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Accepted Manuscript
Preparation and evaluation of non-effervescent gastroretentive tablets containing pregabalin for once-daily administration and dose proportional pharmacokinetics
Seongkyu Kim, Kyu-Mok Hwang, Yoong Sik Park, Thi-Tram Nguyen, EunSeok Park
PII:
DOI:
Reference:
S0378-5173(18)30616-1
https://doi.org/10.1016/j.ijpharm.2018.08.038
IJP 17723
To appear in:
International Journal of Pharmaceutics
Received Date:
Revised Date:
Accepted Date:
25 June 2018
27 July 2018
19 August 2018
Please cite this article as: S. Kim, K-M. Hwang, Y.S. Park, T-T. Nguyen, E-S. Park, Preparation and evaluation of
non-effervescent gastroretentive tablets containing pregabalin for once-daily administration and dose proportional
pharmacokinetics, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm.
2018.08.038
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Manuscript for International Journal of Pharmaceutics
Preparation and evaluation of non-effervescent gastroretentive tablets
containing pregabalin for once-daily administration and dose proportional
pharmacokinetics
Seongkyu Kim1,a,b, Kyu-Mok Hwang1,b, Yoong Sik Parka, Thi-Tram Nguyenb and Eun-Seok
Parkb*
a
Yuhan Research Institute, Yuhan Corporation, Yongin 17084, Republic of Korea
b
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
*Correspondence to:
Eun-Seok Park, Ph.D., School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu,
Suwon-si, Gyeonggi-do, Republic of Korea
Tel: +82-31-290-7715; Fax: +82-31-290-7729
E-mail address: espark@skku.edu
1
These authors contributed equally to this work.
Abstract
The main purpose of this study was to develop gastroretentive tablets with floating and
swelling properties for once-daily administration of pregabalin. The non-effervescent floating
and swelling tablets were prepared using wet granulation and compaction, which are widely
used and easily accessible. All formulations showed sustained release patterns and maintained
buoyancy for over 24 h. The amount of hydroxypropyl methylcellulose and crospovidone
were found to be critical factors affecting in vitro dissolution and floating properties of the
prepared tablets. The optimized tablets containing 300 mg of pregabalin started to float
within 3 min and swelled above 12.8 mm, the reported pyloric sphincter diameter during the
fed state, in all dimensions including length, width, and thickness. In vivo results in beagle
dogs indicated that the optimized formulations are suitable as once-daily dosage forms, and
dose proportionality was observed in doses ranging from 75 to 300 mg. Additionally, the dogs
administered with the formulation having poor in vitro gastroretentive properties showed
highly variable and reduced extent of absorption, signifying the necessity of the
gastroretentive drug delivery system. In conclusion, the developed non-effervescent floating
tablets are promising candidates for once-daily delivery of pregabalin.
Keywords
Pregabalin, Gastroretentive drug delivery system, Non-effervescent, Floating, Swelling, Dose
proportionality
1. Introduction
Pregabalin, chemically known as (S)-(+)-3-aminomethyl-5-methylhexanoic acid, is
initially marketed as immediate release (IR) formulations. Health Canada and the US FDA
5
have approved the medication (Lyrica® capsules 25, 50, 75, 100, 150, 200, 225, and 300 mg,
Pfizer Inc., USA) for the management of chronic pain associated with diabetic peripheral
neuropathy, fibromyalgia, diabetic peripheral neuropathy, post-herpetic neuralgia, and
adjunctive therapy for partial onset seizures (Pfizer, 2018b).
Recently, once-daily sustained release (SR) tablets for pregabalin for treatment of post-
10
herpetic neuralgia was approved by the US FDA (Lyrica® CR extended-release tablets 82.5,
165, and 330 mg, Pfizer Inc., USA). Although the successful development of the SR dosage
form is expected to give patients convenience by reducing the dosing frequency, there is still
plenty of room for the improvement as the product must be taken after an evening meal.
Furthermore, a high calorie diet (e.g., 800 to 1000 kcal) is required to ensure the same extent
15
of absorption. When administrations occurred after a medium calorie (600–750 kcal) morning
meal, the total extent of drug absorption reduced up to ca. 25% (Pfizer, 2018a). The variation
in absorption may be attributed to the narrow absorption site for pregabalin, which is mainly
absorbed in the upper intestine through l-amino acid transporters (Sills, 2006). Gastric
retention time was reported to be affected by the caloric intake, leading to variable exposure
20
of the released drug to the upper intestine (Lalloo et al., 2012). Although not specified in the
product label, the increased doses of the SR dosage form relative to comparative doses IR
dosage form (e.g. 165 mg/day for Lyrica® CR corresponds to 150 mg/day for Lyrica ®
capsules) supports this claim.
1
Abbreviations: GRDDS, gastroretentive drug delivery system; GR, gastroretentive; PGRT, gastroretentive tablet
containing pregabalin; BLT, lag time for complete buoyancy
Among various approaches for increasing gastric retention time of the dosage form, only
floating and swelling mechanisms have shown clinical evidence for prolonged gastric
residence time at fed state (Chen et al., 2013; Oth et al., 1992). Gastroretentive drug delivery
systems (GRDDS) utilizing swelling mechanisms are usually oval or caplet shaped having a
5
short width (ca. 10 mm) for easy swallowing, but swell shortly after ingestion to become
larger than the pyloric ring. However, the swelling mechanism can only increase the overall
gastric retention time of the tested subjects, and there was always a bimodal distribution of
retention time in the subjects. In other words, there was always a group with short retention
time among test subjects no matter how big the initial tablet was (Berner and Cowles, 2006).
10
This implies that the tablets with only swelling properties, presumably Lyrica® CR extendedrelease tablets, always have a risk of premature gastric emptying during the fed state.
Floating GRDDS can effectively minimize the risk of premature gastric emptying of
swellable systems by floating above gastric juice and being away from the pylorus. The
floating system was shown to be especially effective in prolonging gastric residence time in
15
small-to-medium sized tablets and also significantly reducing variations in gastric emptying
time for large-sized tablets (Oth et al., 1992; Timmermans and Moës, 1994). Therefore, a
combination of swelling and floating mechanism can provide a reliable gastric retention time
for all subjects. Several techniques for floating are reported. For effervescent floating
GRDDS, gas-generating agents, e.g., carbonates or bicarbonates, which can react with the
20
gastric acid in situ and create carbon dioxide bubbles to lower tablet density. Additionally,
highly porous floating tablets prepared with sublimation of volatile materials or freeze-drying
were reported to have immediate buoyancy (Kim et al., 2014; Oh et al., 2013). Also, a noneffervescent floating tablet was proposed which use swelling properties of the polymer and
does not require gas-generating agents for floating (Acharya et al., 2014; Meka et al., 2014).
2
25
The advantages of a non-effervescent floating GRDDS are: (A) stability of acid or base-labile
drugs can be secured by excluding the gas-generating agents; (B) floating lag time is not
affected by the gastric pH, which can be problematic for patients with achlorhydria; and (C)
simple manufacturing methods that does not require special manufacturing devices can
provide easy application of many existing drugs. However, the potencies for the model drug
30
used in the previous studies were low (10 mg and 54.5 mg) (Acharya et al., 2014; Meka et al.,
2014), limiting the applicability of the system for other higher-dose model drugs including
pregabalin. Furthermore, little attention has been paid for the swollen size of the tablets,
which is also a significant factor for gastric retention. Hence, there remains a need for a noneffervescent GRDDS with rapid swelling properties and applicability to high dose
35
formulations.
The objectives of this study were to develop a non-effervescent floating and swelling
GRDDS containing pregabalin for once-daily delivery and dose-proportional
pharmacokinetics; to confirm if the optimized GRDDS will show improved pharmacokinetic
properties compared to the tablet with poorer in vitro gastroretentive properties. Therefore,
40
the effects of type and amount of different polymers on in vitro properties were observed. In
vitro properties include buoyancy behavior in the dissolution media, dissolution profiles, and
swelling. The optimized formulation, as well as the formulation with decreased in vitro
floating and swelling behaviors, were evaluated for their in vivo performance in beagle dogs.
The optimized formulation with lower strengths (75 mg and 150 mg) were also evaluated to
45
confirm if dose proportional pharmacokinetics could be obtained.
2. Materials and Methods
3
2.1. Materials
50
The following materials were used in this study without further purification: Pregabalin
(Teva Pharmaceutical Industries Ltd., Petah Tikva, Israel), hydroxypropyl methylcellulose
(HPMC, Metolose® 90SH-100,000SR; Shin-Etsu Chemical Co., Ltd., Tokyo, Japan),
hydroxypropyl cellulose (HPC, KlucelTM JF; Ashland, Covington, USA), polyethylene oxide
(PEO, PolyoxTM WSR 301; Dow Chemical Company, Midland, USA), crospovidone
55
(Kollidon® CL; BASF Corporation, Ludwigshafen, Germany), microcrystalline cellulose
(MCC, CeolusTM PH-101; Asahi Kasei Corporation, Tokyo, Japan), colloidal silicon dioxide
(Aerosil® 200; Evonik Industries, Essen, Germany), and magnesium stearate (NOF
Corporation, Tokyo, Japan). Water was purified by reverse osmosis and filtered in-house. All
other chemicals were of reagent grade, and all solvents were of HPLC grade. Commercially
60
available IR-type pregabalin capsule (Lyrica ® capsule 150 mg, Pfizer Inc., New York, USA)
was used as the reference product for the in vivo study.
2.2. Methods
2.2.1. Preparation of gastroretentive tablets containing pregabalin
65
The formulations were designed to confirm how the lag time for complete buoyancy,
swollen size, and drug release of a gastroretentive tablet containing pregabalin (PGRT) affect
GI absorption. PGRTs were prepared by the wet granulation method, and the composition of
various PGRTs is shown in Table 1. Formulation B-1 was designed for less expansion and
less sustained release pattern compared with formulations in group A. Formulation C and D
4
70
were designed to contain different amounts of pregabalin while maintaining gastroretentive
properties. Briefly, pregabalin was blended with HPMC using a high shear mixer (YC-SMG3J; Yenchen machinery co., Ltd., Taoyuan, Taiwan). The powder blends were granulated with
6% (w/w) of HPC in 44% ethanol, and then the resultant granules were dried at 50°C for
approximately 5 h until less than 1% moisture remained. Dried granules were milled via
75
0.065-inch aperture size stainless steel screen by the Fitzmill® comminuting machine
(Fitzpatrick Company, Waterloo, Canada). The granules were mixed with different ratios of
excipients, lubricated with magnesium stearate, and compressed into a tablet by the single
punch tablet press (Manesty machines Ltd., Liverpool, England) equipped with oval concave
punches. The dimensions and hardness values of prepared PGRTs are demonstrated in Table
80
2.
2.2.2. In vitro drug release and buoyancy
The release of pregabalin from the PGRTs was studied using USP dissolution apparatus II
(VK7025; Varian, Palo Alto, USA). Media containing 900 mL of 0.06 N hydrochloric acid for
85
all formulations or 900 mL of 0.5 M sucrose solution containing 0.15 M sodium chloride and
0.015 M trisodium citrate for selected formulations were used as dissolution media. The 0.06
N hydrochloric acid was used to represent the dissolution of the drug in an acidic gastric fluid
as the drug was mainly absorbed in the upper intestine. In addition, highly concentrated
sucrose solution containing salt was used to mimic the fed stomach containing a high amount
90
of sugar and salts, which was reported to affect swelling properties of HPMC (Williams et al.,
2010). As 0.06 N hydrochloric acid was un-buffered, the prepared medium was checked for
its pH immediately before each study. The pH of 0.06 N hydrochloric acid and sucrose
5
solution containing salts was ca. 1.3 and 7.8, respectively. The temperature was maintained at
37 ± 0.5°C and the rotation speed of the paddle was 50 rpm. Samples of 5 mL were collected
95
at pre-determined time points, filtered through a 0.45 μm polyvinylidene fluoride (PVDF)
syringe filter, and replenished with equal volumes of fresh dissolution medium. Samples were
analyzed by high performance liquid chromatography at 210 nm of UV spectroscopy to
calculate the dissolution rates (Oh et al., 2016). To study the buoyancy of PGRTs, the floating
lag time and floating-maintenance time were evaluated for 24 h in dissolution tests. The
100
buoyant behavior of PGRTs was evaluated simultaneously at the same sampling time points
for the dissolution studies by their relative heights in the dissolution vessel as illustrated in
Fig. 1.
Due to the hydrophilic nature of the drug, the dissolution of raw pregabalin powder was
completed even before the first time point, 5 min using the conventional dissolution method
105
described above. Hence, it was regarded difficult to differentiate dissolution profile of raw
drugs by discrete sampling, and a UV Vis spectrophotometer (UV-2700l; Shimadzu, Kyoto,
95 Japan) equipped with a peristaltic pump for continuous sampling was utilized. Briefly, 100
mL of 0.06 N hydrochloric acid or sucrose solution was maintained at 37°C with mild
stirring, and the media were distributed into the UV-Vis spectrophotometer at 133 mL/min.
110
300 mg of pregabalin as a raw powder was added into media, and the absorbance values of
the samples collected via 0.1 μm PVDF filters were measured continuously at 210 nm for
0.06 N hydrochloric acid and at 220 nm for sucrose solution. The analysis method was
validated in each medium and showed suitability even for highly concentrated sucrose
solution (R2>0.993) in the range of 0.3 to 3 mg/mL.
115
2.2.3. Drug release kinetics
6
Release profiles of optimized tablets were fitted to Korsmeyer-Peppas model to study their
release mechanism using Eq. (1) (Korsmeyer et al., 1983):
Mt

120
= ∙ tn
(1)
∞
Where Mt/M∞ is the cumulative fraction of drug released at time t, k is the kinetic exponent,
and n is the release exponent that can tell if the release is erosion-based, diffusion-based or a
combination of both. In addition, similarity factor (f2) between PGRT containing 300 mg of
pregabalin (PGRT300) and formulations with decreased strength (PGRT150 and PGRT75
containing 150 and 75 mg of pregabalin, respectively) were calculated using Eq. (2) (US-
125
FDA, 1997):
1
−0.5
2 = 50 × log{[1 +  ∑=1( −  )2 ]
× 100}
(2)
130
Where n is the number of withdrawal time points, Rt is the percentage dissolved of
reference drug at time point t, and Tt is the percentage dissolved of the test drug at time point
t, and two profiles of drug release are regarded similar if f2 value is above 50 according to the
FDA guidance.
135
2.2.4. In vitro swelling
The swelling studies of PGRTs were performed after a 24 h dissolution testing to confirm
their robustness in swelling. Each tablet was recovered after a 24 h dissolution study in both
media (0.06 N hydrochloric acid solution, solution containing 0.5 M sucrose, 0.15 M sodium
7
chloride and 0.015 M trisodium citrate) and the swollen tablets were left for 1 min to remove
140
excess dissolution media. Each dimension of PGRTs was measured using the image analysis
software (ImageJ, release 1.50i, National Institutes of Health, Bethesda, USA).
2.2.5. In vivo pharmacokinetics
The in vivo study was conducted in accordance with the principles of animal care and use,
145
and the study protocol was approved by an Institutional Animal Care and Usage Committee
(IACUC). Healthy male beagle dogs with a body weight of approximately 10 kg were used
for the in vivo study. Fourteen beagle dogs were randomly divided into three groups: A-3
(n=4), B-1 (n=5), and marketed IR capsules (Lyrica® capsule, n=5), and the study was
conducted in parallel. The beagle dogs were housed in an animal facility in separate stainless-
150
steel cages at constant room temperature (23 ± 2°C) and humidity (40–60% RH) with an
artificial 12/12 h light-(150–300 lux)-dark cycle. The room was maintained at conditions
below 200 ppm of ammonia concentration and below 60 dB of noise, and ventilated from
above 10 times per day. Beagle dogs had free access to water and food before the study. Food
intake was withheld for 12 h prior to the experiment, and standard dog food were given to the
155
animals 30 min before oral administration of PGRTs. In a separate study for evaluating dose
proportionality, five healthy male beagle dogs with a body weight of approximately 10 kg
dogs were administered with ascending single doses of PGRTs. A washout period of one
week separated the doses.
One mL of blood sample was collected via the cephalic vein using a disposable syringe
160
coated with heparin at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after dosing. Each sample
was centrifuged immediately at 10,000 rpm for 2 min. Plasma samples were taken and
stored at -70°C until analysis.
8
The pharmacokinetic parameters, including maximum plasma concentration (Cmax), time
to reach maximum plasma concentration (Tmax), and area under the curve (AUC) were
165
analyzed by the non-compartmental method using WinNonlin (Pharsight Corp., St. Louis,
USA). Proportional dose-response relationship of PGRTs was evaluated by the power model
using the Eq. (3) (Gough et al., 1995; Hummel et al., 2009; Sakurai et al., 2015):
y = α
(3)
170
Where y can be a pharmacokinetic parameter such as Cmax or AUC, and β is the slope
when plotting logDose against logy. Thus, it can be concluded that the formulations
containing different amount of pregabalin possess dose proportional pharmacokinetics if β is
close to unity.
175
2.2.6. Sample preparation
Frozen plasma samples were allowed to equilibrate to 37°C and were vortexed for
homogeneity. Additionally, 200 µL of an internal standard containing 500 ng/mL of
metformin in acetonitrile was added to 100 µL of the plasma sample. The mixture was
180
vortexed for 5 s and centrifuged at 13,000 rpm for 5 min to precipitate plasma proteins. The
100 µL of clear supernatant was diluted with 900 µL of 50% acetonitrile in distilled water,
and 5 µL of sample was injected into the mass spectrometer (QTRAP® 4000 LC-MS/MS
system; SCIEX, Framingham, USA). The standard calibration curve was generated in the
range of 0.1 to 50 µg/mL by the same preparation method used for blank plasma.
185
9
2.2.7. LC-MS/MS conditions
The LC-MS/MS analytical method was developed based on previously reported methods
(Nirogi et al., 2009; Shah et al., 2010). The chromatographic separations were achieved on a
Luna® C18 column (50 × 2.0 mm, 3 µm; Phenomenex, Torrance, USA) with a guard cartridge
190
(3.0 × 2.0 mm; Phenomenex, Torrance, USA), and the temperature of the column was
maintained at 40°C. The mobile phase consisted of 70% acetonitrile in distilled water
containing 0.1% formic acid at a flow rate of 0.2 mL/min. Electrospray ionization with
positive polarity was used for the detection of pregabalin and the internal standard, and the
Multiple Reaction Monitoring (MRM) mode was used for analysis. The transition of m/z was
195
160.1-142.116 for pregabalin and 130.030-71.034 for the internal standard.
2.2.8. Statistical analysis
All statistical analyses were performed with the SigmaPlot software (release 12.5; Systat
Software, Inc., San Jose, USA). The means were compared using a two-tailed Student’s t-test
200
or one-way analysis of variance (ANOVA), followed by Tukey post hoc test. P values less
than 0.05 were considered statistically significant.
3. Results and Discussion
205
3.1. Effect of HPMC and PEO on in vitro buoyancy and dissolution
The effect of different HPMC amounts on buoyancy and drug release of PGRT300
prepared by this hydrophilic matrix technology is shown in Fig. 2. The prepared tablets were
10
all oval, convex shaped for high drug loading and easy swallowing. In addition, most of the
formulations had hardness values higher than 12 kgf, which was suggested as an appropriate
210
tablet hardness for medium-sized tablets (Porter et al., 2017). It was observed that the lag
time for complete buoyancy or score 10 (BLT) for A-2 and A-3 containing 350 mg of HPMC
and 300 mg of HPMC, respectively, was decreased compared with A-4 containing 250 mg of
HPMC. As previously mentioned, there have been cases where only hydrophilic polymers
were used for floating the tablets without any modifications in the internal porosity (Acharya
215
et al., 2014; Meka et al., 2014). Since the tablets obtained buoyancy after contacting water, it
is evident that the swelling process has increased the internal porosity of the tablet. Swelling
is a common property observed in hydrophilic polymers, where water acts as a plasticizer and
mobilizes the polymer particles and eventually entangle each other (expand) to reach a lower
energy state (Faroongsarng and Peck, 1994). Therefore, it could be expected that the rapid
220
swelling of tablets by increasing the HPMC content will decrease the BLT and consequently
minimize the risk of premature gastric emptying.
As shown in Fig. 2B, the release rate of pregabalin tended to increase with the decrease of
HPMC content. It is generally known that hydrophilic matrices composed of HPMC or PEO
are robust in sustaining the drug release. During dissolution, the drug diffusion from the core
225
to dissolution media is inhibited by a viscously hydrated layer. The larger amount of HPMC
in the formulation implies a thicker diffusion barrier and slower dissolution rate, which
concur well with previous results for effervescent and non-effervescent floating dosage forms
(Garg and Gupta, 2009). The decreased dissolution rate for the formulation with higher
HPMC content is also due to shorter BLT. The upper surface of the floating tablet is not
230
available for dissolution, and it must be wet from the lower surface to enable drugs to diffuse
11
out. Hence, the tablets inherently release drug more slowly when they are floating than when
they are immersed in the medium using sinkers. This tendency was also reported in a
previous study (Hwang et al., 2017).
As illustrated in Fig. 3, the amount of PEO did not show a significant effect on buoyancy
235
or in vitro dissolution profiles. The dissolution profiles of formulations with different PEO
contents were all very similar to each other (f2 values above 75). Although the floating
properties showed a slight tendency to improve (decrease in BLT) with the increase in PEO
amount, the buoyant behavior of all formulations also showed statistically similar profiles.
Thus, it seems plausible that HPMC plays a crucial role in determining floating properties
240
and dissolution profiles of PGRT300. The insignificant effect of PEO on dissolution rate
could be due to its insignificant effect on the floating behavior, which is the opposite case for
HPMC. The more significant effect of HPMC on the buoyancy of the dosage form could be
due to its more suitable swelling properties (production of internal voids) compared to those
of PEO. This was confirmed in a preliminary study where the round, flat tablets composed
245
purely of either HPMC or PEO were immersed in the dissolution media and only HPMC
tablets started to float after a lag time whereas PEO tablets remained at the bottom until the
end of the test (data not shown).
3.2. Effect of crospovidone and MCC on in vitro buoyancy and dissolution
250
The effect of crospovidone, MCC, or their combination was evaluated on drug release and
buoyancy of PGRT300 which is a hydrophilic matrix system. As observed in previous
reports, crospovidone or MCC can enhance water uptake in a hydrophilic matrix system
(Chavanpatil et al., 2005; Garg and Gupta, 2009; O'connor and Schwartz, 1993). Fig. 4 shows
12
that BLT of A-2 containing 50 mg of crospovidone is approximately 15 min, whereas BLT of
255
A-1 not containing crospovidone was approximately 2 h. In addition, formulations containing
50 mg of MCC (formulations A-7 and A-8), BLT of A-7 containing 50 mg of crospovidone
was significantly decreased compared with that of A-8 containing 25 mg of crospovidone. It
seems that expansion of crospovidone upon contact with water affected buoyancy resulting in
decreased BLT, which corroborates with a previous study (Garg and Gupta, 2009).
260
Unexpectedly, an antagonistic effect of combining the two excipients was observed for the
BLT. This may be due to the differences in the speed and degree of expansion of the two
disintegrants. Although both crospovidone and MCC can expand after contacting water
(Moreton, 2008), crospovidone is a more potent disintegrant and conventionally used in small
amounts (e.g., 3–5% w/w). In contrast, MCC requires more than 20% w/w for disintegration
265
and is only effective for non-hydrophobic drugs (Rowe et al., 2009). The major disintegration
mechanism of crospovidone is the shape recovery as well as swelling, in which water only
acts as an initiator for the active disintegration action (Desai et al., 2012; Quodbach and
Kleinebudde, 2015). MCC on the contrary acts as a disintegrant mainly by wicking
mechanism, in which water molecules enter the tablet through pores by capillary action and
270
disrupt the hydrogen bonding and intermolecular bonding between the particles (Patel and
Hopponent, 1966). Hence, crospovidone, a swelling and shape recovering superdisintegrant,
is presumed to have expanded the tablet volume upon contacting the dissolution media and
reduced the overall tablet density whereas MCC, a wicking disintegrant, absorbed water, thus
giving negative effects on buoyancy.
275
Drug release profile of A-2 was retarded compared with that of A-1, A-7, and A-8,
although they all showed sustained release patterns. As the addition of crospovidone
13
increases the gel layer thickness by expansion, the diffusion pathway for the dissolved drug
to move through could have been increased. It could also be attributed to the better floating
properties which constrict the upper surface area from rapid dissolution as discussed in the
280
above section.
It was also confirmed that the amount of MCC used in this study was not enough to affect
drug release profiles along with buoyancy profiles (f2 value is 67 between A-2 and A-7).
Therefore, it can be concluded that HPMC and crospovidone are the critical excipients in
determining both buoyancy and dissolution profiles for non-effervescent floating GRDDS
285
containing pregabalin. Hence, the formulation A-3 containing only crospovidone and HPMC
as swellable agents was chosen for its good floating properties and hardness.
3.3. Characterization of selected PGRT300 formulations for in vivo study
As mentioned above, one of the objectives of this study was to confirm if formulations
290
with better in vitro gastroretentive (GR) properties will show better absorption behavior for a
drug with limited absorption site in the upper intestine. A-3 and B-1 were selected for their
differences in buoyancy and swelling behavior. Formulation B-1 was designed to have
reduced extent of swelling by reducing the amount of swellable polymer and excluding the
disintegrant. It was hypothesized that the dosage form with longer BLT and less amount of
295
swellable polymer will show reduced and highly variable extent of absorption in vivo due to
unpredictable gastric retention time. Therefore, the two formulations were tested in
conventional acidic media as well as in media containing high amounts of sugar and salts to
assess their robustness in maintaining drug release and matrix integrity.
14
300
3.3.1. In vitro swelling
As shown in Table 3, all three expanded dimensions of A-3 in sucrose solution and 0.06 N
HCl solution were similar to or longer than 12.8 mm, which is the reported cutoff diameter
for improved gastric retention (Timmermans and Moës, 1993). On the contrary, formulation
B-1 showed less extent of swelling and its swollen width and thickness was shorter than the
305
cutoff diameter in the sucrose solution. For a non-disintegrating dosage form to stay in the
stomach, at least two dimensions have to be longer than the reported gastric pylorus diameter
during fed state. Hence, the formulation B-1 was expected to show unreliable gastric
retention in vivo.
As shown in Fig. 5 and Table 3, both formulations showed a decreased extent of swelling
310
in sucrose media than 0.06 N HCl solution. However, the difference was more significant for
B-1 which showed much deformation in shape whereas A-3 could maintain its integrity even
in the sucrose solution. Media with a high concentration of sugar and salts are reported to
significantly suppress polymer hydration, resulting in accelerated drug release from the
HPMC matrix (Williams et al., 2010). Therefore, it is considered that the in vitro properties
315
of PGRT300s in sucrose solution may be critical in assessing the robustness of GRDDS as
they should be administered after meals, which may contain diverse concentrations of sugar
and salts. The concentration of the sucrose was chosen to be higher than that of soft drinks,
and to represent a high concentration of sodium chloride and trisodium citrate, which are
commonly found in various kinds of food (Foster-Powell et al., 2002; Purna et al., 2006).
320
These findings indicate the superior and robust in vitro swelling property of the optimized
formulation A-3 even in harsh conditions.
15
3.3.2. Buoyancy, drug release profiles, and release kinetics
The results of the buoyancy profiles in 0.06 N HCl confirmed that A-3 started to float
325
after 3 min, and its BLT was within 10 min, whereas B-1 started to float after 12 min, and its
BLT was close to 1 h (Fig. 6A). These differences were expected as the formulation B-1
contains crospovidone that was shown to improve floating properties. In contrast, BLT for
both formulations was significantly decreased in the sucrose solution compared with that in
0.06 N HCl, as shown in Fig. 6C. It is also expected as the density of sucrose solution was
330
approximately 1.1 g/mL. However, this result has to be taken with caution regarding
buoyancy in vivo as the sucrose concentration is higher than the commercially available soft
drinks. Furthermore, the ingested foods and drinks are usually diluted by water and secreted
gastric juice which their densities are close to 1.0 g/mL (Murata et al., 2000). Hence, a more
conservative approach, such as testing in low-density medium, is feasible for assessing the
335
floating properties and securing buoyancy in vivo.
As illustrated in Fig. 6B and D, dissolution was maintained for 24 h or longer, indicating
the robustness of the developed formulation against harsh conditions such as concentrated
sucrose solution. The drug release and buoyancy testing were conducted for a longer duration
(24 h) than actual expected gastric retention time to ensure the robustness against strong
340
contractile forces impinged by the stomach (Kostewicz et al., 2014). Namely, if the dosage
form can float and sustain the drug release for 24 h in vitro, the dosage form has a higher
chance of maintaining its integrity to remain floating and release the drug until being emptied
from the stomach. Unexpectedly, their drug release rates decreased significantly in the
sucrose solution, which is inconsistent with the previous study conducted for HPMC matrix
345
containing caffeine as the model drug (Williams et al., 2010). Above the critical sugar
16
concentration, swelling and solubility of the HPMC particles are decreased by increasing
their hydrophobic interactions, making the gel layer more susceptible to erosion. On the
contrary, adding sugar below its critical concentration was reported to increase the gel layer
thickness and suppress the drug dissolution (Williams et al., 2009). However, considering that
350
the swollen tablet dimensions after 24 h in sucrose solution was shorter and shape integrity
was poorer than those tested in 0.06 N HCl (Fig. 5 and Table 3), the claim that sucrose
increased the gel layer thickness seems to be unlikely.
In order to investigate the possible causes of the decreased release rate, dissolution
profiles of raw pregabalin powder were evaluated in the two media. As shown in Fig. 7, raw
355
pregabalin had significantly faster dissolution rate in 0.06 N HCl than in sucrose solution (P
< 0.001). Decreased release rate in sucrose solution might be due to reduced solubility of
pregabalin and slower dissolution rate of the drug itself. Although pregabalin is regarded very
soluble, its dose is high and solubility is lower than caffeine (Cook et al., 2008; Williams et
al., 2009), and the effect of decreased solubility could have overcome the effect of increased
360
erosion. It could also be due to increased gel tortuosity as reported for HPMC matrix in an
ionic media (Mitchell et al., 1990) or the effect of adding PEO to the HPMC-based
formulation.
Table 4 shows the parameters that describe drug release using the Korsmeyer-Peppas
model. The Korsmeyer-Peppas model explains two mechanisms for drug release behavior
365
from the swellable matrix, i.e. Fickian diffusion and Case-II transport. For a cylindricalshaped matrix, the release exponent n indicates Fickian transport (diffusion-based) when n ≤
0.45, non-Fickian transport (anomalous) when 0.45 < n < 0.89, Case II transport (erosionbased) when n = 0.89 (Siepmann and Peppas, 2001). As shown in Table 4, calculated release
exponent values indicated anomalous release behavior (0.45 < n <0.89) for both formulations
17
370
in all media. Formulation B-1 in 0.06 N HCl, however, showed more erosion-based
dissolution as the calculated release exponent was closer to 0.89. This is associated with less
resistance of the HPMC matrix against erosion due to lower HPMC content in the
formulation. It is useful to note that the release exponent values for both formulations were
increased in sucrose solution. This indicates that pregabalin exhibits more erosion-based
375
release behavior in sucrose solution due to decreased solubility and its tendency to diffuse out
from the gel layer. Increased effect of erosion was commonly observed for hydrophilic
matrices containing low solubility drugs (Bettini et al., 2001; Hwang et al., 2017). This again
signifies the decreased ability of the drug to diffuse out from the gel layer either due to
decreased drug solubility or increased tortuosity of the gel layer in high concentration sucrose
380
and salt solution. A more in-depth study may be required for clarifying the specific
mechanism. Nevertheless, the in vitro results show the robustness of the developed system,
and thus sustained absorption of the drug is anticipated in vivo.
3.4. In vivo pharmacokinetics
385
In order to prove the gastroretention effect of optimized formulation A-3 over slowly
floating formulation B-1, the two formulations and commercially marketed Lyrica® IR
capsules were administered orally to fed-state beagle dogs. It was hypothesized that the
formulation B-1 will show highly variable and lower AUC values compared to A-3 due to
inconsistent gastric retention time. The pharmacokinetic profiles and parameters are
390
displayed in Fig. 8 and Table 5. Both A-3 and B-1 showed sustained absorption with 5 to 6 h
of Tmax, and this indicates that no burst release occurred in the fed stomach which is
anticipated by in vitro drug-release results in sucrose solution.
18
Regarding the total extent of absorption, the ratio of AUC0-24 h was 2.05 for A-3 against the
IR capsules, showing a statistically significant difference against the group administered with
395
IR capsules. It is also noteworthy that the dose strength of the developed GR tablets is
different from marketed CR products. The marketed CR tablets have dose strengths which are
more than double for marketed IR capsules (e.g., 330 mg q.d. of CR tablet corresponding to
150 mg b.i.d. of IR capsule), supposedly due to rapid gastric emptying and reduced
absorption in other parts of the GI tract (Bockbrader et al., 2010) than upper intestine. It thus
400
follows that if the GR dosage form can stay long enough in the stomach to release most of its
drug, the relative bioavailability for GR formulation to the marketed IR capsule will be close
to unity, which is confirmed in this study.
In contrast, the AUC value of B-1 group was lower than that of the A-3 group.
Additionally, among the group B-1with high variability, could be easily divided into two
405
groups with high and low absorption (AUC0-24 h and Cmax). A group with good absorption
(n=3) had AUC0-24 h of 317.84 ± 16.66 µg·h/mL and Cmax of 26.53 ± 2.08 µg/mL whereas
poor absorption group (n=2) had AUC0-24 h of 92.58 ± 36.77 µg·h/mL and Cmax of 6.8 ± 1.41
µg/mL. The inconsistencies in the absorption profiles could be due to premature gastric
emptying and passing the main absorption site, upper intestine. As formulation B-1 had poor
410
floating properties and weak matrix integrity, some of the tablets (in poor absorption groups)
may have been crushed by harsh contractile actions and emptied from the stomach
prematurely. Although radiographic imaging studies were not conducted to locate the tablets
in vivo, the higher extent of absorption and lower standard variation nevertheless indicates
the robustness of the optimal formulation A-3 over B-1. High swelling and floating properties
415
of the optimized formulation enabled consistent gastric emptying time. As the GI motility in
dogs was reported to be even stronger than that of humans (Martinez and Papich, 2009),
19
success in dog trials indicates a higher chance of success in human clinical trials.
3.5. In vivo dose proportionality
420
The in vitro dissolution and GR properties of formulations with decreased strengths are
represented in Table 6. PGRT150 (C-1) and PGRT75 (D-1) were formulated to acquire
similar in vitro properties with the optimal PGRT300 (A-3). The release profiles of the three
formulations were similar to each other, as indicated by f2 values higher than 50. In addition,
all three expanded dimensions of the formulations were longer than 12.8 mm, the critical size
425
for gastric retention. Although the BLT was delayed slightly due to the reduced amount of
HPMC in the formulation, they could float within ca. 21 min. It is important for PGRTs to be
prepared in multiple strengths not only because the marketed products are prescribed in
various doses, but this is also a way to confirm the applicability of the developed noneffervescent floating GRDDS. If the developed system is not robust, the system will not show
430
dose proportionality as the total extent of absorption will decrease for formulations with poor
GR properties and premature gastric emptying. The preparation methods were also kept the
same and minimal changes to the formulation except for the dose was applied to maintain its
floating and swelling properties.
As given in Fig. 9 and Table 7, all three formulations showed similar Tmax and differed
435
only in the total extent of absorption. More importantly, they showed that systemic exposure
of pregabalin from the optimized GRDDS was dose-proportional in which the slope (β) of
Cmax and AUC was 0.9872 and 1.0885, respectively, in the range of 75 mg to 300 mg with
high correlation coefficients (R2>0.992). The pharmacokinetic profiles for the formulations
were also reliable as the variability in AUC values and Cmax for three groups was smaller than
20
440
that of the group administered with B-1, which has reduced GR properties (Table 5). Thus, it
seems that the developed non-effervescent GRDDS showed robust in vivo performance in
various strengths and could be suggested as once-daily formulations for a narrow absorption
window drug, pregabalin.
445
4. Conclusion
The in vitro results confirmed that HPMC and crospovidone are significant for controlling
BLT and drug-release in the gastroretentive formulations. The optimized PGRT300
formulation showed a sustained drug release pattern with the non-Fickian release behavior,
450
began to float within 3 min, floated completely within 10 min, maintained buoyancy for over
24 h, and expanded above the fed-state pyloric sphincter diameter, 12.8 mm, in three
dimensions. In the in vivo pharmacokinetic study, A-3 showed total extent of absorption twofold to that of the IR formulation, indicating the relative bioavailability is close to unity. In
contrast, formulation B-1 having poor floating and swelling properties showed highly
455
variable and poor extent of absorption, which emphasizes the importance of in vitro GR
properties for narrow absorption window drugs. Dose proportionality for optimal PGRTs
developed in this study was observed from 75 mg to 300 mg. The developed non-effervescent
floating GRDDS may aid formulation scientists in developing effective GR dosage forms for
drugs with a narrow absorption site.
460
Conflicts of interest (COI)
21
The authors declare no conflict of interest.
Acknowledgments
465
This research did not receive any specific grant from funding agencies in the public,
commercial, or non-for-profit sectors.
22
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27
Tables and figures
Table 1. Composition of PGRTs.
Table 2. Physical properties of PGRTs (n = 5, Mean ± SD).
Table 3. Swelling properties of A-3 and B-1 after 24 h in different dissolution media (n = 3,
Mean ± SD).
Table 4. Korsmeyer-Peppas kinetic parameters of PGRT300 with different gastroretentive
properties.
Table 5. Pharmacokinetic parameters of PGRTs and marketed immediate release product in
beagle dogs (n = 4 for A-3, n = 5 for B-1 and Lyrica® capsule, Mean ± SD).
Table 6. Summary of in vitro results for PGRT300, 150 and 75 in 0.06 N HCl (n = 3, Mean ±
SD).
Table 7. Pharmacokinetic parameters of PGRTs in beagle dogs (n = 5, Mean ± SD).
Figure 1. Schematic illustration of scoring grade for buoyant behavior. Score 0 indicates nonfloating, whereas score 10 indicates emerging above dissolution medium.
Figure 2. Effect of HPMC on buoyancy behavior (A) and drug release (B) in 0.06 N HCl.
The inset shows the initial buoyancy behavior until 30 min (n = 3, Mean ± SD).
Figure 3. Effect of PEO on buoyancy behavior (A) and drug release (B) in 0.06 N HCl. The
inset shows the initial buoyancy behavior until 30 min (n = 3, Mean ± SD).
Figure 4. Effect of crospovidone and MCC on buoyancy behavior (A) and drug release (B) in
0.06 N HCl. The inset shows the initial buoyancy behavior until 120 min (n = 3, Mean ± SD).
Figure 5. Representative photographs of PGRTs after swelling in different dissolution media.
Figure 6. Comparison of A-3 and B-1 on in vitro buoyancy behavior in 0.06 N HCl (A), drug
release in 0.06 N HCl (B), buoyancy behavior in sucrose solution (C), and drug release in
sucrose solution (D). The inset shows the initial buoyancy behavior until 60 min (n = 3, Mean
± SD).
Figure 7. Dissolution of raw pregabalin powder in different media. The inset shows the initial
profile until 120 s.
Figure 8. Mean plasma concentration profiles of PGRTs and marketed immediate release
capsules (Lyrica® capsule) in beagle dogs. (n = 4 for A-3, n = 5 for B-1 and Lyrica® capsule,
Mean ± SD).
Figure 9. Mean plasma concentration profiles of PGRT75, PGRT150, and PGRT300 (n = 5,
Mean ± SD).
28
29
30
31
32
33
34
35
36
37
Table 1. Composition of PGRTs.
(mg)
Intragranular
Formulation code
A-1
A-2
A-3
A-4
A-5
A-6
A-7
A-8
B-1
C-1
D-1
Pregabalin
300
300
300
300
300
300
300
300
300
150
75
HPMC
350
350
300
250
300
300
350
350
200
300
275
HPC
25
25
25
25
25
25
25
25
20
20
20
PEO
100
100
100
100
150
50
100
100
100
100
125
50
50
50
50
50
50
25
50
50
50
50
Crospovidone
Extragranular
MCC
Colloidal silicon dioxide
15
15
15
15
15
15
15
15
15
10
10
Magnesium stearate
5
5
5
5
5
5
5
5
5
5
5
Total
795
845
795
745
845
745
895
870
640
635
560
38
Table 2. Physical properties of PGRTs (n = 5, Mean ± SD).
Formulation code
Length (mm)
Width (mm)
Thickness (mm)
Hardness (kgf)
A-1
18.9
9.1
6.23 ± 0.04
14.9 ± 0.2
A-2
18.9
9.1
6.44 ± 0.03
10.1 ± 0.3
A-3
18.9
9.1
6.28 ± 0.06
14.2 ± 0.6
A-4
18.9
9.1
6.24 ± 0.05
15.0 ± 0.7
A-5
18.9
9.1
6.33 ± 0.01
13.8 ± 0.8
A-6
18.9
9.1
5.74 ± 0.01
10.6 ± 0.5
A-7
18.9
9.1
6.41 ± 0.05
13.5 ± 0.6
A-8
18.9
9.1
6.44 ± 0.05
13.3 ± 0.7
B-1
18.9
9.1
5.37 ± 0.06
10.7 ± 0.3
C-1
18.9
9.1
5.41 ± 0.02
13.7 ± 0.5
D-1
19.0
7.8
5.10 ± 0.02
14.9 ± 0.4
39
Table 3. Swelling properties of A-3 and B-1 after 24 h in different dissolution media (n = 3, Mean ± SD).
Formulation
code
A-3
B-1
Dissolution
media
Dimensions after swelling (mm)
Change in dimensions (%)
Length
Width
Thickness
Length
Width
Thickness
0.06 N HCl
28 ± 0
15 ± 1
15 ± 1
148.1 ± 0.0
161.2 ± 6.3
244.1 ± 9.2
23 ± 1
13 ± 2
14 ± 1
121.7 ± 5.3
142.9 ± 22.0
217.6 ± 9.2
26 ± 1
13 ± 0
13 ± 1
137.6 ± 5.3
142.9 ± 0.0
241.9 ± 18.6
22 ± 5
12 ± 1
12 ± 0
116.4 ± 26.5
128.2 ± 6.3
223.3 ± 0.0
Sucrose
solution
0.06 N HCl
Sucrose
solution
40
Table 4. Korsmeyer-Peppas kinetic parameters of PGRT300 with different gastroretentive properties.
Formulation code
Dissolution medium
R2
n
k
0.06 N HCl
1.000
0.591
18.132
Sucrose solution
0.999
0.776
6.977
0.06 N HCl
1.000
0.685
20.706
Sucrose solution
0.998
0.787
7.418
A-3
B-1
41
Table 5. Pharmacokinetic parameters of PGRTs and marketed immediate release product in beagle dogs
(n = 4 for A-3, n = 5 for B-1 and Lyrica® capsule, Mean ± SD).
Formulation code
Dose (mg)
Cmax
(µg/mL)
Tmaxa
(h)
AUC0-24 h
(µg·h/mL)
Ratio of
AUC0-24 hb
A-3
300
27.2 ± 6.1
5.0 (4.0–6.0)
319.2 ± 68.5*
2.05
B-1
300
18.6 ± 10.9
6.0 (2.0–6.0)
227.7 ± 125.3
1.46
Lyrica® capsule
150
22.0 ± 4.3
0.5 (0.5–1.5)
155.9 ± 11.2
-
*
Statistically significant difference compared with Lyrica ® capsule (p < 0.05).
Median (range).
b
Ratio of PGRT300 (A-3 or B-1) to Lyrica® capsule.
a
42
Table 6. Summary of in vitro results for PGRT300, 150 and 75 in 0.06 N HCl (n = 3, Mean ± SD).
Formulation code
Parameters
PGRT300 (A-3)
PGRT150 (C-1)
PGRT75 (D-1)
Similarity factor (f2)a
-
63.6
51.1
Lag time for initiation of buoyancy (s)
170 ± 17
287 ± 95
765 ± 114
Lag time for complete buoyancy (s)
470 ± 35
940 ± 69
1245 ± 102
Floating duration (h)
> 24
> 24
> 24
Length (cm)
2.8 ± 0.0
2.8 ± 0.0
3.1 ± 0.1
Width (cm)
1.5 ± 0.1
1.8 ± 0.1
1.3 ± 0.1
Thickness (cm)
1.5 ± 0.1
1.7 ± 0.1
1.3 ± 0.0
Expanded size after 24 h
in 0.06 N HCl
a
f2 values of PGRT150 and PGRT75 were calculated by comparing their mean dissolution values to those of
PGRT300.
43
Table 7. Pharmacokinetic parameters of PGRTs in beagle dogs (n = 5, Mean ± SD).
Dose
(mg)
Parameters
Formulation code
Cmax (µg/mL)*
Tmaxa (h)
AUC0-24 h (µg·h/mL)*
PGRT300 (A-3)
300
22.1 ± 6.3
4.0 (2.5–4.0)
250.1 ± 62.8
PGRT150 (C-1)
150
11.2 ± 1.0
4.0 (3.0–12.0)
132.2 ± 28.5
PGRT75 (D-1)
75
5.6 ± 0.7
4.0 (2.5–4.0)
55.3 ± 4.7
*
Statistically significant differences between A-3, C-1 and D-1 (p < 0.05).
a
Median (range).
44
Graphical abstract
45
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ijpharm, 2018, 038
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