tiomers was observed after the administration of racemic drug tochrome P450 2D6 does not play a role in its metabolism.31,40,41
mixture.31,32 In general, its disposition is not considered to be Bisoprolol is eliminated by two equally effective routes, that
stereospecific, which is in contrast to other $-blockers such as is, about half of the dose is metabolized to three inactive po-
verapamil, propranolol, and metoprolol.34 lar metabolites in the liver that are then eliminated by the
kidneys.13,23 The other half is excreted via the kidneys in un-
changed form. Because of this balanced clearance, a dosage ad-
PK PROPERTIES justment is not required for patients with impaired liver func-
tion or renal insufficiency at daily doses of 10 mg or less.42–44
Absorption and Permeability
Bisoprolol has a long plasma elimination half-life of 10–12 h,
Bisoprolol is almost completely absorbed from the gastroin- hence once daily administration is sufficient to elicit a thera-
testinal tract and has an absolute BA of about 90% after peutic effect, which in turn has a beneficial effect on patient
oral administration, with approximately 90% of the dose of compliance.18,45
Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

COMMENTARY 381
DOSAGE FORM PERFORMANCE products with MA in ICH countries. For these products, it can
be assumed that the product successfully passed an in vivo BE
Excipients
assessment.
Various excipients have been used in the manufacture of biso- Many of the formulations listed in Table 3 contain man-
prolol IR tablets. Table 3 lists excipients used in its oral drug nitol and sodium lauryl sulfate as excipients. Mannitol may
Table 3. Excipients* Present in Bisoprolol Fumarate IR Solid Oral Drug Products** with a Marketing Authorization (MA) in Belgium (BE),
Canada (CA), Czech Republic (CZ), Germany (DE), Denmark (DK), Spain (ES), Finland (FI), France (FR), Greece (GR), Hungary (HU), Ireland
(IE), Italy (IT), The Netherlands (NL), Norway (NO), Portugal (PT), Romania (RO), Sweden (SE), Slovakia (SK), United Kingdom (UK), and the
United States (US)***, and the Minimal and Maximal Amount of that Excipient Present Per Dosage Unit in Solid Oral Drug Products with a
MA in the US****
Drug Products Containing That Excipient with a MA Granted by Range Present in Solid Oral Dosage
Excipient the Named Country Forms with a MA in the US (mg)
Calcium carbonate CZ[1] DE[2] SK[3] 8.6—350

Calcium hydrogen phosphate BE[4–8] CA[9–14] CZ[15–19] DE[20–25] DK[26–32] ES[33–37] 104–850
FI[38,39] FR[40–57] GR[58] HU[59–64] IE[65–77] IT[78–92]
NL[93–105] NO[106–110] PT[111–118] RO[119–121]
SE[122–135] SK[136–141] UK[142–147] US[148–156]
Calcium phosphate CA[157] 86–362
Carnauba wax CA[157] 0.1–58
Cellulose, microcrystalline BE[4–8,158–163] CA[9–14,157,164–166] CZ[1,15–19,167–171] 4.6–1385a
DE[2,20–25,172,173] DK[26–32,174–177] ES[33–37,178–187]
FI[38,39,188,189] FR[40–57,190–201] GR[58,202]
HU[59–64,203–207] IE[65–77,208–216] IT[78–92,217–221]
NL[93–105,222–238] NO[106–110,239] PT[111–118,240–246]
RO[119–121,247–250] SE[122–135,251–260]
SK[3,136–141,261–265] UK[142–147,266,267] US[148–156,268]
Copovidone CA[9,12,13] 357–854
Croscarmellose sodium BE[4,158,161–163] CZ[168,169] DE[20] DK[26,27,175–177] 2–180
ES[33,178–181,183,186,187] FI[38,189]
FR[50,193–196,198,199,201] GR[202] HU[59,205,207]
IE[65,210,212,213,215,216] IT[82,83,217–220]
NL[99,101,102,222,225,226,231,235–237] NO[106,239]
PT[113,114,116,241–246] RO[248,250]
SE[125,252,254–256,258–260] SK [265] UK[143] US[268]
Crospovidone BE[5–8,159,160] CA[164–166] CZ[1,16–19,167,170,171] 4.4–792a
DE[2,21–25,172,173] DK[29–32,174] ES[34–37,182,184,185]
FI[188] FR[40–49,51–57,190–192,197,200] GR[58]
HU[61–64,203,204,206] IE[66–77,208,209,211,214]
IT[78–81,84–86,88,89,91,92,221]
NL[93–98,100,103–105,223,224,227–230,232–234] NO[108–110]
PT[111,112,115,117,118] RO[119–121,247,249]
SE[122–124,126,128–135,251,253,257]
SK[3,136–139,141,261,263,264] UK[142,144–147,267]
US[148,149,152,153,156]
Dimeticone CZ[18] FR[57] SK[139] 3.7
Disodium hydrogen phosphate ES[180,181] PT[241–243] 0.001–500
Glycerol dibehenate CZ[19] HU[64] RO[120] SK[141] 2.5–14
Hydroxypropylcellulose CA[164–166] 2.9–132
Hypromellose CA[9–13,157,164–166] CZ[1,18,167,269] DE[2,20,172] DK[27] 0.8–537
ES[180,181] FR[57] IE[65] IT[82,87,90] NL[101]
PT[113,114,241–243] SK[3,139,262,263,270] US[148–156,268]
Isopropanol CA[9,12,13] 2–46
Lactose BE[159,160,163] CA[164–166] CZ[168,171,269] DE[20,173] 23–1020a
DK[27,174,175] ES[178,179,182,184,185] FI[188,189]
FR[190–192,197,200] HU[203,205,206,271]
IE[65,208–211,214,215] IT[82,220,221]
NL[101,223,224,227–230,232–234,236] PT[113,114,246]
RO[247–249] SE[251–254,257] SK[261,264,270] UK[267]
US[268]
Macrogols CA[10,11,157,164–166] CZ[1,18,167,269] DE[2,20,172] DK[27] 0.12–961a
ES[180] FR[57] IE[65] IT[82,87,90] NL[101] PT[113,114]
SK[3,139,262,263,270] US[148–156,268]
Continued

382 COMMENTARY
Table 3. Continued
Drug Products Containing That Excipient with a MA Granted by Range Present in Solid Oral Dosage
Excipient the Named Country Forms with a MA in the US (mg)
Magnesium stearate BE[4–8,158–163] CA[9–14,157,164–166] CZ[1,15–18,167–171,269] 0.15–401a

DE[2,20–25,172,173] DK[26–32,174–177] ES[33–37,178–187]
FI[38,39,188,189] FR[40–57,190–201] GR[58,202]
HU[59–63,203–207,271] IE[65–77,208–216] IT[78–92,217–221]
NL[93–105,222–238] NO[106–110,239] PT[111–118,240–246]
RO[119,121,247–250] SE[122–135,251–260]
SK[3,136–140,261–265,270] UK[142–147,266,267]
US[148–156,268]
Mannitol BE[161,162] ES[183,186] FR[195,198] GR[202] HU[207] 33–484
IE[213,216] NL[222,225,226] NO[239] PT[244,245]
Polydextrose US[268] 3.8–8.1
Polysorbate CA[10,11,157] CZ[1] DE[2] SK[3] US[148–156] 0.4–418a
Povidone IT[87,90] NL[238] PT[240] UK[266] 0.17–80
Silica BE[4–8,158,163] CA[9–14,157] CZ[1,15–19,167–169,269] 0.50–100
DE[2,20–25,172] DK[26–32,175–177] ES[33–37,178–181,187]
FI[38,39,189] FR[40–57,193,194,196,199,201] GR[58]
HU[59–64,204,205,271] IE[65–77,210,212,215]
IT[78–92,217–220] NL[93–105,231,235–238] NO[106–110]
PT[111,112,114–118,240–243,246] RO[119–121,248,250]
SE[122–135,252,254–256,258–260]
SK[3,136–141,262,263,265,270] UK[142–147,266]
US[148–156,268]
Sodium laurilsulfate BE[163] CZ[19,168,269] DK[175] ES[178,179] FI[189] 0.65–52
HU[64,205,271] IE[210,215] IT[220] NL[236] PT[246]
RO[120,248] SE[252,254] SK[141,262,270] US[268]
Sodium starch glycolate BE[158] CZ[169] DK[176,177] ES[187] FR[193,194,196,199,201] 2–876a
IE[212] IT[217–219] NL[231,235,237,238] PT[240]
SE[255,256,258–260] SK[265] UK[266]
Starch BE[5–8] CA[10,11,14] CZ[16–18,269] DE[21–25] DK[29,31] 0.44–1135a
ES[35–37,180,181] FR[40–49,51–57] GR[58] HU[61–63,271]
IE[67–77] IT[85–92] NL[93–97] NO[108–110]
PT[117,118,241–243] RO[121] SE[122,123,128,129,131–135]
SK[136–139,262,270] UK[144–147] US[150,151,156]
Starch, pregelatinised BE[4,7] CA[9,12,13,157] CZ[1,167] DE[2,20,21,24,172] 4.2–600
DK[26,27,30] ES[33] FI[38] FR[40,46,50,53,55] HU[59,62,204]
IE[65,66,70,73,74] IT[79–85,88,92] NL[96,98–103] NO[106,109]
PT[112–114,116] RO[250] SE[122,125,126,128,132,134]
SK[3,263] UK[143,144] US[148,149,154,155]
Talc CZ[167,269] DE[2,172] HU[271] SK[3,263,270] 0.1–220a
Triacetin CA[9,12,13] 0.72–15
*Colorants and ingredients present in the coating and/or the printing ink are not included.
Substances are excluded if it can be assumed that the constituents are only present in the coating/polish.
**Excluded are: combination products.
***Sources of data: BE, www.bcfi.be/ (accessed May 27, 2013); CA, www.hc-sc.gc.ca (accessed May 28, 2013); CZ, www.sukl.cz/ (accessed May 28, 2013); DE,
www.rote-liste.de; (accessed May 28, 2013); DK, www.dkma.dk (accessed May 29, 2013); ES, www.aemps.es (accessed May 29, 2013); EU, www.ema.europa.eu
(accessed June 3, 2013); FI, www.fimea.fi (accessed June 3, 2013); FR, http://www.theriaque.org/ (accessed June 5, 2013); GR, www.eof.gr (accessed June 10, 2013); HU,
www.ogyi.hu (accessed June 18, 2013); IE, www.imb.ie/ (accessed June 18, 2013); IT, www.torrinomedica.it/ (accessed June 19, 2013); NL, www.cbg-meb.nl (accessed
May 21, 2013); NO, www.legemiddelverket.no/ (accessed June 24, 2013); PT, http://www.infarmed.pt/infomed/ (accessed June 24, 2013); RO, www.anm.ro/ (accessed
June 24, 2013); SE, www.lakemedelsverket.se (accessed July 8, 2013); SK, www.sukl.sk (accessed July 9, 2013); UK, www.medicines.org.uk/emc/ (accessed July 9,
2013); US, http://dailymed.nlm.nih.gov (accessed July 9, 2013).
****US: FDA’s Inactive Ingredient Database, http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm (version date March 29, 2013).
a
The upper range value reported is unusually high for solid oral dosage forms and the authors doubt its correctness.
1. Bisogamma 10, potahované tablety; 2. Bisogamma 10 Filmtabletten; 3. Bisogamma 10; 4. Bisoprolol Sandoz 2.5 mg filmomhulde tabletten; 5. Bisoprolol
R
Apotex 5/-10 mg filmomhulde tabletten; 6. Emconcor -Minor 2.5/-mitis 5/-10 mg filmomhulde tabletten; 7. Isoten 1.25 mg filmomhulde tabletten; 8. Isoten -
R
Minor 2.5/-3.75/-5/-7.5/-10 mg filmomhulde tabletten; 9. Pr BISOPROLOL (Bisoprolol Fumarate tablets 5/-10 mg, USP) [Sorres Pharma Inc.]; 10. Pr BISOPROLOL,
Bisoprolol fumarate tablets 5/-10 mg, USP [Sivem Pharmaceuticals ULC]; 11. Pr BISOPROLOL, Bisoprolol fumarate tablets 5/-10 mg, USP [Sanis Health Inc.]; 12.
Pr
phl- BISOPROLOL (Bisoprolol Fumarate tablets 5/-10 mg, USP); 13. Pr pms-BISOPROLOL (Bisoprolol Fumarate tablets 5/-10 mg, USP); 14. Pr Sandoz Bisoprolol,
Bisoprolol fumarate tablets 5/-10 mg, USP; 15. Bisoprolol Vitabalans 5/-10 mg tablety; 16. Concor 5/-10, potahované tablety; 17. Concor COR 2.5/-5/-10 mg, potahované
tablety; 18. RIVOCOR 5/-10; 19. TYREZ 2.5/-5/-10 mg, potahované tablety; 20. Bisobeta 5/-10 Filmtabletten; 21. Bisoprolol-ratiopharm 1.25 mg Filmtabletten; 22.
R
Bisoprolol-ratiopharm 2.5/-3.75 mg Filmtabletten; 23. Concor 5/-10 mg Filmtabletten; 24. Concor COR 1.25 mg Filmtabletten; 25. Concor COR 2.5/-3.75/-5/-
R R R
7.5/-10 mg Filmtabletten; 26. Bisoprolol “Sandoz,” filmovertrukne tabletter 1.25/-2.5/-5/-10 mg; 27. Speridol, filmovertrukne tabletter 1.25/-2.5 mg; 28. Bisoprolol
“Vitabalans,” tabletter 5/-10 mg; 29. Cardicor, filmovertrukne tabletter 2.5 mg; 30. Bisoprolol “Stada,” filmovertrukne tabletter 5/-10 mg; 31. Emconcor, filmovertrukne
tabletter 5/-10 mg; 32. Bisoprolol “Pfizer,” filmovertrukne tabletter 5/-10 mg; 33. Bisoprolol Cor Sandoz 1.25/-2.5/-5/-10 mg comprimidos recubiertos con pelı́cula
EFG; 34. Bisoprolol Pharmacia 5/-10 mg comprimidos recubiertos con pelı́cula EFG; 35. Emconcor Cor 2.5/-5/-10 mg comprimidos recubiertos con Pelı́cula; 36.
Emconcor 5/-10 mg comprimidos recubiertos con pelı́cula; 37. Euradal 5/-10 mg comprimidos recubiertos con pelı́cula; 38. Bisoprolol Sandoz 1.25/-2.5/-3.75/-5/-7.5/-
10 mg tabletti, kalvopäällysteinen; 39. Bisoprolol Vitabalans 5/-10 mg tabletit; 40. BISOCE 1.25 MG CPR Gé; 41. BISOCE 2.5/-3.75/-5/-7.5/-10 MG CPR Gé; 42.
BISOPROLOL ACT 10 MG CPR; 43. BISOPROLOL ARW 10 MG CPR; 44. BISOPROLOL BGA 10 MG CPR; 45. BISOPROLOL BGR 2.5/-3.75/-5/-7.5/-10 mg
CPR; 46. BISOPROLOL BGR 1.25 MG CPR; 47. BISOPROLOL EG 10 MG CPR; 48. BISOPROLOL MYL 10 MG CPR; 49. BISOPROLOL QUA 10 MG CPR.
Continued

COMMENTARY 383
Table 3. Continued
50. BISOPROLOL SDZ 1.25/-2.5/-3.75/-5/-7.5/-10 MG CPR; 51. BISOPROLOL ZEN 10 MG CPR; 52. BISOPROLOL ZYD 10 MG CPR; 53. CARDENSIEL 1.25 MG
CPR; 54. CARDENSIEL 2.5/-3.75/-5/-7.5/-10 MG CPR; 55. CARDIOCOR 1.25 MG CPR. 56. CARDIOCOR 2.5/-5 MG CPR; 57. DETENSIEL 10 MG CPR; 58. PACTENS
5/-10 mg gB46"8L:: ǵ<" :g 8gBJó L: ǵ<4o *4F64́"; 59. Bisoprolol Sandoz 2.5/-5/-10 mg filmtabletta; 60. Bisoprolol Vitabalans 5/-10 mg tabletta; 61. Concor 5/-10 mg
filmtabletta; 62. Concor COR 1.25 mg filmtabletta; 63. Concor COR 2.5/-5/-10 mg filmtabletta; 64. Dorez 2.5/-5/-10 mg filmtabletta; 65. Bisop 1.25/-2.5/-3.75/-
5/-7.5/-10 mg film-coated tablets; 66. Bisoprolol Hemifumarate Genthon 5/-10 mg, film-coated tablets; 67. Cardicor 3.75/-5/-7.5/10 mg, film-coated tablets [Imbat
Limited]; 68. Cardicor 10 mg film-coated tablets [IPS Healthcare Limited]. 69. Cardicor 2.5 mg film-coated tablets [PCO Manufacturing]; 70. Cardicor 1.25 mg
film-coated tablets [Merck Serono Ltd.]; 71. Cardicor 2.5/-3.75/-5/-7.5/-10 mg film-coated tablets [Merck Serono Ltd.]; 72. Cardicor 2.5 mg film-coated tablets [Imbat
Limited]; 73. Cardicor 1.25 mg film-coated tablets [Imbat Limited]; 74. Cardicor 1.25 mg film-coated tablets [PCO Manufacturing]; 75. Emcolol 5/-10 mg film-
coated tablets; 76. Emcor 5/-10 mg film-coated tablets [B&S Healthcare]; 77. Emcor 5/-10 mg film-coated tablets [Merck Serono Limited]; 78. BISOPROLOLO
AUROBINDO PHARMA ITALIA [1.25/2.5/3.75/5/7.5/10 mg]; 79. BISOPROLOLO DOC GENERICI [10 mg]; 80. BISOPROLOLO EG 10 mg; 81. BISOPROLOLO
EG 5 mg COMPRESSE RIVESTITE CON FILM; 82. BISOPROLOLO HEXAL 1.25 mg COMPRESSE RIVESTITE CON FILM; 83. BISOPROLOLO SANDOZ
1.25/-2.5/-3.75/-5/-7.5/-10 mg; 84. BISOPROLOLO WINTHROP [10 mg]; 85. CARDICOR [2.5/-3.75/-5/-7.5/-10 mg]; 86. CARDICOR [1.25mg]; 87. CONCOR 10 mg
COMPRESSE; 88. CONGESCOR [1.25mg]; 89. CONGESCOR [2.5/-3.75/-5/-7.5/-10 mg]; 90. PLUSCOR 10 mg COMPRESSE RIVESTITE CON FILM; 91. SEQUACOR
COMPRESSE RIVESTITE CON FILM [2.5/-3.75/-5/-7.5/-10]; 92. SEQUACOR COMPRESSE RIVESTITE CON FILM [1.25mg]; 93. Emcor 5, filmomhulde tabletten
5 mg; 94. Bisoprolol fumaraat Mylan 10 mg, filmomhulde tabletten [I]; 95. EMCOR DECO 2.5/-7.5, filmomhulde tabletten 2.5/-7.5 mg; 96. Bisoprolol fumaraat
Deco Mylan 1.25mg, filmomhulde tabletten; 97. Bisoprolol fumaraat Deco Mylan 2.5/-3.75/-5/-7.5/-10 mg, filmomhulde tabletten; 98. Bisoprolol fumaraat 5/-10 mg,
filmomhulde tabletten [Genthon BV]; 99. Bisoprolol fumaraat 1.25/-2.5/-3.75/-5/-7.5/-10 mg, filmomhulde tabletten [Sandoz B.V.]; 100. Bisoprolol fumaraat CF 5/-10 mg,
filmomhulde tabletten; 101. Bisoprolol fumaraat 1.25/-2.5/-3.75/-5/- 7.5/-10 mg, filmomhulde tabletten [Hexal AG]; 102. Bisoprolol fumaraat Sandoz tablet 1.25/-2.5/-
3.75/-5/-7.5/-10, filmomhulde tabletten 1.25/-2.5/-3.75/-5/-7.5/-10 mg; 103. Bisoprolol fumaraat 5/-10 mg, filmomhulde tabletten [Synthon BV]; 104. Bisoprolol fumaraat
Aurobindo 5/-10 mg, filmomhulde tabletten; 105. Bisoprolol fumaraat Deco Aurobindo 1.25/-2.5/-3.75/-5/-7.5/-10 mg, filmomhulde tabletten; 106. Bisoprolol Sandoz
1.25/-2.5/-3.75/-5/-7.5 mg filmdrasjerte tabletter; 107. Bisoprolol Vitabalans 5/-10 mg tabletter; 108. Emconcor 5/-10 mg tabletter, filmdrasjerte; 109. Emconcor CHF
1.25 mg tablett, filmdrasjert; 110. Emconcor CHF 2.5/-3.75/-5/-7.5/10 mg tablett, filmdrasjert; 111. Bisoprolol Aurobindo 1.25/-2.5/-3.75/-5/-7.5/-10 mg comprimidos
revestidos porPelı́cula; 112. Bisoprolol Stada 10 mg Comprimidos; 113. Bisoprolol Marpidum 1.25 mg comprimidos revestidos por pelı́cula; 114. Bisoprolol Marpidum
2.5/-5/-10 mg comprimidos revestidos por pelı́cula; 115. Bisoprolol Glob 5/-10 mg comprimidos revestidos por Pelı́cula; 116. Bisoprolol Sandoz 5/-10 mg Comprimidos
revestidos 5/-10 mg Comprimidos revestidos por pelı́cula; 117. Concor 5/-10 mg comprimido revestido; 118. Concor IC 2.5 mg comprimidos revestidos por pelı́cula;
119. Bisoprolol Fumarat AUROBINDO 5/-10 mg comprimate filmate; 120. BOREZ 2.5/-5/-10 mg comprimate filmate; 121. CONCOR 5/-10 mg; 122. Bisoprolol
Merck 1.25 mg filmdragerad tablett; 123. Bisoprolol Merck 2.5/-3.75/-5/-7.5/-10 mg filmdragerad tablett; 124. Bisoprolol Pfizer 5/-10 mg filmdragerade tabletter; 125.
Bisoprolol Sandoz 1.25/-2.5/-3.75/-5/-7.5/-10 mg filmdragerade tabletter; 126. Bisoprolol STADA 5/-10 mg, filmdragerade tabletter; 127. Bisoprolol Vitabalans 5/-10 mg
tabletter; 128. Cardicor 1.25 mg filmdragerade tabletter; 129. Cardicor 2.5/-3.75/-5/-7.5/-10 mg filmdragerade tabletter; 130. Dekria 1.25/-2.5/-3.75/-5/-7.5/-10 mg
filmdragerade tabletter; 131. Emconcor 5/-10 mg filmdragerade tabletter; 132. Emconcor CHF 1.25 mg filmdragerade tabletter; 133. Emconcor CHF 2.5/-3.75/-5/-7.5/-
10 mg filmdragerade tabletter; 134. Libracor 1.25 mg filmdragerad tablett; 135. Libracor 2.5/-3.75/-5/-7.5/-10 mg filmdragerad tablett; 136. Concor 5/-10; 137. Concor
COR 2.5/-5/-10 mg; 138. Bisomerck 5/-10; 139. RIVOCOR 5/-10; 140. Bisoprolol Vitabalans 5/-10 mg tablety; 141. TYREZ 5/-10 mg, filmom obalené tablety; 142.
Bisoprolol Fumarate 1.25/-2.5/3.75/-5/-7.5/-10 mg film-coated tablets [Milpharm Limited]; 143. Bisoprolol Fumarate 1.25/-2.5/-3.75/-5/-7.5/-10 mg film-coated tablets
[Sandoz Limited]; 144. Cardicor 1.25 mg film-coated tablets; 145. Cardicor 2.5/-3.75/-5/-7.5/-10 mg film-coated tablets; 146. Emcor LS 5 mg film-coated Tablets; 147.
Emcor 10 mg film-coated tablets; 148. BISOPROLOL FUMARATE tablet 5/-10 mg [Rebel Distributors Corporation]; 149. BISOPROLOL FUMARATE tablet 5/-10 mg
[Unichem Pharmaceuticals, Inc.]; 150. BISOPROLOL FUMARATE tablet, coated 5/-10 mg [American Health Packaging]; 151. BISOPROLOL FUMARATE tablet,
coated 5/-10 mg [Eon Labs, Inc.]; 152. BISOPROLOL FUMARATE tablet, film coated 5/-10 mg [Aurobindo Pharma Limited]; 153. BISOPROLOL FUMARATE tablet,
film coated 5/-10 mg [Greenstone LLC]; 154. BISOPROLOL FUMARATE tablet, film coated 5/-10 mg [Physicians Total Care, Inc.]; 155. BISOPROLOL FUMARATE
tablet, film coated 5/-10 mg [Teva Pharmaceuticals USA Inc.]; 156. ZEBETA (bisoprolol fumarate) tablet 5/-10 mg [Duramed Pharmaceuticals, Inc.]; 157. Pr NOVO-
BISOPROLOL, Bisoprolol Fumarate tablets 5/-10 mg; 158. Bisoprolol EG 2.5 mg tabletten; 159. Bisoprolol EG 5/-10 mg tabletten; 160. Bisoprolol-ratiopharm
5/-10 mg tabletten; 161. Bisobloxus 5/-10 mg filmomhulde tabletten; 162. Bisoprolol Teva 5/-10 mg filmomhulde tabletten; 163. Bisoprolol Mylan 2.5/-5/-10 mg
filmomhulde tabletten; 164. APO-BISOPROLOL, Bisoprolol Fumarate tablets 5/-10 mg; 165. AVA-BISOPROLOL, Bisoprolol Fumarate tablets 5/-10 mg; 166. Pr PRO-
BISOPROLOL-5/-10 (Bisoprolol Fumarate tablets 5mg, USP); 167. Bisogamma 5, potahované tablety; 168. Bisoprolol Mylan 2.5/-5/-10 mg, potahované tablety;
169. Bisoprolol Orion 2.5/-5/-10 mg tablety; 170. Bisoprolol PMCS 2.5/-5/-10 mg tablety; 171. BISOPROLOL-RATIOPHARM 5/-10 mg, tablety; 172. Bisogamma 5 R
Filmtabletten; 173. Bisoprolol-ratiopharm 5/-10 mg Tabletten; 174. Bisoprolol “Actavis,” tabletter 2.5/-5/-10 mg; 175. Bisoprolol “Mylan,” filmovertrukne tabletter
R
5/-10 mg; 176. Bisoprolol “Orion,” tabletter 2.5/-5/-10 mg; 177. Bisoprolol “Orifarm,” tabletter 2.5 mg; 178. Bisoprolol COR MYLAN 2.5/-5/-10 mg comprimidos
recubiertos con pelı́cula EFG; 179. Bisoprolol MYLAN Pharmaceuticals 5/-10 mg comprimidos recubiertos con pelı́cula EFG; 180. Bisoprolol Edigen 5/-10 mg
comprimidos recubiertos con pelı́cula EFG; 181. Bisoprolol NORMON 2.5/-5/-10 mg Comprimidos recubiertos EFG; 182. Bisoprolol ratiopharm 5/-10 mg comprimidos
EFG; 183. Bisoprolol Sándoz 5/-10 mg comprimidos con cubierta pelicular EFG; 184. Bisoprolol–Sumol 10 mg comprimidos EFG; 185. Bisoprolol Tarbis 5/-10 mg
comprimidos EFG; 186. Bisoprolol TEVA 5/-10 mg comprimidos recubiertos con pelı́cula EFG. 187. Bisoprolol Teva 2.5 mg comprimidos EFG; 188. Bisoprolol Actavis
5/-10 mg tabletti; 189. Bisoprolol Mylan 5/-10 mg tabletti, Kalvopäällysteinen; 190. BISOPROLOL ACF 10 MG CPR; 191. BISOPROLOL ACT 2.5/-5 mg CPR; 192.
BISOPROLOL ALM 10 MG CPR; 193. BISOPROLOL EG 1.25/-2.5/-3.75 mg CPR; 194. BISOPROLOL RBX 1.25/-2.5/-3.75/-7.5 mg CPR; 195. BISOPROLOL RPG
5/-10 mg CPR; 196. BISOPROLOL RTP 1.25/-2.5/-3.75 mg CPR; 197. BISOPROLOL RTP 10 MG CPR; 198. BISOPROLOL TVC 5/-10 mg CPR; 199. BISOPROLOL
TVS 1.25/-2.5/-3.75 mg CPR; 200. BISOPROLOL ZTL 2.5/-5/-10 mg CPR; 201. BISOPROLOL ZYF 1.25/-2.5/-5 mg CPR; 202. Speridol 5/-10 mg, gB46"8L:: ǵ<" :g
8gBJó L: ǵ<4o *4F64́"; 203. Bisoblock 5/-10 mg tabletta; 204. Bisogamma 5/-10 mg filmtabletta; 205. Bisoprolol Mylan 1.25/-2.5/-5/-10 mg filmtabletta; 206. Bisoprolol-
ratiopharm 5/-10 mg tabletta; 207. Coviogal 5/-10 mg filmtabletta; 208. Bisocor 5/-10 mg tablets; 209. Bisopine 5/-10 mg tablets; 210. Bisoprolol 5/-10 mg film-coated
tablets; 211. Bisoprolol Fumarate 2.5/-5/-10 mg tablets [Niche Generics Limited]; 212. Bisoprolol Fumarate 1.25/-2.5/-3.75/-5/-10 mg tablets [Chanelle Medical];
213. Bisoprolol fumarate 5/-10 mg tablets [Pinewood Laboratories Ltd.]; 214. Bisoprolol Fumarate Actavis 5/-10 mg tablets; 215. Bisoprolol Mylan 1.25/-2.5/-3.75/-
5/-7.5/-10 mg film-coated tablets; 216. Soprol 5/-10 mg film-coated tablets; 217. BISOPROLOLO DOC COMPRESSE [1.25/2.5/3.75/5/10 mg]; 218. BISOPROLOLO
EUROGENERICI [1.25/2.5/3.75 mg]; 219. BISOPROLOLO MYLAN GENERICS [1.25/2.5/3.75/5/10 mg]; 220. BISOPROLOLO MYLAN COMPRESSE RIVESTITE
CON FILM [1.25/2.5/3.75/5/7.5/10 mg]; 221. BISOPROLOLO ZENTIVA ITALIA 2.5 mg COMPRESSE; 222. Bisoprolol fumaraat 5/-10 PCH, filmomhulde tabletten
5 mg; 223. Bisoprolol fumaraat ratiopharm 5/-10 mg, tabletten; 224. Bioglan Bisoprolol fumaraat 5/-10 mg tabletten; 225. Bisoprolol fumaraat Disphar 5/-10 mg,
filmomhulde tabletten; 226. Bisoprolol fumaraat Sandoz 5/-10, filmomhulde tabletten 5/-10 mg; 227. Bisoprolol fumaraat Unichem 5/-10 mg tabletten; 228. Bisoprolol
fumaraat 5/-10 mg tabletten [Unichem Laboratories Limited]; 229. Bisoprolol fumaraat actavis 5/-10 mg, tabletten [I]; 230. Bisoprolol fumaraat ozone 5/-10 mg
tabletten; 231. Bisoprolol fumaraat ratiopharm 2.5 mg, tabletten; 232. Bisoprolol fumaraat 2.5/-5/-10 A tabletten 2.5/-5/-10 mg; 233. Bisoprolol fumaraat Actavis
2.5/-5/-10 mg, tabletten [II]; 234. Bisoprolol fumaraat Niche Generics 5/-10 mg, tabletten; 235. Bisoprolol fumaraat CF 1.25/-2.5 mg, tabletten; 236. Bisoprolol fumaraat
Mylan 1.25/-2.5/-3.75/-5/-7.5/-10 mg, filmomhulde tabletten [II]; 237. Bisoprolol fumaraat 1.25/-2.5 mg Teva, tabletten; 238. Bisoprolol fumaraat accord 2.5/-5/-10 mg
filmomhulde tabletten; 239. Bisoprolol Sandoz 10 mg filmdrasjerte tabletter; 240. Bisoprolol Accord 2.5/-5/-10 mg comprimido revestido por pelı́cula; 241. Bisoprolol
gp 5/-10 mg Comprimidos; 242. Bisoprolol Generis 5/-10 mg Comprimidos; 243. Bisoprolol Germed 5/-10 mg Comprimidos revestidos por pelı́cula; 244. Bisoprolol
Jaba 5/-10 mg, Comprimidos revestidos; 245. Bisoprolol Labesfal 5/-10 mg Comprimidos revestidos; 246. Bisoprolol Mylan 5/-10 mg comprimidos revestidos por
pelı́cula; 247. BISOBLOCK 5/-10 mg; 248. Bisoprolol fumarat 1.25/-2.5/-5/-10 mg comprimate filmate [Jenson Pharmaceutical Services Ltd.]; 249. Bisoprolol LPH
5/-10 mg comprimate; 250. Bisotens 5/-10 mg, comprimate filmate; 251. Bisocard 2.5/-5/-10 mg tabletter;252. Bisomyl 1.25/-2.5/-5/-10 mg filmdragerade tabletter; 253.
Bisoprolol Actavis 5/-10 mg tablett; 254. Bisopropol Mylan 5/-10 mg filmdragerade tabletter; 255. Bisoprolol Orifarm 1.25/-2.5 mg tabletter; 256. Bisoprolol Orion
2.5/-5/-10 mg tabletter; 257. Bisoprolol ratiopharm 5/-10 mg tabletter; 258. Bisoprolol ratiopharm 1.25/-2.5 mg tabletter; 259. Bisoprolol Teva 1.25/-2.5/-3.75 mg
tabletter; 260. Bisostad 1.25/-2.5 mg tabletter; 261. Bisoprolol-ratiopharm 5/-10 mg; 262. Coronal 5/-10; 263. Bisogamma 5; 264. BISOBELA 2.5/-5/-10 mg tablety;
265. Bisoprolol Orion 2.5/-5/-10 mg tablety; 266. Bisoprolol 2.5/-5/-10 mg film-coated tablet [Accord Healthcare Ltd.]; 267. Bisoprolol Fumarate 2.5 mg tablets
[Actavis Group PTC ehf.]; 268. BISOPROLOL FUMARATE tablet, film coated 5/-10 mg [Mylan Pharmaceuticals Inc.]; 269. BISOCARD 5/-10, potahované tablety;
270. Bisocard 5/-10 mg; 271. Bisocard 5/-10 mg filmtabletta.

384 COMMENTARY
negatively influence drug absorption when present in a high profiles of test and reference products were found to be similar,
concentration, because of the stimulation of gastrointestinal but dissolution conditions were not specified.49
motility and a resultant reduction in intestinal transit time, A comparative BA study of bisoprolol test (PT Ferron Par
whereas sodium lauryl sulfate can improve drug absorption Pharmaceuticals, Cikarang Bekasi, Indonesia) and reference
through solubilization effects and/or an increase in membrane tablets (Concor 5 mg; Merck, Jakarta, Indonesia) in 18 healthy
permeability. On the contrary, sodium lauryl sulfate has also volunteers was performed by Tjandrawinata et al.50 The 90% CI
been shown to inhibit drug absorption in some cases.46 How- for log-transformed test/reference drugs were 93.90%–107.09%
ever, as bisoprolol is a BCS class I drug, neither a modest reduc- for Cmax and 95.66%–107.29% forAUC0–∞ .50 With intrasubject
tion in intestinal transit time (mannitol effect), nor an increase CV of 9.49% for AUC0–t , the number of subjects were found
in its already good solubility and permeability (usual sodium adequate to confer a power of 80% and " of 0.05.50 The authors
lauryl sulfate effect) appear to pose a risk of bioinequivalence did not indicate whether or not accompanying dissolution tests
to formulations containing this API. were run.
In a further study, the BE of bisoprolol 10 mg test tablet
formulation (manufactured by Ratiopharm GmbH, Graf-Arco-
Street, Ulm, Germany) to the reference formulation (Cardi-
In Vivo BE
cor 10 mg film-coated tablets, Merck) was demonstrated in
Bioequivalence of several generic IR bisoprolol tablets has been a single dose, randomized, two-way crossover study using 28
demonstrated and the results are summarized in Table 4.33,47–58 healthy subjects.51 The 90% CIs of log-transformed ratios of
In an open, randomized three-way crossover study in 27 sub- Cmax (103.21%–114.70%) and AUC0–∞ (101.17%–109.90%) fell
jects (25 subjects completed the study), a single dose 10 mg within the acceptable range of 80%–125%.51 Dissolution pro-
bisoprolol fumarate (one 10 mg tablet or two 5 mg tablets man- files of bisoprolol 5 and 10 mg test tablets against correspond-
ufactured by Rottendorf Pharma GmbH, Ostenfelder Street, ing reference tablets were found similar and satisfactory.51 The
Ennigerloh, Germany) was shown to be bioequivalent to the ref- conditions used in these dissolution studies were not men-
erence product (Emcor 10 mg tablets; Merck, Feltham, Middle- tioned.
sex, UK). The 90% of confidence intervals (CIs) of the treatment An open, randomized, single dose, two period crossover study
ratios for log-transformed values of Cmax , AUC0–t , and AUC0–∞ used 25 healthy volunteers to compare BA of 10 mg bisopro-
for bisoprolol 10 mg tablets (1 × 10 mg tablet) were 99.9%– lol tablets (Ozone Laboratories B.V., Delft, The Netherlands)
110.8%, 95.8%–105.9%, and 95.8%–105.7%, respectively.47 For with reference tablets (Concor tablets 10 mg, Merck KGaA,
bisoprolol 5 mg tablets (2 × 5 mg tablets), the corresponding Frankfurter Straße Darmstadt, Germany).52 The 90% CI of log-
CIs for Cmax , AUC0–t , and AUC0–∞ were 94.5%–104.9%, 96.4%– transformed ratios of Cmax (96.0%–109%) and AUC0–∞ (98.0%–
106.6%, and 96.7%–106.7%, respectively.47 Dissolution in wa- 109.0%) of 24 subjects were within the acceptable range of 80%–
ter, 0.1 M HCl, pH 4.75, and pH 7.2 buffers was complete within 125%.52 Bisoprolol 5 and 10 mg test products complied with the
10–20 min, and similarity of dissolution profiles was demon- dissolution profile requirements resulting in biowaiver of biso-
strated between test and reference formulations.47 prolol 5 mg tablets based on the BE results of bisoprolol 10
A two-way crossover BE study between test formulation mg tablets.52 Although the dissolution conditions were not in-
(bisoprolol fumarate tablets manufactured by Synthon B.V., dicated, it seems likely that the compendial methods were used
Microweg, Nijmegen, The Netherlands) and reference formu- to obtain the waiver at the lower dose strength.
lation (Detensiel 10 mg tablets from Merck, Saint-Romain, A two-period crossover study under fasting conditions was
Lyon, France) was performed in 24 subjects.48 The 90% CIs of performed to compare the BA of bisoprolol film-coated test for-
the treatment ratios for log-transformed values were 95.0%- mulation (Pfizer Ltd., Great Abington, Cambridgeshire, UK)
103.0% for AUC0–∞ and 96.0%–104.0% for Cmax . Dissolution versus the reference product Emcor tablets (Merck, UK).33
profiles of bisoprolol 5 and 10 mg tablets were found to be The 90% CI for the geometric mean ratio of test/reference for
similar48 but the dissolution conditions were not mentioned. Cmax (99.17%–109.02%) and AUC0–∞ (104.18%–114.58%) were
Aurobindo Pharma Ltd. (Valletta Waterfront, Floriana, within the 80%–125% BE limits.33 The conditions and results
Malta) performed two comparative BA studies for their generic of the comparative dissolution profiles of test and reference
version of biosprolol fumarate tablets using the comparator products were not described.33
Cardicor tablets (E Merck Ltd., Feltham, Middlesex, UK).49 In a further study, the BE of a test product containing
The two strengths chosen for BE were bisoprolol 10 and 1.25 bisoprolol 10 mg of Jenson Pharmaceutical Services Ltd.
mg (2 × 1.25 mg) tablets. As the linearity of PK of bisoprolol (Barnstaple, Devon, UK) was demonstrated using Cardicor of E
in the dose range of 2.5–10.0 mg has been established,18 the Merck Ltd. as the reference product in a single dose, open label,
bisoprolol 1.25 mg tablet strength was additionally selected randomized two-period crossover study.53 The 90% CIs of the
by the sponsor as it does not fall in the published linear PK test/reference ratios of geometric means of Cmax and AUC0–∞
range.18 Both of these two-way crossover, single dose studies were 97.53%–102.47% and 94.42%–101.30%, respectively.53
were open label, randomized, and involved 28 healthy male Comparative dissolution profiles of test and reference prod-
subjects. For Study 1 on 2 × 1.25 mg tablets, the 90% CIs for ucts were described but the conditions under which they were
log-transformed Cmax and AUC0–∞ ratios were 89.52%–97.96% obtained were not specified.53
[with a coefficient of variation (CV) of 14.3% for test product Similarly, a two-way crossover, single-dose study was con-
and 15.1% for reference product] and 90.63%-96.83% (with a ducted to assess the BE of bisoprolol tablets (Ivowen Ltd.,
CV of 15.4% for test product and 16.4% for reference product), Clonmel Co. Tipperary, Ireland) with bisoprolol 10 mg ref-
respectively.49 Similarly, for Study 2 on the 10- mg tablets, the erence tablets (Concor; Merck Pharma GmbH, Germany).54
90% CIs for log-transformed values of 98.66%–107.31% for Cmax The 90% CI for Cmax (95.90%–108.48%) and AUC0–∞ (98.3%–
and 97.18%–103.04% for AUC0–∞ were obtained.49 Dissolution 109.13%) for test versus the reference product for bisoprolol

Table 4. Bioequivalence Study Results of Bisoprolol Tablets Reported in the Public Assessment Reports for Assessment of Generic Products
Strength on Test Formulation
Which BE Manufacturer or Bioequivalence
Performed Subjects License Holder Composition Reference Product Study Design Prandial Criteria/Statistics Results In Vitro Results References
1 × 10 mg 27 male and Bisoprolol 5 and Bisoprolol fumarate 5 and 10 mg Emcor 10 mg Three-way Fasting 90% confidence Bioequivalent Dissolution in 47
tablets and female 10 mg Excipients: maize starch, tablets (Merck) crossover, interval (Cmax , water, 0.1 M
DOI 10.1002/jps.23817
2 × 5 mg subjects (25 film-coated crospovidone, open, AUC0–t , HCl, pH 4.75
tablets subjects tablets microcrystalline cellulose, randomized, AUC0–" )/ANOVA and pH 7.2
completed the (Rottendorf/ anhydrous calcium hydrogen single dose buffers is rapid
study) Zanza phosphate, magnesium and complete in
Healthcare stearate, colloidal anhydrous 10–20 min.
Limited) silica, purified water, Dissolution
hypromellose, titanium profile
dioxide, macrogol 6000, similarity
dimeticone, yellow iron oxide, between test
red iron oxide and reference
formulations
demonstrated
10 mg tablets 24 male and Bisoprolol fumaraat Bisoprolol fumarate 5 and 10 mg Detensiel 10 mg Two-way Fasting 90% confidence Bioequivalent Dissolution profiles 48
female 5 and 10 mg Excipients: microcrystalline tablets (Merck crossover, open interval (Cmax , of bisoprolol 5
subjects film-coated cellulose, calcium hydrogen Lipha Sante) randomized, AUC0–t , and 10 mg
tablets (Synthon phosphate, pregelatinised single dose AUC0–" )/ANOVA tablets found
B.V.) maize starch, crospovidone, similar
colloidal anhydrous silica,
magnesium stearate,
hypromellose, macrogol 400,
titanium dioxide, iron oxide
yellow, iron oxide red
Two studies: 28 male subjects Bisoprolol fumarate Bisoprolol fumarate 1.25, 2.5, Cardicor 2.5 mg Two-way Fasting 90% confidence Bioequivalent Comparative 49
2 × 1.25 mg 1.25, 2.5, 3.75, 3.75, 5, and 10 mg and Cardicor crossover, open interval (Cmax , dissolution
tablets and 5.0, 7.5, and Excipients: microcrystalline 10 mg label, AUC0–t , profiles between
10 mg 10 mg cellulose, crospovidone, film-coated randomized, AUC0–" )/ANOVA test and
tablets film-coated calcium hydrogen phosphate tablets (E single dose reference
tablets anhydrous, magnesium Merck Ltd.) formulations
(Aurobindo stearate, colloidal anhydrous
Pharma Ltd.) silica, hypromellose, titanium
dioxide, macrogol 400
5 mg tablets 18 male and Bisoprolol fumarate – Concor 5 mg Two-way Fasting 90% confidence Bioequivalent – 50
female 5 mg (Merck) crossover, interval (Cmax ,
subjects film-coated blind, single AUC0–t ,
tablets, (PT dose AUC0–" )/ANOVA
Ferron Par
Pharmaceuti-
cals)
10 mg tablets 28 subjects Bisoprolol fumarate Bisoprolol fumarate 1.25, 2.5, Cardicor 10 mg Two-way Fasting 90% confidence Bioequivalent Dissolution profiles 51
1.25, 2.5, 3.75 and 3.75 mg Excipients: film-coated crossover, open interval (Cmax , found similar
tablets microcrystalline cellulose, tablets (Merck) label, AUC0–t , and satisfactory
(Ratiopharm colloidal anhydrous silica, randomized, AUC0–" )/ANOVA
Gmbh) croscarmellose sodium, single dose
sodium starch glycolate,
magnesium stearate
10 mg tablets 25 male and Bisoprolol fumaraat Bisoprolol fumarate 5 and 10 mg Concor 10 mg Two-way Fasting 90% confidence Bioequivalent Bisoprolol 5 and 52
female 5 and 10 mg Excipients: lactose tablets (Merck) crossover, interval (Cmax , 10 mg tablets
subjects (24 tablets (Ozone monohydrate, open, AUC0–t , complied with
subjects Laboratories microcrystalline cellulose, randomized, AUC0–" )/ANOVA dissolution
completed the B.V.) magnesium stearate, single dose profile
COMMENTARY
study) crospovidone, iron oxide requirements

Continued
385
Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

386
Table 4. Continued
Strength on Test Formulation
Which BE Manufacturer or Bioequivalence
Performed Subjects License Holder Composition Reference Product Study Design Prandial Criteria/Statistics Results In Vitro Results References
10 mg tablets – Bisoprolol 5 and Bisoprolol fumarate 5 and 10 mg Emcor 10 mg Two-way Fasting 90% confidence Bioequivalent Comparative 33
COMMENTARY
10 mg tablets Excipients: maize starch, tablets (Merck) crossover, interval (Cmax , dissolution
(Pfizer Ltd.) microcrystalline cellulose open, AUC0–t , profile between
crospovidone, anhydrous randomized, AUC0–" )/ANOVA test and
calcium hydrogen phosphate, single dose reference
magnesium stearate, colloidal products
anhydrous silica,
hypromellose, titanium
dioxide, macrogol 400, iron
oxide yellow
10 mg tablets – Bisoprolol Bisoprolol fumarate 5 and 10 mg Cardicor Two-way Fasting 90% confidence Bioequivalent Comparative 53
Fumarate 5 and Excipients: microcrystalline film-coated crossover, open interval (Cmax , dissolution
10 mg cellulose, lactose anhydrous, tablets 10 mg label, AUC0–t , profiles between
film-coated colloidal anhydrous silica, (E Merck randomized, AUC0–" )/ANOVA test and
tablets (Jenson magnesium stearate, sodium Limited) single dose reference
Pharmaceutical lauryl sulfate, iron oxide products
Services Ltd.) yellow, croscarmellose
sodium, titanium dioxide,
Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

polydextrose FCC,
hypromellose, macrogol,
tartrazine, indigo carmine
10 mg tablets – Bisoprolol Bisoprolol fumarate 2.5, 5, and Concor tablets Two-way Fasting 90% confidence Bioequivalent Comparative 54
Fumarate 2.5, 5, 10 mg Excipients: 10 mg, (Merck crossover, open interval (Cmax , dissolution
and 10 mg microcrystalline cellulose, Pharma label, AUC0–t , profiles between
tablets (Ivowen lactose monohydrate, GmbH) randomized, AUC0–" )/ANOVA test and
Ltd.) magnesium stearate, single dose reference
crospovidone, iron oxide products
10 mg tablets 26 male subjects Bisoprolol Bisoprolol fumarate 1.25, 2.5, Concor tablets Three-way Fasting 90% confidence Bioequivalent Similarity of 55
(two subjects fumaraat 1.25, 3.75, 5, 7.5, and 10 mg 10 mg, (Merck crossover, interval (Cmax , dissolution
were 2.5, 3.75, 5, 7.5, Excipients: calcium hydrogen Pharma blind, single AUC0–t , profiles between
standbyes) and 10 mg phosphate, croscarmellose GmbH) dose AUC0–" )/ANOVA bio-batch and
film-coated sodium, microcrystalline production
tablets (Hexal cellulose, hydroxypropyl batch was
AG) methylcellulose, lactose demonstrated
monohydrate, macrogol 4000, by dissolution of
magnesium stearate, maize more than 85%
starch, silicon dioxide, after 15 min
titanium dioxide, ferric oxide
10 mg tablets 28 male subjects Bisoprolol Bisoprolol fumarate 1.25, 2.5, 5, Cardicor Two-way Fasting 90% confidence Bioequivalent In vitro dissolution 56
fumarate1.25, and 10 mg Excipients: film-coated crossover, open interval (Cmax , data between
2.5, 5, and microcrystalline cellulose, tablets 10 mg label, single AUC0–t , different
10 mg anhydrous colloidal silica, (Merck Phar- dose AUC0–" )/ANOVA strengths
film-coated croscarmellose sodium, maceuticals) similar
tablets (Orifarm sodium starch glycolate,
Generics A/S) magnesium stearate
Continued
DOI 10.1002/jps.23817
COMMENTARY 387
were within BE acceptance criteria.54 Similarity in the dissolu-
References
tion of the products was indicated but the dissolution conditions
57
58
were not specified.54
In a further study, a three-way crossover study was per-
formed on 26 subjects under fasting conditions. BE was demon-
Dissolution profiles
and satisfactory
In Vitro Results
Comparative test
and reference
strated between test (Hexal AG, Industriestr, Holzkirchen, Ger-
found similar
dissolution
product
many) and reference (Concor tablets; Merck Pharma GmbH,
profiles
Germany) formulations of bisoprolol 10 mg tablets as 90%
CIs for Cmax (98.0%–104.0%) and AUC0–∞ (99.0%–106.0%) were
within the BE acceptance criteria.55 The dissolution profiles of
test and reference products were found to be comparable,55 but
Bioequivalent
Bioequivalent
the dissolution conditions were not described.

Results
Another BE study was performed between bisoprolol fu-

marate tablets of Orifarm Generics A/S and comparator prod-
uct, Cardicor film-coated tablets of 10 mg (Merck).56 The design
adopted was two-period crossover, open label, and randomized,
AUC0–" )/ANOVA
AUC0–" )/ANOVA
performed under fasting conditions. The 90% CIs for the ge-
Criteria/Statistics
interval (Cmax ,
interval (Cmax ,
Bioequivalence
ometric mean ratios of Cmax (96.69%–104.03%) and AUC0–∞

90% confidence
90% confidence
(97.94%–104.75%) for bisoprolol met the BE criteria.56 Test

AUC0–t ,
AUC0–t ,
and reference product dissolution profiles were found to be

comparable and dissolution data of different strengths were
also found similar.56 Dissolution conditions used for perform-
ing these studies were not reported.
Prandial
Fasting
Fasting
Similarly in References 56 and 57, the 90% CIs for geometric

mean ratios of Cmax (94.47%–101.81% and 103.21%–114.70%),
and AUC0–∞ (94.03%–101.98% and 101.17%–109.90%), respec-
crossover, open
tively, were found to meet BE criteria.57,58 Dissolution profiles

Study Design
randomized,
single dose
single dose
of test and reference products were found to be comparable but

crossover,
the conditions were not specified.57,58

Two-way
Two-way
label,
Dissolution
(Merck Serono)
Reference Product
The USP and FDA dissolution specification for bisoprolol

tablets 10 mg
tablets 10 mg
tablets is not less than 80% (Q) dissolved within 20 min in

film-coated
film-coated
(E Merck)
900 mL water at 75 rpm in the paddle apparatus.24

Cardicor
Cardicor
The dissolution of bisoprolol fumarate in water, 0.1 M HCl,

pH 4.75, and pH 7.2 buffers is rapid and essentially complete
within 20 min.47 Dissolution profiles of test and reference prod-
anhydrous silica, magnesium
titanium dioxide, ferric oxide

hypromellose, Macrogol 400,
ucts in these media were found similar in one of the BE studies

Excipients: microcrystalline
Bisoprolol fumarate Bisoprolol fumarate 1.25, 2.5,
Bisoprolol fumarate 1.25, 2.5,
microcrystalline cellulose,
described above.47 In another BE study, similarity of dissolu-

sodium starch glycolate,
stearate, purified water,
colloidal silicon dioxide,

cellulose, maize starch,
croscarmellose sodium,
3.75, 5, 7.5, and 10 mg
yellow, ferric oxide red

crospovidone, colloidal
tion profiles of biobatch and production scale batch was demon-

magnesium stearate
and 3.75 Excipients:
Composition
strated by virtue of more than 85% drug release after 15 min.55

In a further study, the dissolution of bisoprolol 10 mg biobatch
tablets was shown to be comparable to the bisoprolol 1.25, 2.5,
3.75, 5.0, and 7.5 mg tablets. Additionally, dissolution profiles
of test and reference products were found to be comparable.55
However, the dissolution conditions were not reported in either
of these studies. In summary, dissolution appears to be similar
1.25, 2.5, 3.75, 5,
3.75 mg tablets
Fumarate 1.25,
Test Formulation
7.5, and 10 mg
(Medreich Plc.)
Manufacturer or
License Holder
between test and reference products, when these are run in con-
Arzneimittel
film-coated
junction with the BE study, but it is often not easy to interpret

(STADA
2.5, and
tablets
Bisoprolol
the result in terms of reliability for biowaiver purposes, as the

AG)
conditions of dissolution are usually not described.
DISCUSSION
Male subjects
Subjects
Solubility
Continued
According to the solubility of 33 mg/mL reported in the litera-

ture, the dose/solubility ratio at the highest dose strength, 10
10 mg tablets
10 mg tablets
mg, of bisoprolol tablets is 0.303 mL.25 Considering the max-

Strength on
Table 4.
Performed
Which BE
imum recommended dose of 20 mg/day (which can be admin-

istered in a single dose),33,55 the dose/solubility ratio would be
0.606 mL according to this solubility value. Both of these ratios

388 COMMENTARY
are far less than the 250 mL criterion for a BCS highly soluble These findings underline a previous observation that the
drug.3,59,60 rate and extent of absorption of high-solubility/high-permeable
According to the experimental values for solubility shown drugs formulated in IR dosage forms are not influenced by
in Table 1, the solubility at pH 6.5, 6.8, and 7.5 was 831.27, excipient interactions when well-established excipients are
816.29, and 836.73 mg/mL, respectively. However, because of used.67
the significant pH change in 1.2 and 4.5 pH media post drug
addition, the solubility values obtained in Table 1 for these Surrogate Techniques for In Vivo BE Testing
two pH media should not be used for the dose/solubility ratio
calculation. As a result of its BCS characteristics, the BA of bisoprolol may
Bisoprolol fumarate is a weak base and ionizes in acidic con- be limited by gastric emptying, in vivo disintegration, and/or
ditions. Because of its higher solubility at lower pH values, a dissolution. However, according to the dissolution specification
large quantity of drug will dissolve under acidic conditions and of USP and FDA, bisoprolol tablets should release at least 80%
this can have an influence on the pH of the medium. To main- of their contents in 20 min, in water. So, it seems safe to as-
tain the acidic pH, an impractically high concentration of the sume, that if bisoprolol tablets are able to dissolve rapidly (Q >
buffer would have to be used. Therefore, the goal of the solu- 85% in 30 min) within the physiological pH range, absorption
bility experiments reported in Table 2 was not to find the true will be limited only by gastric emptying and not by disinte-
thermodynamic equilibrium solubility in pH 1.2 and pH 4.5, gration/dissolution or permeability. Moreover, comparative in
but to demonstrate that more than the highest daily dose could vitro dissolution testing in different pH 1.2, 4.5, 6.8, as rec-
be dissolved in less than 250 mL of buffers having an initial pH ommended by the various BCS guidance documents, appears
in the range of 1.2–4.5. According to Henderson–Hasselbalch to provide reasonable assurance for BE of the product.3,59,60
equation, the solubility of weak base will be higher at lower Indeed, similarity of dissolution profiles between test and ref-
pH values, so at pH less than 4.5, the solubility at 37◦ C should erence products in various BE studies was reported in several
also meet the “highly soluble” criteria. The theory was con- of the BE studies summarized in this monograph, including
firmed by the experimentally determined solubility values of one study that used the three buffers recommended by the
approximately 6 mg/mL in pH 1.2 and 4.5 media (Table 2). guidance.33,47,49,51,53–55,58
The dose/solubility ratio corresponding to this solubility value
for the highest recommended daily dose of 20 mg is 3.33 mL, Patient’s Risks Associated with Bioinequivalence
which is much lower than the 250-mL limit. Therefore, biso-
An inappropriate biowaiver decision for a product that is not
prolol fumarate can be unequivocally categorized as a highly
bioequivalent with the reference product may result in four
soluble drug.
possible scenarios as described below.
Absorption and Permeability
Lower AUC than Reference Product
As its BA is about 90% following oral administration, biso-
prolol can be considered highly permeable according to WHO, In general, a lower AUC can result in the product being clini-
EMA, and FDA BCS criteria. This is underlined by its per- cally less effective, which in life threatening diseases can have
meability coefficient, which is greater than the range of 1 × serious implications. Medical attention is to be sought immedi-
10−6 –10 × 10−6 cm/s values generally considered to imply high ately in such cases. Periodic monitoring for prescription drugs
permeability.61–64 Further, bisoprolol is not a substrate for P- will lead to adjustment of dose by the physicians.
glycoprotein efflux protein.38
Higher AUC than Reference Product
BCS Classification
In general, a higher AUC can result in unwanted side effects
The data presented above classify bisoprolol unequivocally in and toxicity.
BCS class I. Bisoprolol was also assigned to BCS class 1 by However, bisoprolol is a safe drug with a high therapeutic
Kaunzinger et al.38 and Ramirez et al.65 index and supra-BA is not a critical factor.13–16 Further, the
patient leaflet provides the details of symptoms that should
Risks with Respect to Excipient and/or Manufacturing Variations
be immediately brought to the physician’s notice. In long-term
The excipients used in bisoprolol conventional tablets and their clinical trials of 6–24 months duration, bisoprolol was found to
usual quantities used in conventional IR tablets are shown in be well tolerated by most patients.68 The most commonly ad-
Table 3. By virtue of their MAs and national regulations, these verse reactions reported were giddiness, headache, and tired-
products may be inferred to have successfully passed an in vivo ness during the first few weeks of therapy, which subsided with
BE criteria. However, it cannot be taken for granted that every continued therapy.23 Tolerability of bisoprolol 5–20 mg/day was
registered product has successfully met the current in vivo BE comparable to atenolol 50–100 mg/, metoprolol 100 mg/day,
criteria, as some may have been approved at a time when BE and verapamil 240–360 mg/day. Its tolerability was superior
criteria were not as stringent.66 Nevertheless, it seems safe to to nifedipine SR 40–80 mg/day.69
conclude that the risk of bioinequivalence caused by an excip- The $1 -selectivity of bisoprolol is higher in comparison to
ient effect is low for the excipients that are present in several other $1 -selective $-blockers such as atenolol, metoprolol, and
drug products registered in ICH countries, as long as these ex- betaxolol.70,71 Higher $1 selectivity infers minimization of the
cipients are present in amounts not exceeding usual levels in side effects that might occur from administration of nonspecific
IR tablets. For bisoprolol, this also appears to be the case for $-blockers. Compared with propranolol, bisoprolol was found
two excipients that are usually regarded as “critical,” that is, to have less sedative effects and only slightly reduced glucose
mannitol and sodium lauryl sulfate. tolerance.37

COMMENTARY 389
Lower and Higher Cmax than Reference Product 5. Konishi M, Haraguchi G, Kimura S, Inagaki H, Kawabata M,
Hachiya H, Hirao K, Isobe M. 2010. Comparative effects of carvedilol vs
Differences in Cmax of therapies for chronic ailments will have bisoprolol for severe congestive heart failure. Circulation J 74(6):1127–
few clinical implications.72 Hence, the impact of small differ- 34.
ences in Cmax in a single dose study between the test and refer- 6. Salpeter S, Ormiston T, Salpeter E. 2005. Cardioselective beta-
ence products of bisoprolol are not expected to have any major blockers for chronic obstructive pulmonary disease. Cochrane Database
impact on the therapeutic outcome under the steady-state con- Syst Rev 4:CD003566.
ditions of clinical use. 7. Ishiguro H, Ikeda T, Abe A, Tsukada T, Mera H, Nakamura K, Yusu
S, Yoshino H. 2008. Antiarrhythmic effect of bisoprolol, a highly selec-
tive beta1-blocker, in patients with paroxysmal atrial fibrillation. Int
CONCLUSIONS Heart J 49(3):281–293.
8. Plewan A, Lehmann G, Ndrepepa G, Schreieck J, Alt EU, Schomig A.
Biopharmaceutics Classification System class I drugs are eli- 2001. Maintenance of sinus rhythm after electrical cardioversion of per-
gible for biowaiver according to all guidance documents.3,59,60 sistent atrial fibrillation; sotalol vs bisoprolol. Eur Heart J 22(16):1504–
Bisoprolol, with its high solubility and high permeability, thus 1510.
qualifies for the consideration of the biowaiver. Because of its 9. Hiltunen TP, Suonsyrja T, Hannila-Handelberg T. 2007. Predic-
tors of antihypertensive drug responses: Initial data from a placebo-
broad therapeutic index and lack of severe side effects, even
controlled, randomized, crossover study with four antihypertensive
in the unlikely event of an incorrect biowaiver decision, pa- drugs (The GENRESStudy). Am J Hypertens 20(3):311–318.
tients would not be subjected to undue risk. However, the test 10. Neutel JM, Smith DHG, Ram CV. 1993. Application of ambulatory
products should be evaluated against the reference product in blood pressure monitoring in differentiating between antihypertensive
comparative in vitro dissolution tests, and only excipients com- agents. Am J Med 94:181–187.
monly used in the IR dosage form of that product, such as those 11. Deary AJ, Schumann AL, Murfet H, Haydock S, Foo RS-Y, Brown
shown in Table 3, should be used. MJ. 2002. Double blind, placebo controlled crossover comparison of five
A biowaiver for IR solid dosage form of bisoprolol present classes of antihypertensive drugs. J Hypertens 20:771–777.
in the same fumarate salt form are scientifically justified sub- 12. Schliep HJ, Harting J. 1984. $1 -selectivity of bisoprolol, a new
jected to following conditions: (1) the test product contains only $-adrenoceptor antagonist in anesthetised dogs and guinea pigs.
J Cardiovasc Pharmacol 6:1156–1160.
excipients that are well known and used in normal amounts, for
13. Summary of product characteristics. Bisoprolol, Merck 1.25
example, those tabulated for products with MA in ICH and as- mg film-coated tablets. 2012. Accessed November 8, 2012, at:
sociated countries and (2) both the test and comparator dosage http://www.lakemedelsverket.se/LMF/Lakemedelsinformation/
form are very rapidly dissolving, or, rapidly dissolving with sim- ?nplid=19990604000392 &type=product.
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1.2, 4.5, and 6.8. cation to indication. Eur Heart J Suppl 8 Suppl C:C19–C27.
15. Brodde OE, Kroemer HK. 2003. Drug-drug interactions of beta-
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ACKNOWLEDGMENTS 16. Bonelli J, Staribacher H. 1986. Hemodynamic effects of bisoprolol
in patients with coronary heart disease: Influence of various bisoprolol
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Group BCS and Biowaiver, www.fip.org/bcs. This article reflects 17. Höffler D. 1988. Zur Monotherapie der hypertonie mit einem lang
the scientific opinion of the authors and not necessarily the wirksamen betablocker. Therapiewoche 38:391.
policies of the regulating agencies, the FIP, RIVM, ANVISA, or 18. Leopold G. 1986. Balanced pharmacokinetics and metabolism of
the World Health Organization (WHO). bisoprolol. J Cardiovasc Pharmacol 8 (Suppl 11):S16–S20.
19. Leopold GPJ, Ungethüm W, Bühring KU. 1986. Basic pharmacoki-
netics of bisoprolol, a new highly $1-selective adrenoceptor antagonist.
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COMMENTARY

Biowaiver Monograph for Immediate-Release Solid Oral Dosage

Received 9 October 2013; revised 20 November 2013; accepted 20 November 2013

Pharm Sci 103:378–391, 2014

378 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

angiotensin converting enzyme inhibitors, diuretics and option-

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Hydrochloric acid (0.1N) 1.2 6.1 6.2 795 ± 15

Hydrochloric acid (0.1N) 1.2 1.4 1.4 310 ± 5

reported to be 4.8 and 2.5, respectively.18,30 The lipophilicity of 14

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

Calcium carbonate CZ[1] DE[2] SK[3] 8.6—350

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Magnesium stearate BE[4–8,158–163] CA[9–14,157,164–166] CZ[1,15–18,167–171,269] 0.15–401a

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

study) crospovidone, iron oxide requirements

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

were within BE acceptance criteria.54 Similarity in the dissolu-

the dissolution conditions were not described.

Another BE study was performed between bisoprolol fu-

ometric mean ratios of Cmax (96.69%–104.03%) and AUC0–∞

(97.94%–104.75%) for bisoprolol met the BE criteria.56 Test

and reference product dissolution profiles were found to be

Similarly in References 56 and 57, the 90% CIs for geometric

tively, were found to meet BE criteria.57,58 Dissolution profiles

of test and reference products were found to be comparable but

the conditions were not specified.57,58

The USP and FDA dissolution specification for bisoprolol

tablets is not less than 80% (Q) dissolved within 20 min in

900 mL water at 75 rpm in the paddle apparatus.24

The dissolution of bisoprolol fumarate in water, 0.1 M HCl,

titanium dioxide, ferric oxide

ucts in these media were found similar in one of the BE studies

Bisoprolol fumarate 1.25, 2.5,

described above.47 In another BE study, similarity of dissolu-

colloidal silicon dioxide,

yellow, ferric oxide red

tion profiles of biobatch and production scale batch was demon-

strated by virtue of more than 85% drug release after 15 min.55

junction with the BE study, but it is often not easy to interpret

the result in terms of reliability for biowaiver purposes, as the

conditions of dissolution are usually not described.

According to the solubility of 33 mg/mL reported in the litera-

mg, of bisoprolol tablets is 0.303 mL.25 Considering the max-

imum recommended dose of 20 mg/day (which can be admin-

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014 DOI 10.1002/jps.23817

DOI 10.1002/jps.23817 Charoo et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:378–391, 2014

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