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Preparation and investigation of mefenamic acid - polyethylene glycol - sucrose ester solid dispersions

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Mefenamic acid (MA) is a widely used non-steroidal anti-inflammatory (NSAID) drug. The adverse effects typical of NSAIDs are also present in the case of MA, partly due to its low water solubility. The aim of this study was to increase the water solubility of MA in order to influence its absorption and bioavailability. Solid dispersions of MA were prepared by the melting method using polyethylene glycol 6000 and different types (laurate, D-1216; palmitate, P-1670; stearate, S-1670) and amounts of sucrose esters as carriers. The X-ray diffraction results show that MA crystals were not present in the products. Dissolution tests carried out in artificial intestinal juice showed that the product containing 10 % D-1216 increased water solubility about 3 times. The apparent permeability coefficient of MA across human Caco-2 intestinal epithelial cell layers was high and, despite the difference in solubility, there was no further increase in drug penetration in the presence of the applied additives.
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453
Acta Pharm. 65 (2015) 453–462 Origi nal research pap er
DOI: 10.1515/acph-2015-0035
Preparation and investigation of mefenamic acid –
polyethylene glycol – sucrose ester solid dispersions
Mefenamic acid (MA) is a widely used non-steroidal anti-
inammatory (NSAID) drug. The adverse eects typical of
NSAIDs are also present in the case of MA, partly due to its
low water solubility. The aim of this study was to increase
the water solubility of MA in order to inuence its absorp-
tion and bioavailability. Solid dispersions of MA were pre-
pared by the melting method using polyethylene glycol
6000 and dierent types (laurate, D-1216; palmitate, P-1670;
stearate, S-1670) and amounts of sucrose esters as carriers.
The X-ray diraction results show that MA crystals were
not present in the products. Dissolution tests carried out in
articial intestinal juice showed that the product contain-
ing 10 % D-1216 increased water solubility about 3 times.
The apparent permeability coecient of MA across human
Caco-2 intestinal epithelial cell layers was high and, de-
spite the dierence in solubility, there was no further in-
crease in drug penetration in the presence of the applied
additives.
Keywords: mefenamic acid, sucrose esters, PEG 6000, solid
dispersion, Caco-2 cells
Mefenamic acid [MA, 2-(2,3-dimethylphenyl)aminobenzoic acid], an anthranilic acid
derivative, is a widely used non-steroidal anti-inammatory (NSAID) drug (1).
Regarding the pharmacokinetics of the drug, MA is absorbed from the small intestine
(2), its bioavailability is about 90 % but is inuenced by the amount of water ingested with
the drug in fasting subjects. The tmax is aained in 2–4 hours, and steady-state concentra-
tion is reached in 2–3 days (2, 3).
Like other NSAIDs, MA can cause serious gastrointestinal adverse eects (bleeding,
ulceration) due to its mechanism of action (4) and acting as an irritant of the gastrointesti-
nal mucosa (5).
MA belongs to class II of the biopharmaceutical classication system (BCS) – drugs
with low solubility and high permeability; therefore, its oral bioavailability is determined
by its dissolution rate in the gastrointestinal uid and, consequently, it has variable absorp-
IBOLYA FÜLÖP1
ÁRPÁD GYÉRESI1
LÓRÁND KIS S2
MÁRIA A. DELI 2
MIRCEA DUMITRU CROITORU1*
PIROSKA SZABÓ- RÉVÉSZ3
ZOLTÁN AIGNER3
1University of Medicine and Pharmacy
Tîrgu Mureş, Faculty of Pharmacy
540139, Tîrgu Mureş, Romania
2Institute of Biophysics
Biological Research Centre
Hungarian Academy of Sciences
6726, Szeged, Hungary
3University of Szeged
Faculty of Pharmacy
Department of Pharmaceutical Technology
6720, Szeged, Hungary
Accepted July 14, 2015
* Correspondence; e-mail: croitoru.mircea@umgm.ro
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I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
tion (6, 7). In the literature, there are dierent methods to enhance MA solubility and dis-
solution rate. The most commonly used techniques are the formation of inclusion com-
plexes with several cyclodextrin derivatives (8–10) and preparation of solid dispersions
(SD) with water soluble polymers (polyvinylpyrrolidone, PVP, or polyethylene glycol, PEG)
(11) in binary and ternary systems with a disintegrant and Polysorbate 20, respectively (12).
Solubility increase was achieved in both cases according to literature data, but there is no
information regarding the eect of auxiliary substances on permeability. Auxiliary sub-
stances may negatively aect the permeability (13). The presence of hydroxy-propyl-b-
cyclodextrin decreased the permeability of dexamethasone in a Caco-2 cell model and in
the in situ single-pass rat intestinal perfusion model (14) while Polysorbate 80 decreased
permeability of progesterone across an articial dimethicone membrane (15). Polymers
such as PEG 400 are also able to reduce the permeability of lipophilic drugs (16). PEG with
higher molecular mass increases the permeability coecient (Papp) of indomethacin (17).
The permeability-increasing eect of sucrose esters (SE) on Caco-2 cells was also demon-
strated (18).
The aim of our work was to increase the water solubility of MA in order to reduce its
gastrointestinal adverse eects (19) and the variability of absorption. Modication of the
permeability of MA in dierent solid dispersions was also evaluated (solubility-permea-
bility interplay). Ternary products were prepared with PEG 6000 and sucrose esters as
carriers. Sucrose esters were chosen as ternary components because they can act as pene-
tration enhancers along with their solubility increasing property. Sucrose esters are non-
-ionic surfactants (20, 21) and, due to their thermal behaviour (low melting point), can be
used in preparation of solid dispersions made by the melting technique (21, 22). In this
paper, beside the product preparation method, the solubility and permeability inuencing
properties of the obtained solid dispersions are presented.
EXPERIMENTAL
Materials
Mefenamic acid and all reagents were purchased from Sigma-Aldrich, Hungary, un-
less otherwise indicated. Laurate sucrose ester (D-1216, sucrose laurate) was of pharmaceu-
tical grade, palmitate (P-1670, sucrose palmitate) and stearate (S-1670, sucrose stearate) su-
crose esters were of analytical grade (Mitsubishi Kagaku Foods Co., Japan). PEG 6000 was
supplied by Merck, Germany. All other reagents and solvents were of analytical grade.
Product preparation
Ternary products composed of MA, PEG 6000 and SE were prepared by the melting
method. The SEs were dissolved (D1216) or suspended (P1670 and S1670) in the melted PEG
6000 (80 °C). The temperature was increased to 110 °C, then the accurately weighed MA
powder was added to the blend to dissolve under mixing for 20 minutes. The obtained
mixtures were poured onto a cooled metal plate in a thin layer to cool quickly. The tem-
perature of the cooled plate was contolled by a JULABO cryothermostate model F32 (JU-
LABO model-F32, Labortechnik GmbH, Germany). The mixtures were kept at –20 °C for
24 hours, then scraped o, pulverized in a mortar and passed through a 100-mm sieve. The
products were stored at room temperature until analysis. The composition of the products
455
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Table I. Composition o f the studied products
MA (%) SE (%) PEG (%) Product code
10
D-1216 5 85 D5
10 80 D10
P-1670 5 85 P5
10 80 P10
S-1670 5 85 S5
10 80 S10
10 0 90 PEG
Characterization of solid dispersions
X-ray diraction analysis. – X-ray diraction (XRPD) analyses were conducted using a
Rigaku MiniFlexTM II X-Ray diractometer (Rigaku Co., Japan), where the tube anode was
Cu with Kα = 1.5405 Ǻ. The data was collected using 30-kV tube voltage and 15-mA tube
current in step scan mode (4 ° min–1). The instrument was calibrated using silicon.
In vitro dissolution studies and kinetic calculations. – Dissolution studies were performed
in articial gastric uid (AGF, pH 1.2) and articial intestinal uid (AIF, pH 6.8) without
enzymes, using the rotating paddle method according to Eur. Ph. – Pharma Test PTW-II,
Germany (23), adapted to 100-mL dissolution medium. Amounts of samples equivalent to
30 mg MA were introduced into hydroxypropyl methylcellulose capsules and immersed
into the dissolution medium at a rotation speed of 100 rpm and temperature of 37 °C. Aliq-
uots of 50 mL were collected periodically and replaced with fresh dissolution medium.
Aer ltration the concentration of MA was determined spectrophotometrically (ATI UNI-
CAM UV-VIS, spectrophotometer, USA) at 352 nm (AGF) and 288 nm (AIF). Measurements
were performed in triplicate. Dissolution tests were conducted under non-sink conditions
in order to evaluate the dierences between the formulations. The mechanism of drug re-
lease was evaluated by dierent mathematical models oered by the DDSolver soware
(24). The best t was chosen based on the adjusted coecient of determination (R2adj) (25).
Cell culture, viability and permeability assays
The cell culture conditions and the methods for toxicity and permeability measure-
ments in the case of MA and its products were described by our group previously (26).
Briey, for the cytotoxicity assays, Caco-2 human intestinal epithelial cells were cultured
in 96-well plates in Dulbecco’s modied Eagle’s medium without phenol red containing
10 % fetal bovine serum (Gibco, Invitrogen, USA). During the treatment period, the plates
were placed on a horizontal shaker at 100 rpm. Tested formulations contained 1, 10, 30, 100,
300, 1000, 3000 mg mL–1 MA as the nal concentration. Cytotoxicity was evaluated by: (i)
measuring the lactate dehydrogenase (LDH) enzyme activity from culture supernatant
is presented in Table I. All products contained 10 % of MA, 5 % or 10 % of sucrose ester
(D1216, P1670 and S167, shortened as D, P and S, respectively) and 85 or 80 % of PEG 6000.
456
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
using a LDH detection kit (Roche, Switzerland), (ii) testing cell metabolic activity by meas-
uring MTT dye [3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide] conversion,
reecting the number of viable cells. To study the permeability of MA in solid dispersions,
human Caco-2 cells were cultured on Transwell lter inserts (polycarbonate membrane,
0.4-mm pore size, 1.12 cm2 surface area, Corning Costar Co., USA) for 21 days. The tran-
sepithelial electrical resistance (TEER) of Caco-2 monolayers varied between 450 and 600
W cm–2, indicating good barrier properties. The treatment solutions contained 3 or 100 mg
mL–1 MA dissolved in Ringer-Hepes buer and MA penetration across cell layers was
determined in the apical (donor) to basal (acceptor) direction for 1 hour. The concentrations
of MA were determined both in the basolateral and apical compartments using a Merck
HPLC system (consisting of a quaternary pump L-7100, auto sampler L-7200, column ther-
mostat L-7360, DAD detector L-7455, interface L-7000, solvent degasser L-7612, HSM man-
ager soware) (Merck, Germany). The analysis was carried out at ambient temperature
using a Purospher RP C18e (5 mm, 250 x 4.6 mm, Merck) column. Determinations were
performed by isocratic elution at a ow rate of 1.5 mL min–1. The mobile phase composition
consisted of 55 % 20 mmol L–1 phosphate buer (pH 6.5) and 45 % acetonitrile. Volumes of
100 mL were injected using the loop method; the detection wavelength was set at 281 nm.
Calculations were performed by measurement of peak areas.
The apparent permeability (Papp) was calculated using the formula:
where dQ/dt is the rate of drug permeation across the cells, c0 is the donor compartment
concentration at time zero and A is the area of the cell monolayer (1.12 cm2).
All data presented are means ± standard deviations. The values were compared using
ANOVA followed by Dunnet’s test using (GraphPad Prism 5.0 soware, GraphPad Soware
Inc., USA). The changes were considered statistically signicant at p < 0.05. All experiments
were repeated at least two times, the number of parallel samples varied between 3 and 8.
RESULTS AND DISCUSSION
X-ray diraction analysis
The XRPD paerns of the MA, P1670 and solid dispersions are represented in Fig. 1.
MA exists in two polymorphic forms. Based on our previous DSC thermograms (9) and
the XRPD peaks observed at 6.4, 16.0, 21.5 and 26.3° (2q) (27, 28), the form I polymorph of
MA was identied. The sharp, narrow peaks observed in the case of MA indicate its crys-
talline status. The diractograms of pure PEG 6000 and P1670 showed broad peaks at 19.2,
23.3 and 21.36° (2q), respectively. The peaks related to MA were not present in the case of
solid dispersions and the peaks of PEG 6000 are reduced and shied to higher angles, in-
dicating the amorphous state of the drug. In the case of solid dispersions, the peaks of PEG
6000 are predominantly present. Therefore, it can be conrmed that the active ingredient
is predominantly molecularly dispersed in the carrier or amorphous. The relative degree
of crystallinity (RDC) was calculated at 16.5° using the formula (29):
0
cA
dt
dQ
P
app =
SD
MA
RI
RDC RI
=
457
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
where RISD is the peak height of the solid dispersion and RIMA is the peak height of MA at
the same angle. The RDC for P10 was 0.012 and 0.014, for D5 suggesting that only partially
crystallized MA molecules are present in the products.
Dissolution studies
MA, a drug with an acidic character, dissolves slightly in AGF, especially its form I
polymorph (27); aer 120 minutes only 0.6 % of MA was dissolved. In the case of ternary
products the dissolution curves showed a peak aer 15–30 minutes, indicating that super-
saturation occured only when chiey molecularly dispersed form was present, followed
by recrystallization of the drug, which entailed a decrease in the amount dissolved. The
best results were obtained with the S5 product, where 3.1 % of MA was dissolved aer 120
min.
In AIF, 9 % of MA was dissolved aer 120 minutes (concentration of 2.70 mg per 100
mL–1 was achieved). The amount of dissolved drug increased about 3 times (28.6 %) 8.58
mg in 100 mL–1) in the product containing 10 % D-1216 compared to pure MA. In the case
of other studied products, the dissolution rate of MA proved to be lower. Solubility de-
creased in the following order: D10 > S10 > P10 > D5 > P5 >S5 > PEG. The dissolution proles
in AIF are represented in Fig. 2.
The mechanism of drug release is described by the Gompertz function:
where Fmax is maximum dissolution, a determines the undissolved portion at time t = 1
(scale factor), and b is the dissolution rate per unit time (shape factor) (30). The coecients
of determination were above 0.95 in all cases.
The Gompertz model is typically used for comparing release proles of drugs with
good solubility and intermediate release rates. This model has a steep increase at the
)log(
max
t
e
eFF
β
α
=
Fig. 1. XRPD paerns of the studied products (MA – mefenamic acid, P1670, PEG 6000 and solid dis-
persions D5 and P10 see (Table I).
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I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Fig. 2. Dissolution proles of MA alone and in solid dispersions in articial intestinal uid (mean ±
SD, n = 3).
begin ning and converges slowly to the asymptotic maximal dissolution (27). In our case,
aer fast weing of the matrix, a certain amount of MA dissolved fast; aer that, the dis-
solution media became saturated in MA because of the non-sink conditions. Similarly to
data shown in Fig. 2, D10 was the most ecient of the studied products in increasing the
MA dissolution rate according to dissolution prole data (Table II) compared to the Gom-
pertz model.
Eects of mefenamic acid and formulations on the viability of Caco-2 cells
MA was not toxic in concentrations lower than 100 mg mL–1 in both assays (MTT dye
conversion and LDH release assays) but caused cell death at concentration of 1 mg mL–1
(Table III). Formulation containing only PEG 6000 did not change the toxicity paern of the
active ingredient. Among the formulations, those containing S-1670 (S5 and S10) showed
the highest toxicity, which was increased ten times compared to MA and PEG. P-1670-
containing samples (P5 and P10) were less toxic than formulations with S-1670. The non-
toxic concentrations of P-1670 were three times higher than that for S-1670; however, the
concentrations killing cells were the same for samples S5, S10, P5 and P10. The best formu-
lation was the D5 sample containing D-1216, where the non-toxic concentration was 100 mg
mL–1 and the toxic one was 300 mg mL–1.
Eect of formulations on transepithelial electrical resistance in Caco-2 cells
Caco-2 cell layers were treated by dilution of the samples containing 3 mg mL–1 of MA.
Aer 1-hour treatment, the resistance of cell monolayers did not change; it remained in the
range of the original 450–600 W cm–2 values. No signicant dierences were found in the
resistance of cell monolayers treated with the products.
459
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Permeability measurement across Caco-2 cells
The permeability coecient of MA was 49 × 10–6 cm s–1, reecting its high permeabil-
ity rate and lipophilic character (Fig. 3).
PEG 6000 and sucrose esters could not further increase the permeability of MA at the
tested low concentration (3 mg mL–1), when the active ingredient was already completely
solubilized (Fig. 4). The permeability coecient of MA decreased statistically signicantly
in products D5 and P10 (p < 0.05), since the hydrophilic auxiliary substances reduced the
permeability of MA. The analysis was repeated in the case of MA, D5, D10 and PEG prod-
ucts using 100 mg mL–1 MA in the donor compartment. Similarly to the rst set of experi-
ments, D10 and PEG did not cause any signicant change in the permeability of MA, while
D5 drug penetration decreased signicantly (p < 0.05).
Table II. Dissolution kinetics of solid dispersions in AIF
Product Fmax ± SD
(mg per 100 mL–1)
a ± SD
(min–1)
b ± SD
(min–1)R2
MA 11.17 ± 2.49 223.20 ± 203.28 3.48 ± 1.64 0.9660
PEG 27.06 ± 14.11 88.12 ± 139.25 1.91 ± 1.41 0.9775
D5 21.87 ± 3.49 21.95 ± 20.75 2.28 ± 0.74 0.9514
D10 106.29 ± 36.80 5.98 ± 0.44 0.75 ± 0.08 0.9907
P5 60.32 ± 70.14 11.89 ± 4.96 1.34 ± 0.64 0.9806
P10 89.72 ± 50.31 6.10 ± 0.59 0.82 ± 0.37 0.9884
S5 29.86 ± 30.62 48.47 ± 41.30 2.76 ± 1.85 0.9612
S10 60.55 ± 33.04 8.84 ± 3.67 1.17 ± 0.51 0.9839
Fmax – maximum dissolution; a – undissolved portion at time t = 1 (scale factor); bdissolution rate per unit t ime
(shape factor)
Table III. Toxic eects of MA and its products on Caco-2 human epithelial cells aer 24 hours
Sample
MTT dye conversionaLDH release
TC0
(mg mL–1)
TC100
(mg mL–1)
TC0
(mg mL–1)
TC100
(mg mL–1)
MA 100 1000 100 1000
PEG 100 1000 100 1000
D5 100 300 100 300
D10 30 300 30 300
P5 30 100 30 100
P10 30 100 10 100
S5 10 100 10 100
S10 10 100 10 100
a TC0 – the highest non-toxic concentration (no toxicity); TC100 – 100 % toxic concentration
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I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
Fig. 3. Permeability of mefenamic acid measured on Caco-2 epithelial cell layers aer 1-hour treat-
ments with dierent formulations (Papp – apparent permeability coecient, * statistically signicant
dierences between the MA and the formulations, p < 0.05).
Fig. 4. Relationship between MA solubility and Papp in the case of D-1216 containing products (D5 and
D10) and the binary product (PEG) (the rate of change was calculated by dividing the solubility of the
product by the solubility of MA and the Papp of the products by the Papp of the MA).
The relationship between MA solubility and permeability
The relationship between MA solubility and permeability and its products with
D-1216 is shown in Fig. 4. The solubility rate increased in this order: MA-PEG < D5 < D10.
The rate of change of Papp (at 3 mg mL–1 MA) did not correlate with the solubility increment;
neither ascendant nor descendant tendencies could be observed. This can be explained by
the high permeability of MA and by the dierence in pH values applied in the AIF (pH 6.8)
and permeability (pH 7.4) studies.
CONCLUSIONS
The importance of increasing the water solubility of drugs belonging to BCS II class
is well known. In the case of MA, besides increasing the biopharmaceutical properties of
the drug using hydrophilic auxiliary substances, the severe adverse eects can be also
461
I. Fülöp et al.: Preparat ion and invest igation of mef enamic acid-polye thylene glycol-suc rose ester s olid dispersio ns, Acta Phar m. 65
(2015) 453–462.
reduced in such formulations. Water-solubility increasing auxiliary substances may mod-
ify the permeability of dierent APIs. In this work, dierent formulations of MA were
tested and the relationship between solubility and permeability was evaluated. MA was
embedded in the PEG 6000 polymer in the presence of sucrose ester surfactants. Based on
the dissolution test results, conrmed by the Gompertz-function parameters, the best re-
sults were obtained in the case of the 10 % D-1216 – containing product. This product also
proved to be one of the best formulations in the cellular toxicity test on Caco-2 cells. The
dissolved amount of MA aer 120 min increased only moderately, but aer 30 minutes a
signicant rise in the solubility of MA can be observed. Therefore, under in vivo conditions
the higher dissolved amount of MA – which is available for absorption – may increase the
absorption rate of MA.
Acknowledgments. – This paper was published under the framework of the European Social
Found, Human Resources Development Operational Programme 2007–2013, Project No. **
POSDRU/159/1.5/S/133377.
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... The chemical name of PL is 2-[2-(2-hydroxyethoxy)propoxy]ethanol (Wong et al., 2006). It is approved as an excipient for human use by FDA (Diniz et Various techniques have been used in the investigation of solid dispersions (SDs) of various weakly soluble drugs and other organic compounds (Moneghini et al., 2008;Aso et al., 2009;Moneghini et al., 2009;Menedez et al., 2010;Maurya et al., 2010;Van Eardenbrugh and Taylor, 2010;Issa et al., 2013;Paudel et al., 2013;Li et al., 2014;Xiqiang et al., 2014;Fulop et al., 2015;Kang et al., 2015;Wang et al., 2015;Altamimi and Neau, 2016). Microwave technology has been investigated rarely in literature in order to enhance solubility, in vitro dissolution, therapeutic efficacy and in vivo bioavailability of such drugs. ...
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... Thus their solubility has to be increased to enhance their dissolution rate and consequently to improve their bioavailability. The SDs of MA and FFA have been prepared and evaluated using different techniques and different carriers in order to enhance their solubility, dissolution and bioavailability [26][27][28][29][30][31]. However, the SDs of these drugs have not been investigated using a solvent-free MW technology in literature. ...
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