Beruflich Dokumente
Kultur Dokumente
Original research
a r t i c l e i n f o a b s t r a c t
Article history: Gliclazide is a second generation sulphonylurea used in the treatment of type 2 diabetes characterized by
Received 12 December 2014 a low risk of hypoglycaemia and cardiovascular disorders. This drug shows poor water solubility,
Received in revised form particularly at low pH values, that may cause reduced and variable absorption after oral administration,
30 January 2015
above all in fasted state. To improve gliclazide dissolution behavior, different drug carrier systems were
Accepted 30 January 2015
prepared and tested using two different methods: co-mixing and co-milling. The samples produced were
Available online 31 January 2015
characterized by differential scanning calorimetry, powder X-ray diffraction, and scanning electron mi-
croscopy. Their dissolution rate was tested and compared to an immediate release commercial product.
Keywords:
Gliclazide
Several approaches were effective for a rapid and complete dissolution of this drug: co-milling with
Dissolution rate suitable hydrophilic carriers such as cross-linked swellable polymers or amorphous silica and co-milling
Solid dispersion with a small amount of sodium lauryl sulphate (10 mg). In the case of the highest dose (80 mg) both
Crosslinked polyvinylpyrrolidone approaches should be used at the same time to avoid saturation of the medium.
Co-milling © 2015 Elsevier B.V. All rights reserved.
Solubility
http://dx.doi.org/10.1016/j.jddst.2015.01.002
1773-2247/© 2015 Elsevier B.V. All rights reserved.
18 L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23
been proposed to improve the solubility and/or the dissolution rate modifications.
of poorly soluble drugs such as micronization [17], salt formation
[5], co-crystals [6], complexation [16] and solid dispersions 2. Materials and methods
[7,10,24] [21]. demonstrated an increase in gliclazide dissolution
rate, compared to gliclazide suspension and gliclazide alone, using 2.1. Materials
ordered binary and ternary mixture of the drug with water soluble
excipients. A significant enhancement of gliclazide dissolution rate Gliclazide was kindly donated by Labochim S.p.A. (Milan, Italy);
was also obtained using solid dispersion prepared with silica and crosslinked polyvinylpyrrolidone (PVPC) Polyplasdone® XL-10 was
polyvinypyrrolidone K30 [12], polyvinylpyrrolydone K90 [4] and from GAF corporation (New York, USA); sodium starch glycolate
PEG 6000 [3]. Several mechanisms were suggested for the (SSG) Primojel® from Elko (Milan, Italy); crosslinked carboxymethyl
improvement of the dissolution properties of insoluble drugs from cellulose (CMCC) Ac-Di-Sol® from FMC Europe (Brussel, Belgium);
solid dispersions, including particle size reduction of the drug, amorphous silica (AS) (Syloid® 72FP) from Grace Davison (Milan,
complete or partial transformation to the amorphous state, Italy); mannitol (M) (Pearlitol® 200SD) from Roquette-Italy (Cas-
reduction of aggregation and improved drug wettability [7]; [10]. sano Spinola, Italy); polyoxyethylene polyoxypropylene tri-block
Conventional methods for solid dispersion preparation include copolymer Poloxamer (PO) (Kolliphor P 407 Micro) from BASF
solvent evaporation, melt crystallization, hot-melt extrusion, (Ludwingshafe, Germany). All the chemicals were of reagent grade,
lyophilization; these methods are efficient, but they are charac- and all the materials were used as received. Some dosage forms
terized by several disadvantages [26]; [27]. In the melting method, available on the Italian market were also evaluated. Two immediate
water-soluble polymers which can solve drugs are limited, and the release (IR) formulations were Diabrezide® (80 mg gliclazide;
high process temperatures may adversely affect drug stability. Merck Serono S.p.A., Rome, Italy), gliclazide EG® (80 mg gliclazide;
Solvent evaporation methods have recently attracted considerable EG S.p.A., Milan, Italy). Five modified release (MR) formulations
attention, although they require organic solvents and are quite were: Diamicron® (30 mg gliclazide; Servier Italia S.p.A., Rome,
expensive processes [28]. Powders co-mixing and co-grinding is an Italy) Dramion® (30 mg gliclazide; I.F.B. Stroder S.r.l., Florence,
alternative solid dispersion generating method. Many authors have Italy), gliclazide EG® (30 mg gliclazide; EG S.p.A., Milan, Italy), gli-
demonstrated the efficacy of the co-grinding method for the clazide Mylan generics (gliclazide 30 mg; Mylan S.p.A., Milan, Italy).
enhancement of the dissolution rate of various poorly soluble drugs
such as danazolo, felodipine [29], nateglinide [13], aclofenac [15].
Co-grinding is an environmentally friendly and solvent-free 2.2. Methods
method, it avoids the thermal degradation of the drugs, it does
not require sophisticated equipments, it is industrially feasible and The particle size analysis was determined, by laser diffraction,
can be easily scaled-up. In this work, to enhance the dissolution Coulter LS 230 (CoulterCorp., Miami, FL, USA), on raw gliclazide and
behavior of gliclazide, some solid dispersions were prepared, in on a drug sample treated alone in the same conditions used for the
different drug to polymer ratios. The dissolution behavior of the co- production of the drug-carrier co-milled systems, to verify a
ground systems was evaluated and compared to that of the corre- possible particle size reduction.
sponding physical mixtures and to some commercial gliclazide Gliclazide solubility was determined in triplicate in over satu-
formulations, considered as references. Solid state characterization ration conditions by dispersing an excess of drug in volumetric
of drug-carrier systems was carried out by scanning electron mi- flasks at 21 C in distilled water. The suspensions were left under
croscopy (SEM), differential scanning calorimetry (DSC) and pow- constant magnetic stirring, 300 rpm, for 24 h. At 2, 4, 6 and 24 h, an
der X-ray diffraction (PXRD) to investigate possible drug aliquot of the liquid was filtered through a Millipore membrane
(pore size 0.45 mm), properly diluted and the drug concentration
Table 1
T50% ± Standard Deviations (S.D.) of gliclazide alone, gliclazide treated (T) and physical mixtures (PM) or co-milled (CM) drug-carrier systems in distilled water or HCl 0.1 N (*).
Fig. 3. SEM micrographs of gliclazide (a), treated gliclazide (b), mannitol (c), CM GLI:M 1:8 (d), amorphous silica (e), CM GLI:AS 1:8 (f), PVPC (g) and CM GLI:PVPC 1:8 (h).
L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23 21
Fig. 4. PXRD pattern of gliclazide (a), CM GLI:M 1:8 (b), mannitol (c), CM GLI:AS 1:8 (d) Fig. 7. PXRD pattern of gliclazide (a), CM GLI:PVPC 1:4 (b), CM GLI:PVPC 1:8 (c) and
and amorphous silica (e). PVPC (d).
co-milled 1:8 is only the 25%. The same trend characterizes the
PXRD results: the intensity of the drug diffraction peaks is very low
in the patterns of the physical mixtures and even lower in those of
the co-milled systems (Fig. 7). Thus, these analyses allow to attri-
bute the increased drug dissolution rate also to another cause: the
partial amorphization of the drug.
The dissolution behavior of two other carriers, sodium starch
glicolate (SSG) and crosslinked carboxymethyl cellulose (CMCC)
was also investigated; in this case, only the highest drug:polymer
ratio, 1:8 (w:w), was evaluated. In both cases the carriers were
effective, although the dissolution profile were slightly slower than
that obtained from CM GLI:PVPC 1:8 (the f2 values were respec-
tively of 26.9 and 46.8) (Fig. 8). The CM GLI:CMCC 1:8 system
showed an initial improvement of the dissolution rate, comparable
to that of the system containing PVPC, but after 15 min the rate
decreased and the profile became quite flat, allowing the release of
roughly 75% of the dose in 1 h of test. On the other hand, the CM
GLI:SSG 1:8 formulation exhibited a slower dissolution rate
compared to the co-milled system containing CMCC (f2: 43.2), but
it released 90% of the dose in 60 min.
Fig. 8. Dissolution curves of gliclazide co-milled systems with PVPC, CMCC or SSG in
1:8 w:w drug:polymer ratio and co-milled system containing 10 mg of sodium lauryl These differences in the release profiles can be explained by the
sulfate, compared to gliclazide alone. Dose: 30 mg. different mechanisms of action of the three superdisintegrants.
When exposed to water, SSG and CMCC absorb water quickly and
swell a lot forming, particularly at high concentrations, a viscous gel
layer that could act as a barrier for drug diffusion and thus retarding
drug release. PVPC is characterized by a rigid porous structure, it
absorbs water by capillary action, without gelling, thus increasing
drug particles wettability without reducing drug diffusion.
To improve drug wettability the surfactant sodium lauryl sulfate
(SLS) was also evaluated. The Food and Drug Administration (FDA)
specifies the maximum amount of inactive ingredient for each
route/dosage form containing that ingredient; in the case of oral
tablets the maximum registered amount of SLS is 51,69 mg [9].
Indeed the CM GLI-SLS, containing 10 mg of sodium lauryl sulphate,
released 30 mg of gliclazide in less than 10 min (Fig. 8). We have
decided to use 10 mg in our formulation because the treatment
with gliclazide may involves many daily administrations.
All the co-milled systems were also evaluated on the higher
dosage of 80 mg, but, in this case, the saturation of the medium
occurred and none of the binary systems were able to release the
entire dose during the first 60 min of dissolution (Fig. 9). A ternary
formulation was then designed The superdisintegrant PVPC was improved solubility: preparation, physico-chemical characterization and
in vitro dissolution, Cryst. Eng. Commun. 14 (2012) 6035e6044.
selected for the final ternary formulation containing 80 mg of drug.
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