Journal of Drug Delivery Science and Technology 57 (2020) 101728

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Journal of Drug Delivery Science and Technology

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Transverse comparison of mannitol content in marketed drug products: T

Implication for no-effect dose of sugar alcohols on oral drug absorption
Kazuki Matsuia,b,∗, Susumu Takeuchib,1, Yuka Harunaa,c, Miki Yamaneb, Takahiro Shimizua,d,
Yoshiki Hatsumaa,e, Norihito Shimonoa,f, Machiko Sunadaa,g, Masakane Hayakawaa,h,
Tomo Nishidaa,i, Shusei Itoa,j, Masashi Idea,k, Maki Seinoa,l, Masahisa Sugiharaa,b,
Yasushi Minagawaa,m, Hidehisa Tachikia,c
a
Pharmaceutical Technology Committee, Japan Generic Medicines Association, 3-3-4 Nihonbashi-honcho, Chuo-ku, Tokyo, 103-0023, Japan
b
Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka, 532-0003, Japan
c
Towa Pharmaceutical Co., Ltd., 2-11, Shinbashi-cho, Kadoma, Osaka, 571-8580, Japan
d
Fuji Pharma Co., Ltd., 447-1 Mizuhashi-nakamura, Toyama, 939-3551, Japan
e
Kobayashi Kako Co., Ltd., 5-15, Yachi, Awara, Fukui, 919-0603, Japan
f
Kokando Pharmaceutical Co., Ltd., 2-8-27, Nagasuhondori, Amagasaki, Hyogo, 660-0803, Japan
g
Kyorin Rimedio Co., Ltd., 11, Office Park, Takaoka, Toyama, 939-1119, Japan
h
Kyowa Pharmaceutical Industry Co., Ltd., 3-2-4, Nakanoshima, Kita-ku, Osaka, 530-0005, Japan
i
Mylan Seiyaku Ltd., 5-11-2, Toranomon, Minato-ku, Tokyo, 105-0001, Japan
j
Nihon Generic Co., Ltd., 7, Wadai, Tsukuba, Ibaraki, 300-4247, Japan
k
Nihon Pharmaceutical Industry Co., Ltd., 1281, Isabu, Inashiki, Ibaraki, 300-0603, Japan
l
Nissin Pharmaceutical Co., Ltd., 2-3-1, Shogehigashi, Tendo, Yamagata, 994-0069, Japan
m
Takata Pharmaceutical Co., Ltd., 1-11-1, Numakage, Minami-ku, Saitama, 336-8666, Japan

ARTICLE INFO ABSTRACT

Keywords: Some of pharmaceutical excipients are known to affect oral drug absorption via various mechanisms. Among
Bioequivalence diverse excipients, sugar alcohols (e.g. mannitol and sorbitol) are regarded as critical excipients that significantly
BCS alter drug absorption by osmotic effect. This recognition is based on the previous findings that several grams of
Biowaiver sugar alcohols exhibited clear impact on the bioavailability/bioequivalence of certain drugs. However, com-
Sugar alcohols
monly administered oral drug products contain less amount of sugar alcohol, thus, such a significant impact on
Osmolality
drug absorption is questionable. The purpose of this research was to retrospectively estimate the no-effect dose
of mannitol that may not affect oral absorption of BCS class I and III drugs. Mannitol content in marketed oral
drug products (16 active pharmaceutical ingredients, 132 drug products) was quantified by means of reverse
engineering or questionnaire survey to 11 generic drug manufacturers headquartered in Japan. The transverse
comparison suggested that “practical” amount of mannitol may not have significant impact on oral absorption of
investigated molecules. This implication can be utilized to determine a no-effect threshold of sugar alcohol in the
context of BCS-based biowaiver guideline as well as other guidelines such as formulation change and pharma-
ceutical line extension.

1. Introduction hurdles to be cleared. Subsequent barrier is intestinal permeation

Oral route is by far the most convenient and preferred route of drug
administration. In the meantime, orally administered drugs should
overcome several obstacles before they reach systemic circulation to
exhibit their pharmacological effect. For oral dosage form, disintegra-
tion and dissolution in the gastrointestinal (GI) tract are the first
through epithelial cell membrane. Moreover, intestinal and liver me-
tabolisms are to be other factors that limit oral bioavailability. Since
each active pharmaceutical ingredient (API) possesses different physi-
cochemical and pharmacokinetic properties, rate-determining steps for
their oral drug absorption differ from case to case.
Since 1995, Biopharmaceutical Classification System (BCS) has been

∗
Corresponding author. Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka, 532-0003, Japan.
E-mail address: kazuki.matsui@sawai.co.jp (K. Matsui).
1
Current Affiliation: Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan

https://doi.org/10.1016/j.jddst.2020.101728
Received 5 February 2020; Received in revised form 25 March 2020; Accepted 3 April 2020
Available online 03 April 2020
1773-2247/ © 2020 Elsevier B.V. All rights reserved.
K. Matsui, et al.
recognized as a reliable framework to estimate the rate-determining
processes for oral drug absorption [1]. BCS classifies APIs into four
categories considering their solubility across physiological GI pH range
and intestinal permeability. Highly soluble drugs, which are classified
into BCS class I (high permeability) or III (low permeability), are less
likely to show solubility-limited absorption, and thus, are expected to
have low solubility-derived risk. Therefore, in certain circumstances, a
waiver of human bioavailability/bioequivalence (BA/BE) study can be
granted for these highly soluble drugs (BCS-based biowaiver) [2–4].
This BCS-based biowaiver approach permits applicants to waive human
clinical study to demonstrate BE of test formulation against reference
formulation, provided that reference and test formulation contain BCS
class I or III drugs and fulfill certain criteria for dissolution profiles and
excipient changes [5].
Depending on the magnitude of concerns about false-positive risk,
requirement for BCS-based biowaiver differs by BCS classes. With re-
spect to the requirement for excipient changes, drug formulation con-
taining BCS class I drug accepts wide range of difference except for
certain excipients which may affect oral drug absorption. Whereas, BCS
class III formulation must fulfill restricted excipient changes criteria
(i.e. qualitatively the same and quantitatively very similar, according to
US FDA guidance) to be eligible for BCS-based biowaiver [4]. The
narrower eligibility for BCS class III drugs may reflect the concerns that
drug absorption of lowly permeable APIs can be fairly impacted by
certain excipients [6]. In the current BCS-based biowaiver guidelines,
several excipients are regarded as “critical excipients” which alter oral
drug absorption. For these critical excipients, restrictive criteria for
allowable difference are applied regardless of BCS classes, making it
difficult to change the type, grade, and amount of these excipients in
oral dosage forms to maintain eligibility for BCS-based biowaiver.
As one of such critical excipients, sugar alcohols (e.g. sorbitol and
mannitol) are reported to reduce oral bioavailability of certain drugs
[7]. According to the previous findings, significant effect of sugar al-
cohols on drug absorption has been reported only when huge amount of
sugar alcohols was used in their investigations [8–11]. Table 1 sum-
marizes the scientific literatures which report the effect of sugar alcohol
on drug absorption. These observations indicate that more than 2 g of
sugar alcohols may have some impact on the absorption of BCS class I
and III drugs. However, conventional solid oral dosage forms such as
tablet, capsule, and fine granules have less sugar alcohol content in
most cases. Therefore, it is questionable whether “practical” amount of
sugar alcohols in marketed oral dosage forms may have any impact on
drug absorption.
Among sugar alcohols, mannitol is a frequently employed pharma-
ceutical excipient [12]. Mannitol enables very rapid disintegration due
to its highly soluble property, thus, is a preferable filler for orally dis-
integrating (orodispersible) tablet (ODT). In Japan, ODTs are often
developed not only by innovator drug industries but also by generic
drug industries as a pharmaceutical line extension strategy. Therefore,
there are many drug products on the market, and all of them are
Table 1
Reported effect of sugar alcohols on oral drug absorption.
Target drug (BCS class) Investigated excipient Weight dose of excipient (g)
Cimetidine (III) Mannitol 2.264
Ranitidine hydrochloride (III) Sorbitol 1.25
2.25
5 −44% (solution)
Metoprolol tartrate (I) Sorbitol 5 −7% (solution)
Theophylline (I) Sorbitol 10
Lamivudine (III) Sorbitol 3.2
10.2
13.4
2
Journal of Drug Delivery Science and Technology 57 (2020) 101728
confirmed to be bioequivalent even though they contain different
amount of mannitol. Diverse range of mannitol content in marketed
drug products may suggest the acceptable range of sugar alcohols that
does not affect BE study outcomes. In this study, mannitol content in
marketed drug products of BCS class I and III drugs was robustly in-
vestigated by means of reverse engineering and questionnaire survey to
11 generic drug manufacturers headquartered in Japan. This transverse
comparison of mannitol content in marketed oral drug products enables
us to estimate a threshold which may or may not impact on oral drug
absorption.
2. Materials and methods
2.1. Chemicals
D-Mannitol (purity >98%) was purchased from Sigma Aldrich
(Tokyo, Japan). Acetonitrile (HPLC grade) was obtained from Fujifilm
Wako Pure Chemical (Osaka, Japan) and used as received. Innovator
drug products of amlodipine besylate ODT 5 mg (AMLODIN® ODT
5 mg), donepezil hydrochloride ODT 5 mg (ARICEPT® D 5 mg), done-
pezil hydrochloride dry syrup 1% (ARICEPT® dry syrup 1%), mon-
telukast sodium ODT 10 mg (KIPRES® ODT 10 mg), and olopatadine
hydrochloride ODT 10 mg (ALLELOCK® ODT 10 mg) were purchased
from Japanese drug market.
2.2. Selection of target APIs
Since this study was intended to investigate the effect of sugar al-
cohols on oral absorption of BCS class I and III drugs, other BCS classes
(BCS class II and IV drugs) were excluded from analysis. BCS class I and
III drugs were picked up from BCS database provided by Drug Delivery
Foundation (DDF, http://www.ddfint.org), and only APIs, of which
generic drug products are available in Japanese market, were chosen
for analysis.
2.3. Reverse engineering of mannitol content
Reverse engineering technology was applied to innovator drug
products which are labeled to contain mannitol in the medication
package inserts. Mannitol content was quantified by HPLC-RID (re-
fractive index detector) method as previously described [13]. Briefly,
each drug product was suspended in distilled water for over 30 min.
After that, 1 mL of suspension was filtered through 0.45 μm PVDF
membrane filter (GL Sciences, Tokyo, Japan), and an aliquot of 300 μL
of each filtrate was diluted by 700 μL of acetonitrile. After sufficient
mixing, 100 μL of the reconstituted sample was injected into HPLC-RID
system consisted of a pump (Agilent 1290 Infinity, G4220A, Agilent
Technologies, CA, USA), an auto injector (Agilent 1290 Infinity,
G1316C), and a refractive index detector (Agilent 1260 Infinity,
G1232A). The chromatographic peak of mannitol was separated and
Pharmacokinetic parameters (dosage form) Reference
AUC Cmax
−28.7% (solution) −54.3% (solution) Adkin et al. [9]
−30.5% (tablet) −48.8% (tablet)
−7% (solution) −7% (solution) Chen et al. [10]
−25% (solution) −30% (solution)
−51% (solution)
−23% (solution)
+7% (tablet) +5% (tablet) Fassihi et al. [8]
−19.7% (solution) −27.6% (solution) Adkison et al. [11]
−39.2% (solution) −52.1% (solution)
−44.3% (solution) −54.6% (solution)
K. Matsui, et al. Journal of Drug Delivery Science and Technology 57 (2020) 101728

identified using COSMOSIL Sugar-D Packed Column (250 × 4.6 mm Table 2

i.d., Nakarai Tesque, Kyoto, Japan) with isocratic mobile phase com- Dose strengths, estimated BCS classification, elimination half-life, and com-
positions of acetonitrile: water (70: 30, v/v) at a flow rate of 1 mL/min. pendial dissolution profile of investigated active pharmaceutical ingredients.
The temperature of column oven and RI cell were set at 30 °C. Quan- Active Dose BCS classa Elimination Dissolution
titation assay was conducted in triplicate, and data were expressed as pharmaceutical strength half-life (hr)b rateb
mean ± standard deviation. ingredients (mg)

Amlodipine 5 1 38.1 VR (pH 6.8,

2.4. Questionnaire survey besylate 100 rpm)
Cetirizine HCl 10 1 8.4 VR
Eleven generic drug industries were involved in questionnaire Donepezil HCl 5 1 66.2 VR
Fexofenadine HCl 60 1 3.1 VR (pH 6.8)
survey. All of them are/were member companies of Pharmaceutical
Montelukast Na 10 1 4.7 R (Purified
Technology Committee, Japan Generic Medicines Association (JGA) as water)
of May 31st, 2017. Each industry was requested to provide quantitative
information on several pharmaceutical excipients (mannitol, poly- Alendronate Na 35 3a 1.5 VR
ethylene glycol 400 (PEG400), and sodium lauryl sulfate (SLS)) in their hydrate
b
Entecavir hydrate 0.5 3 46.5 VR
generic drug products. PEG400 and SLS are known to affect oral drug
Famotidine 20 3c 3.0 VR
absorption via various mechanisms [14,15], thus, they may hamper or Imidapril HCl 5 3 1.6 R
enhance the function of mannitol. Other essential information such as Losartan K 100 3 1.8 R (pH 6.8)
API content, total formulation weight, and type of dosage form were Nizatidine 150 3 1.5 VR
Olopatadine HCl 5 3 5.8 VR
also collected. Percentage of mannitol content to total formulation
Pravastatin Na 10 3 1.8 VR
weight was calculated and expressed as w/w%. All generic drug pro- Na Risedronate 2.5 3 5.4 VR
ducts provided in this survey were demonstrated to be bioequivalent in hydrate
clinical BE studies according to Japanese guideline for bioequivalence Sumatriptan 50 3 2.1 VR
studies of generic products (i.e. the 90% confidence interval of the ra- Zolpidem tartrate 10 3 2.4 VR

tios of log-normalized AUC and Cmax fall within 80–125%) [16]. All
clinical studies were approved by Ethics Committees at each facility.
Collected information was listed in a blinded manner to mask the
manufacturer of each drug product. For this blind purpose, drug pro-
ducts that are launched only by one or two generic industries were
excluded from analysis.
3. Results
In total, 16 APIs, 132 drug products were investigated in this study.
BCS class of these APIs was estimated based on the DDF database or
other published literatures. It was revealed that 5 APIs are classified
into BCS class I, and 11 APIs are BCS class III. The list of investigated
APIs along with physicochemical and pharmacokinetic properties was
presented in Table 2. Since these APIs are highly soluble, innovator
drug products of each API exhibited very rapid or rapid dissolution
profiles in overhead paddle dissolution apparatus with 900 mL of test
media.
Reverse engineering by HPLC-RID well quantified the actual man-
nitol content in certain drug product in which mannitol content is al-
ready known (127 ± 4.0 mg as measured value and 121.5 mg as actual
content), indicating the acceptable accuracy (+4.5%) of the assay. This
quantification method was successfully applied to estimate the man-
nitol content in 5 innovator drug products. Mannitol content in in-
novator drug products of amlodipine besylate (AMLODIN ® OD 5 mg),
donepezil hydrochloride (ARICEPT ® ODT 5 mg and 0.5 g of 1% dry
syrup), montelukast sodium (KIPRES ® ODT 10 mg), and olopatadine
hydrochloride (ALLELOCK ® ODT 5 mg) was determined to be
84.9 ± 3.3 mg, 158 ± 6.5 mg, 236 ± 4.7 mg, 18.0 ± 0.67 mg, and
196 ± 5.9 mg, respectively. As for the quantitation in generic drug
products, questionnaire survey was conducted within the framework of
JGA. Pharmaceutical industries participated in this survey launch
generics of the same APIs, thus, full disclosure of pharmaceutical ex-
cipients in their marketed drug products was not possible due to con-
fidentiality reasons. All collected data and measured mannitol content
in innovator drug products were presented in supplemental material
(Supplemental Tables 1~16).
As shown in Table 3, diverse range of mannitol content in in-
vestigated drug products was observed. It was also found that w/w% of
mannitol diverged from 0 up to 94%, indicating that most portion of
formulation weight is derived from mannitol when it is blended as a
main filler. Among investigated APIs, none of drug products of
a
, BCS class was estimated based on the DDF database (http://www.ddfint.org)
otherwise noted.
b
, Elimination half-life and dissolution profile were obtained from medical
package insert or drug interview form. VR indicates very rapid dissolution
(>85% in 15 min), whereas, R indicates rapid dissolution (>85% in 30min) in
both pH 1.2 and pH 6.8 media (900 mL) at the paddle revolution speed of
50 rpm otherwise noted.
a
, Biernacka et al. [17].
b
, Jung et al. [18].
c
, Ono et al. [19].
cetirizine hydrochloride, losartan potassium, nizatidine, and suma-
triptan contains mannitol. Since eight out of nine drug products of ce-
tirizine hydrochloride, all four products of losartan potassium, all four
of nizatidine, and all four of sumatriptan are not ODTs but conventional
dosage forms (immediate release tablets (IRTs) or capsules), mannitol
was not blended for the purpose of instant disintegration. Besides these
four APIs, wide range of mannitol content was observed no matter
whether investigated APIs are BCS class I or III (Figs. 1 and 2). As ex-
pected, all oral solid dosage forms contain less than 250 mg of mannitol
as a filler in order to fit within patient-friendly tablet size. These
amounts are clearly lower than previously examined dose (i.e. several
grams of mannitol which exhibited clear impact on oral drug absorption
as shown in Table 1). As for other dosage forms (fine granules, oral
jelly, and dry syrup), several hundred milligrams of mannitol was
blended for their bulky property, but was still low in value.
4. Discussion
It has been argued that the possible mechanism of impaired drug
absorption by sugar alcohols is not the reduction in intestinal drug
permeability, but their osmotic effect on the GI physiology [7]. Several
research groups revealed that sugar alcohol solution retains high os-
molality, which induces water secretion into the intestinal lumen after
oral intake [20–22]. Increased intraluminal fluid volume dilutes its
solute, which results in less concentration gradient across intestinal
epithelial membrane, and subsequently, impairs intestinal absorption
rate of the solute. In addition, it was also reported that sugar alcohols
reduce intestinal transit time in a dose-dependent manner [23,24],
which leads to shorten absorption window in the GI tract. By these
mechanisms, sugar alcohols exert their suppressive effect on oral drug
absorption.

3
K. Matsui, et al. Journal of Drug Delivery Science and Technology 57 (2020) 101728

Table 3
Range of mannitol content and w/w% of mannitol in investigated drug products.
Active pharmaceutical ingredients Mannitol Number of investigated drug products

(mg) (w/w%) IRT ODT CAP FG DS OJ Total

Amlodipine besylate 0–126 0–78 7 6 – – – 1 14

Cetirizine HCl 0 0 8 1 – – – – 9
Donepezil HCl 0–480 0–94 6 5 – 1 1 – 13
Fexofenadine HCl 0–843 0–84 7 4 – – 2 – 13
Montelukast Na 0–246 0–68 7 4 – – – – 11

Alendronate Na hydrate 0–86 0–49 5 – – – – – 5

Entecavir hydrate 0–50 0–50 5 1 – – – – 6
Famotidine 0–132 0–68 3 3 – 2 – – 8
Imidapril HCl 0–71 0–89 5 – – – – – 5
Losartan K 0 0 4 – – – – – 4
Nizatidine 0 0 – – 4 – – – 4
Olopatadine HCl 0–543 0–89 6 5 – 2 – – 13
Pravastatin Na 0–150 0–88 8 – – – – – 8
Na Risedronate hydrate 0–53 0–47 5 – – – – – 5
Sumatriptan 0 0 4 – – – – – 4
Zolpidem tartrate 0–169 0–63 9 2 – – – – 11

IRT; immediate release tablet (conventional), ODT; oral disintegration tablet, CAP; capsule, FG; fine granules, DS; dry syrup, OJ; oral jelly.

Fig. 1. Mannitol content in innovator and generic drug products of BCS class I
drugs. Black, red, green, blue, and orange circles indicate immediate release
tablet, oral disintegration tablet, oral jelly, fine granules, and dry syrup, re-
spectively. (For interpretation of the references to colour in this figure legend,
the reader is referred to the Web version of this article.)

Theoretically, sugar alcohols may be problematic for BCS class III

drugs because luminal fluid volume and intestinal residence time are
key determinant factors for the rate and extent of oral absorption of BCS
class III drugs. Fig. 2 depicts that at least 50 mg difference in mannitol
content have been widely observed among different BCS class III drugs
in our study. Therefore, 50 mg of sugar alcohol could be a provisional
no-effect threshold on oral drug absorption. The maximum content of
mannitol among investigated BCS class III drug products in this study
was 543 mg of olotapadine hydrochloride fine granules (Table 3,
Fig. 2). Though olopatadine hydrochloride is classified into BCS class
III, its oral bioavailability is reported to be moderate in preclinical
animals (60.8, 74.2, 83.3, 102% in rat, guinea pig, dog, and monkey,
respectively) [25]. Considering its fairly rapid appearance in plasma
(0.8 h as Tmax), it may possess class boundary permeability. In this
sense, it may not be appropriate to argue the acceptable amount of
mannitol for all BCS class III drugs by just one example of olopatadine
hydrochloride (543 mg). From a conservative point of view, several
hundred milligrams of sugar alcohol still remain skeptical. To address
this uncertainty, mechanistic approach (e.g. sensitivity analysis per-
formed by physiologically-based biopharmaceutics model, PBBM) could
be worthy of further investigation.
As for BCS class I drugs, they are instantly absorbed from GI lumen,
hence, neither increased luminal fluid volume nor shorten intestinal
Fig. 2. Mannitol content in innovator and generic drug products of BCS class 3
drugs. Black, white, red, and blue circles indicate immediate release tablet,
capsule, oral disintegration tablet, and fine granules, respectively. (For inter-
pretation of the references to colour in this figure legend, the reader is referred
to the Web version of this article.)
transit time affect their rate and extent of oral absorption. This theory is
in line with our observations in which plenty amount of mannitol (up to
843 mg of fexofenadine hydrochloride dry syrup) did not affect BE
outcomes of BCS class I drugs (Table 2, Fig. 1). However, it should be
taken into consideration that Cmax can significantly fluctuate if BCS
class I drugs have short elimination half-life. It has been reported that
Cmax of BCS class I molecules having short elimination half-life (<3 h)
is very sensitive to tiny difference in dissolution rate and physiological
variations in the GI tract [26,27]. Considering these reports, not only
intestinal permeability but also elimination half-life should be of con-
cern to presume the osmotic effect on BE of certain molecule. In this
study, the shortest elimination half-life of investigated BCS class I drugs
was 3.1 h of fexofenadine hydrochloride of which maximum difference

4
K. Matsui, et al.
in mannitol content was 843 mg, suggesting that typical amount of
mannitol does not have significant impact on pharmacokinetic profile
of BCS class I drugs having short elimination half-life. Yet, there is still
some room for further investigation to clarify the acceptable range of
mannitol content in drug products of BCS class I molecules with ex-
tremely short elimination half-life (e.g. < 1 h).
Since this study compared mannitol content across innovator and
several generic drug products manufactured by different pharmaceu-
tical industries, it should be acknowledged that mannitol content may
not be the sole difference between these drug products. For example, it
can be anticipated that API particle size distribution may be different as
each manufacturer may have purchased API from different suppliers.
However, in this study, comparative analysis was performed only for
highly soluble drugs (BCS class I and III). Accordingly, most of in-
vestigated drug products exhibit very rapid (>85% within 15 min) or
rapid dissolution (>85% within 30 min) profiles (Table 2). Therefore,
it is not likely that drug dissolution can be altered by API particle size,
indicating that different particle size distribution should be negligible
to investigate mannitol effect in this study.
Another limitation of this survey is that each drug product may
contain various types and different amount of excipients besides man-
nitol. Some of pharmaceutical excipients are reported to alter drug
absorption via various mechanisms [6,14,28–31]. In this study, all
pharmaceutical excipients in each drug product were not disclosed due
to confidential issues. Nonetheless, two major critical excipients,
PEG400 and SLS, were also quantitatively analyzed in our survey. It
was found that none of investigated drug products contains sufficient
amount of PEG400 or SLS (Supplemental Table 1~16) except for one
drug product (14 mg of SLS in amlodipine besyl oral jelly). Therefore,
although the possibility of interruptive effect by other excipients cannot
be completely ruled out, it is likely that mannitol effect on oral ab-
sorption may not be prominent if it falls within the range of “practical”
amount.
In the current guidelines of BCS-based biowaiver, sugar alcohols are
regarded as critical excipients so that quantitative similarity between
reference and test formulation must be fulfilled in order to be eligible
for biowaiver [2–4]. However, our study revealed that 12 out of 16 APIs
had several oral drug products those are different in mannitol content
each other, but demonstrated to be BE. All investigated drug products
contain lower amount of mannitol than the amount which was pre-
viously shown to impair drug absorption. It was also found that ap-
proximately 50 mg difference in mannitol content has been widely
observed among different BCS class I and III drugs, indicating that
50 mg could be a provisional no-effect dose. In addition, % weight of
mannitol ranged from 0 to 94%, which is far beyond acceptable dif-
ference in biowaiver guidelines (i.e. within 10% of the amount of ex-
cipient in the reference product). This investigation stresses that BE can
be achievable even when some deviation in mannitol content was ob-
served between reference and test formulations. Therefore, as generic
industrial perspectives, “practical” amount of sugar alcohols may not
affect oral drug absorption. This implication could be a trigger for
science-based discussion on the allowable difference of sugar alcohols
that does not affect oral drug absorption. Subsequently, such discussion
will be considered and reflected in the context of BCS-based biowaiver
guideline as well as other guidelines such as formulation change and
pharmaceutical line extension.
CRediT authorship contribution statement
Kazuki Matsui: Conceptualization, Methodology, Validation,
Investigation, Data curation, Writing - original draft. Susumu
Takeuchi: Conceptualization, Methodology, Validation, Investigation,
Writing - review & editing. Yuka Haruna: Methodology, Validation,
Investigation, Data curation, Writing - review & editing. Miki Yamane:
Methodology, Investigation, Writing - original draft. Takahiro
Shimizu: Investigation, Writing - review & editing. Yoshiki Hatsuma:
5
Journal of Drug Delivery Science and Technology 57 (2020) 101728
Investigation, Writing - review & editing. Norihito Shimono:
Investigation, Writing - review & editing. Machiko Sunada:
Investigation, Writing - review & editing. Masakane Hayakawa:
Investigation, Writing - review & editing. Tomo Nishida: Investigation,
Writing - review & editing. Shusei Ito: Investigation, Writing - review &
editing. Masashi Ide: Investigation, Writing - review & editing. Maki
Seino: Investigation, Writing - review & editing. Masahisa Sugihara:
Conceptualization, Methodology, Investigation, Writing - review &
editing, Supervision. Yasushi Minagawa: Methodology, Investigation,
Writing - review & editing, Supervision. Hidehisa Tachiki:
Conceptualization, Methodology, Investigation, Writing - review &
editing, Supervision, Project administration.
Acknowledgement
All authors declare no conflict of interest. Authors would like to Dr.
Shinichiro Hirose for his valuable comments. This research did not re-
ceive any specific grant from funding agencies in the public, commer-
cial, or not-for-profit sectors.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.jddst.2020.101728.
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