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Iki Fazlı Çözünme Hızı Testi Makale
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Article history: The formulation developments and the in vivo assessment of Biopharmaceutical Classification System
Received 3 August 2017 (BCS) class II drugs are challenging due to their low solubility and high permeability in the human
Revised 1 September 2017 gastrointestinal (GI) tract. Since the GI environment influences the drug dissolution of BCS class II drugs,
Accepted 7 September 2017
the human GI characteristics should be incorporated into the in vitro dissolution system to predict
Available online 15 September 2017
bioperformance of BCS class II drugs. An absorptive compartment may be important in dissolution
apparatus for BCS class II drugs, especially for bases (BCS IIb) because of high permeability, precipitation,
Keywords:
ASD and supersaturation. Thus, the in vitro dissolution system with an absorptive compartment may help
GIS predicting the in vivo phenomena of BCS class II drugs better than compendial dissolution apparatuses. In
ketoconazole this study, an absorptive compartment (a biphasic device) was introduced to a gastrointestinal simulator.
raloxifene
This addition was evaluated if this in vitro system could improve the prediction of in vivo dissolution for
BCS class II drug
simulation BCS class IIb drugs, ketoconazole and raloxifene, and subsequent absorption. The gastrointestinal
in vivo performance simulator is a practical in vivo predictive tool and exhibited an improved in vivo prediction utilizing the
biphasic format and thus a better tool for evaluating the bioperformance of BCS class IIb drugs than
compendial apparatuses.
© 2018 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Introduction drugs like ibuprofen have a favorable environment for their solu-
bility at the small intestine, whereas BCS class IIb drugs have an
In vitro dissolution studies have often been conducted to assess unfavorable environment for their solubility.24,25 To improve the
in vivo gastrointestinal dissolution of oral formulations rather than dissolution rate and solubility for BCS class IIb drugs, the reduction of
performing a quality control type dissolution test with compendial drug particle size, the modification of drug forms/processes such as
dissolution systems.1-17 Accordingly, numerous dissolution meth- solid dispersion, and the addition of surfactant and polymer into oral
odologies have been utilized.1,3,4,9,12,13,18-21 The physicochemical dosage forms have been embraced to enhance the oral absorption of
properties such as pKa, log P, solubility, and solid state of active BCS class IIb drugs.26-29 Unlike compendial apparatuses, supersat-
pharmaceutical ingredients (API) are important factors for their uration and precipitation have been observed by in vitro dissolution
dissolution and absorption. The physiological parameters in the transfer models such as artificial stomach and duodenum (ASD) and
gastrointestinal (GI) tract like pH, buffer capacity, and the volume of gastrointestinal simulator (GIS).3,4,7,8,12,13,30 However, the observed
GI contents also significantly affect the dissolution and absorption of precipitation time and rate from in vitro studies tends to be faster
oral dosage forms, especially for Biopharmaceutical Classification than the precipitation time in vivo or the observed dissolution rate
System (BCS) class IIa and IIb drugs. Their drug dissolution depends and dissolved amount tends to be slower than in vivo because most
on the pH of the local environment at the different GI sites and those of in vitro dissolution studies do not have an absorptive phase to
display completely different dissolution profiles.22,23 BCS class IIa account for the disappearance of drug molecules from the aqueous
lumen.19,31,32 Organic solvents have been introduced into the in vitro
dissolution methodology as an absorptive phase to evaluate in vivo
* Correspondence to: Gordon L. Amidon (Telephone: 734-764-2226; Fax: 734-763-
drug dissolution and to understand it mechanistically, and this
6423). 2-phase dissolution platform has provided meaningful in vivo pre-
E-mail address: glamidon@umich.edu (G.L. Amidon). diction of test drugs.9,11 The oral dosage forms of poorly soluble
https://doi.org/10.1016/j.xphs.2017.09.002
0022-3549/© 2018 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
308 Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316
Materials
Figure 1. The diagram of gastrointestinal simulator (GIS) with the presence of
Ketoconazole tablets were obtained from Taro Pharmaceuticals absorptive/organic phase.
U.S.A., Inc. (Hawthorne, NY) through University of Michigan Hos-
pital. Raloxifene tablets and raloxifene standards were provided by gastric fluid and 250 mL of water as the dose volume). The
Sawai Pharmaceuticals (Osaka, Japan). Ketoconazole, 1-decanol, duodenal chamber (GISduodenum) was filled with 50 mL of 50-mM
hydrochloric acid, sodium phosphate dibasic, and sodium chloride sodium phosphate buffer (pH 6.5) and the volume was main-
were obtained from Sigma-Aldrich Chemical Co. (St. Louis, MO). tained constant. The jejunal chamber (GISjejunum) was filled with
Trifluoroacetic acid, formic acid, methanol, and acetonitrile were 100 mL of distilled water as the resting volume and simply collected
obtained from Fisher Scientific Inc. (Pittsburgh, PA). All chemicals the output from the GISduodenum. To avoid any unfavorable inter-
were of analytical grade or HPLC grade. action between excipients in aqueous buffer media and organic
phase, distilled water was adopted as the resting volume in the
In Vitro Dissolution of Raloxifene and Ketoconazole in Dissolution GISjejunum. With collecting the output (mainly 50-mM sodium
Media in the Presence and Absence of Absorptive/Organic Phase phosphate buffer) from the GISduodenum at the first-order kinetics,
With United States Pharmacopeia Dissolution Apparatus II (Biphasic the alteration of experimental condition was thought to be mini-
Dissolution) mal. The presence and absence of organic phase, 100 mL 1-decanol,
as an absorptive phase was incorporated only in the jejunal
The dissolution profiles of raloxifene and ketoconazole tablets in chamber. During the experiment, simulated gastric fluid (0.01-N
the presence and absence of an absorptive phase were determined HCl) and simulated duodenal fluid (100-mM sodium phosphate
using a Hanson SR6 Dissolution Test Station (Chatsworth, CA) buffer, pH 6.5) were pumped into the GISstomach and the GISduodenum
equipped with United States Pharmacopeia (USP) apparatus II at the constant rate of 1 mL/min, respectively. The tablet of keto-
(paddles). The paddle speed was set to 50 rpm. Dissolution tests conazole (200 mg) and raloxifene (60 mg) was placed into the
were conducted on single dosage unit (a 60-mg raloxifene tablet or GISstomach and the dissolution study was started. The test solution,
a 200-mg ketoconazole tablet) at 37 ± 0.5 C in either 300 mL or 500 simulated gastric fluid with test drug, in the GISstomach entered into
mL of 50-mM sodium phosphate buffer at pH 6.5 with the presence the GISduodenum at a first-order rate, which was set 8 min as the
and the absence of 100 mL of 1-octanol. Tablets were introduced to gastric half-emptying time (t1/2 ¼ 8 min). Sampling (100 mL) was
the vessel by adding them directly to the aqueous medium without performed at specific time points: 3, 5, 8, 11, 14, 17, 20, 23, 26, 29, 45,
contacting the organic solvent. Samples (1 mL) were manually and 60 min, and no replacement of the buffer solution was made.
taken from each chamber at the specific time points and super- Those studies were performed, at least, 3 times in each condition, in
natant was diluted with H2O/methanol (1/1, v/v) after centrifuga- the presence or absence of absorptive phase. The sample from the
tion (17,000 g, 1 min) at room temperature. The drug aqueous phase was spun at 17,000 g for 1 min at room temper-
concentration was determined by HPLC analysis. ature and the supernatant was mixed with the same volume of
H2O/methanol (1/1, v/v) to prevent further precipitation. The
Raloxifene and Ketoconazole Dissolution Studies With the sample from the organic phase was immediately mixed with the
Gastrointestinal Simulator (GIS) in the Presence and Absence of the same volume of H2O/methanol (1/1, v/v). Concentration of raloxi-
Absorptive/Organic Phase fene and ketoconazole was determined by HPLC analysis.
The GIS dissolution diagram and the mass transport kinetics are HPLC Methodology for Raloxifene and Ketoconazole
shown in Figures 1 and 2, and the function and theory of the GIS
have been previously described.7,8,12,13 The gastric chamber All GIS experimental samples were analyzed with an Agilent
(GISstomach) was filled with 300 mL (50 mL of 0.01-N HCl as the HPLC system (Agilent Technologies, Santa Clara, CA). The HPLC
Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316 309
Figure 2. The mass transport kinetics of gastrointestinal simulator (GIS) with the presence of absorptive/organic phase.
system consisted of Agilent pumps (1100 series), an Agilent auto- and ksec(duodenum), to the GISstomach and GISduodenum are both 1 mL/
sampler (1200 series), and an Agilent UV-Vis detector (1100 series) min. GE is a gastric emptying time (gastric half-emptying time
controlled by Chemstation® 32 software (version B.01.03). Samples (t1/2) ¼ 8 min).
were resolved in Agilent Eclipse XDB-C18 reverse-phase column Mass transit kinetics in the GIS was applied to both drug species,
(3.5 mm, 4.6 150 mm) equipped with a guard column for raloxi- undissolved and dissolved drugs. Those transit rates between
fene and ketoconazole. The mobile phase consisted of 0.1% TFA/ chambers were calculated as a function of fluid transfer rate and
water (solvent A) and 0.1% TFA/acetonitrile (solvent B) with the drug amount (observed drug concentration in the GISstomach and
solvent B gradient changing from 0% to 56% at a rate of 2%/min transferred volume) from the previous chamber. The drug amount
during a 14-min run. Standard curves generated for raloxifene and for undissolved and dissolved drugs in each chamber of the GIS can
ketoconazole were utilized for quantitation of integrated area un- be respectively expressed as:
der peaks. The detection wavelength was 254 nm for raloxifene and
ketoconazole. dXudðstomachduodenumÞ dVstomach
¼ þ ksecðstomachÞ
dt dt
Mass Transport Analysis and Model by In Vitro Dissolution XudðstomachÞ
(4)
Vstomach
The equations and theories of derivation of the models have
been reported previously.9,33 The mass transport of dissolution
studies with GIS, 3 chamber dissolution apparatus, have been dXdðstomachduodenumÞ dVstomach
¼ þ ksecðstomachÞ
described (Fig. 2).7,8,12,13,33 The movement of fluid volume in each dt dt
chamber can be expressed as:
XdðstomachÞ
(5)
Vstomach
lnð2Þ
Vstomach ¼ Vstomach;0 e t (1)
GE
dXudðduodenumjejunumÞ dVstomach
¼ þ ksecðstomachÞ
Vduodenum ¼ Vduodenum;0 (2) dt dt
XudðduodenumÞ
ðlnð2ÞÞt
þ ksecðduodenumÞ
Vjejunum ¼ 100 þ Vstomach;0 e GE þ ksecðstomachÞ Vduodenum
(6)
þ ksecðduodenumÞ t (3)
dXdðduodenumjejunumÞ dVstomach
where Vstomach, Vduodenum, and Vjejunum are the fluid volume at time ¼ þ ksecðstomachÞ
dt dt
t in each chamber of the GIS, GISstomach, GISduodenum, and GISjejunum
and Vstomach,0 and Vduodenum,0 are the initial volumes in the XdðduodenumÞ
þ ksecðduodenumÞ (7)
GISstomach and GISduodenum. The fluid secretion rates, ksec(stomach) Vduodenum
310 Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316
Figure 3. The concentration of ketoconazole-time profiles in USP II with the presence Figure 4. The concentration of raloxifene-time profiles in USP II with the presence and
and the absence of absorptive phase (a): black circle, red square, and green triangle the absence of absorptive phase (a): black circle, red square, and green triangle
represent the observed drug concentration with the absence of absorptive phase, the represent the observed drug concentration with the absence of absorptive phase, the
observed drug concentration in the aqueous phase with the presence of absorptive observed drug concentration in the aqueous phase with the presence of absorptive
phase, and the observed concentration in the absorptive phase, respectively. The dis- phase, and the observed concentration in the absorptive phase, respectively. The dis-
solved amount (%) of ketoconazole-time profiles in USP II (b): black circle and red solved amount (%) of raloxifene-time profiles in USP II (b): Black circle and red square
square represent the observed dissolved drug amount (%) with the absence of represent the observed dissolved drug amount (%) with the absence of absorptive
absorptive phase and the total observed dissolved drug amount (%), the combined phase and the total observed dissolved drug amount (%), the combined amount in the
amount in the aqueous and organic phases, with the presence of absorptive phase, aqueous and organic phases, with the presence of absorptive phase, respectively. Each
respectively. Each data point represents mean ± SD (n ¼ 3). data point represents mean ± SD (n ¼ 3).
aqueous phase, 1-octanol in the aqueous phase interacted with presence and the absence of 100 mL organic solvent, 1-decanol, in
excipients of oral dosage forms to cause the aggregation, which the GISjejunum (biphasic study). Figure 5 shows similar dissolution
might prohibit the further drug dissolution. profiles of ketoconazole in the aqueous phase in each chamber,
GISstomach, GISduodenum, and GISjejunum, regardless of the presence or
Raloxifene Dissolution Study in the USP II absence of organic phase. Since the saturated drug concentration of
ketoconazole would be around 10 mg/mL in 50-mM sodium phos-
The dissolution studies with raloxifene in the USP II were con- phate buffer (pH 6.5) at 37 C, observed ketoconazole concentration
ducted with 50-mM sodium phosphate buffer (pH 6.5) with the was tenfold and fourfold higher in the GISduodenum and GISjejunum
presence and the absence of 1-octanol (biphasic study). Figure 4a than the saturated concentration, suggesting supersaturation
shows raloxifene drug concentration in each phase. The decline (Figs. 5b and 5c and Table 1). The gradual decline of drug concen-
of raloxifene concentration in the aqueous phase was observed tration was observed in the GISjejunum, suggesting the precipitation,
with a corresponding increase of raloxifene concentration in the even though the supersaturation level was maintained during
organic phase (Fig. 4a). However, the total amount of dissolved 60-min experiment (Fig. 5c). In the GIS, the decline of ketoconazole
raloxifene was similar regardless of the presence or absence of concentration in the aqueous phase of the GISjejunum was not
organic phase (Fig. 4b). As seen in ketoconazole, the aggregation of observed even though the mass transport of ketoconazole was
raloxifene oral product was also observed in the aqueous phase observed from the aqueous phase to the organic phase in the
with the presence of organic phase. 2-phase experiments (Fig. 5c).
Ketoconazole Dissolution Study in the GIS Raloxifene Dissolution Study in the GIS
The dissolution studies with an IR ketoconazole tablet in the GIS The dissolution studies with raloxifene in the GIS were con-
were conducted with 50 mL of 50-mM sodium phosphate buffer ducted under the same condition as the ketoconazole experiments.
(pH 6.5) in the GISduodenum and 100 mL of distilled water with the Figure 6 displays the similar dissolution profiles of raloxifene in the
312 Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316
Figure 5. The concentration of ketoconazole-time profiles in the gastric (a), the Figure 6. The concentration of raloxifene-time profiles in the gastric (a), the duodenal
duodenal (b), and the jejunal chambers (c): solid line represents the theoretical con- (b), and the jejunal chambers (c): solid line represents the theoretical concentration
centration curve and dot line represents the saturated drug concentration in 50-mM curve and dot line represents the saturated drug concentration in 50-mM sodium
sodium phosphate buffer (pH 6.5) at 37 C. Black circle, red square, and green trian- phosphate buffer (pH 6.5) at 37 C. Black circle, red square, and green triangle represent
gle represent the observed drug concentration with the absence of absorptive phase, the observed drug concentration with the absence of absorptive phase, the observed
the observed drug concentration with the presence of absorptive phase, and the drug concentration with the presence of absorptive phase, and the observed concen-
observed concentration in the absorptive phase, respectively. Each data point repre- tration in the absorptive phase, respectively. Each data point represents mean ± SD
sents mean ± SD (n ¼ 3). (n ¼ 3).
aqueous phase in each chamber, GISstomach, GISduodenum, and about sevenfold higher than the saturated concentration, suggest-
GISjejunum, regardless of the presence or absence of organic phase. ing supersaturation (Fig. 6b and Table 1). However, observed
Since the saturated drug concentration of raloxifene would be raloxifene concentration in the GISjejunum was not as high as the
around 13.3 mg/mL in 50-mM sodium phosphate buffer (pH 6.5) at concentration in the GISduodenum, suggesting the quick precipitation
37 C, observed raloxifene concentration in the GISduodenum was (Fig. 6c). In the GIS, the decline of raloxifene concentration in the
Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316 313
smaller, 60 mg and 35, compared with ketoconazole's, 200 mg and Clinical results34 4.22 e 14.74 e
321, the drug movement of raloxifene from the aqueous phase to USP II without Organic 0.02 99.5 0.12 99.2
USP II with Organic 0.04 99.0 0.40 97.4
the organic phase, either in 1-octanol or 1-decanol, would affect
GIS without Organic 1.78-2.15 49.1-57.8 7.14 51.6
their mass balance (Table 1). GIS with Organic 2.63-3.03 28.2-37.7 7.14 51.6
Figure 9. The total dissolved amount (%) of ketoconazole-time profiles in (a) and
raloxifene-time profiles in (b): Black circle represents the dissolved drug amount (%) in
SIF (pH 6.5) with USP II, red square represents the total dissolved drug amount (%) in
GISduodenum and GISjejunum, and green triangle represents the total dissolved drug
amount (%) in GISduodenum, GISjejunum, and organic phase as an absorptive phase in
GISjejunum. Each data point represents mean ± SD (n ¼ 3).
II until the end of those studies (Figs. 5c and 6c). The dose number
of raloxifene (35) is lower than ketoconazole (321) and raloxifene
dissolves relatively quicker than ketoconazole in the GISstomach
(Figs. 5a and 6a and Table 1). Since undissolved particles may
accelerate the precipitation by the growth of small particles and the
initiation of nucleation, the quick dissolution in the stomach before
moving into the small intestine would extend the supersaturation
period and slow the precipitation rate.69,70 Also, the reduction of
apparent drug concentration in the small intestinal lumen by
absorption would theoretically slow its drug precipitation. For
investigating the precipitation behavior of oral drug products,
biphasic dissolution formats may be an appropriate approach to
predict in vivo than compendial dissolution formats due to the
dissolution-partitioning phase for test drugs.9,11,63,71,72 In this study,
the addition of organic phase (biphasic format) into the GIS was
evaluated to improve in vivo prediction. Several reports suggest
that in vitro experimental results tend to overestimate the precip-
itation rate due to the lack of absorptive phase in the dissolution Figure 10. The drug concentration in the jejunal chamber of GIS (mg/mL) of
system.32,58,65,68,73 The calculated precipitation rate constants for ketoconazole-time profiles in (a) and raloxifene-time profiles in (b): dot lines represent
ketoconazole with the GIS with the absence of organic phase agree the calculated concentration curves of ketoconazole and raloxifene in the organic
with the previous reports.30,31,74 However, the results of ketoco- phase, respectively. Black circle represents the drug concentration in the aqueous
phase in GISjejunum and red square represents the drug concentration in the organic
nazole displayed slower decline of drug concentration in the small phase in GISjejunum. Arrows represent the ideal range of the ratio between the surface
intestinal chambers with the presence of absorptive phase than area of the aqueous-organic interface and the aqueous volume. Each data point rep-
those without, suggesting the potential overestimation of resents mean ± SD (n ¼ 3).
Y. Tsume et al. / Journal of Pharmaceutical Sciences 107 (2018) 307-316 315
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In vitro digestion of short-dough biscuits enriched in proteins and/or fibres
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for biphasic dissolution. Due to the physicochemical properties of of a multi-compartmental, dynamic, system of the upper gastrointestinal tract
to support formulation development and establish bioequivalence of poorly
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intestine. J Pharm Pharmacol. 2004;56(1):43-51.
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