European Journal of Pharmaceutical Sciences 24 (2005) 355–361
Fast-dissolving mucoadhesive microparticulate delivery system containing piroxicam Francesco Cilurzoa,∗ , Francesca Selmina , Paola Minghettia , Isabella Rimoldib , Francesco Demartinc , Luisa Montanaria a
Istituto di Chimica Farmaceutica e Tossicologica, Universit`a degli Studi di Milano, Viale Abruzzi, 42-20131 Milan, Italy Istituto di Chimica Organica “A. Marchesini”, Universit`a degli Studi di Milano, Via G. Venezian, 21-20133 Milan, Italy Dipartimento di Chimica Strutturale e Stereochimica Inorganica, Universit`a degli Studi di Milano, Via G. Venezian, 21-20133 Milan, Italy b
c
Received 11 August 2004; received in revised form 18 November 2004; accepted 24 November 2004
Abstract We have studied the feasibility of preparing fast-dissolving mucoadhesive microparticulate delivery systems containing amorphous piroxicam to improve drug residence time on sublingual mucosa and drug dissolution rate. Two new mucoadhesive carriers, Eudragit® L100 (EuLNa) and Eudragit® S100 (EuSNa) sodium salts, both characterized by a fast intrinsic dissolution rate, have been selected. Microparticles containing piroxicam and EuLNa (series 1) or EuSNa (series 2) in ratios from 15/85 to 85/15% (m/m) were prepared by spray drying. The morphology and physical state of the microparticles and the effect of the microparticle composition on the piroxicam release and mucoadhesion were investigated. Piroxicam loaded into the microparticles was found to be in the amorphous form at all drug/copolymer ratios. This feature was ascribed to the presence of an H-bond between the NH of piroxicam and a CO of the copolymers. The formation of solid solutions improved the dissolution rate and the apparent drug solubility. The mucoadhesive properties were affected by the drug/copolymer ratio and in series 2 the microparticles containing more than 50% (m/m) of piroxicam did not show mucoadhesive properties. The delivery system made of piroxicam and EuLNa in the ratio 70/30% (m/m) appears to be the most promising because it contains the lowest amount of polymer able to confer mucoadhesive properties and increase apparent drug solubility. © 2004 Elsevier B.V. All rights reserved. Keywords: Mucoadhesive microparticles; Piroxicam; Polymethylmethacrylate sodium salts; Spray drying
1. Introduction Piroxicam is a drug with low water solubility and high membrane permeability included in class 2 of the Biopharmaceutic Drug Classification System proposed by Amidon et al. (1995). It is absorbed slowly and gradually through the gastrointestinal tract and consequently the onset of the analgesic and anti-inflammatory actions is delayed (Yuksel et al., 2003). In the management of migraine (Nappi et al., 1993), dismenorrea (Ragni and Ciccarelli, 1993), emergency renal colic (Supervia et al., 1998), and postoperative pain ∗
Corresponding author. E-mail address:
[email protected] (F. Cilurzo).
0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2004.11.010
(Pookarnjanamorakot et al., 2002; Alpaslan et al., 1997), piroxicam is administered by fast-dissolving tablets. These dosage forms show a quick onset of action (about 15 min), and a prolonged analgesic effect (Nappi et al., 1993; Minisola et al., 1993). In animal models it has been demonstrated that the rapid onset of action is due to an extensive absorption through the oral mucosa (Diez-Ortego et al., 2002). Nevertheless, focal contact esophagitis can be induced in patients during treatment with piroxicam (Levine, 1999). Fast-dissolving mucoadhesive microparticles intended for sublingual administration could be a suitable alternative to fast-dissolving tablets because the sublingual absorption can be improved as a consequence of prolonging residence time on the mucosa and reducing the amount of swallowed drug (Ahuja et al., 1997).
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The present work aimed to evaluate the feasibility of preparing fast-dissolving mucoadhesive microparticulate delivery systems containing piroxicam in amorphous form to improve drug dissolution rate. Two new low-swellable mucoadhesive methacrylic copolymers, namely Eudragit® L sodium salt (EuLNa) and Eudragit® S sodium salt (EuSNa), have been chosen as carriers for the preparation of the microparticles. Their intrinsic dissolution rates are faster than those of the most commonly used mucoadhesive polymers (Cilurzo et al., 2003). Two series of microparticles containing piroxicam and EuLNa (series 1), or EuSNa (series 2), in ratios ranging from 15/85 to 85/15% (m/m) were prepared by spray drying. The physical state of the microparticles was investigated by means of X-ray diffraction and ATR–FTIR spectroscopy. The effect of the composition on the piroxicam dissolution profile and the mucoadhesive performance of microparticles were evaluated.
Form II (needle) was crystallized from saturated absolute ethanol solution. Form III was obtained by spray-drying the solution of piroxicam in absolute ethanol in a Lab-Plant model SD04 spray-drier using the following parameters; air flow rate: 800 ml/min, inlet air temperature: 94 ◦ C and outlet air temperature: 50–55 ◦ C. The monohydrate form was obtained by dissolving piroxicam in acetone and adding the same amount of water. The precipitate was collected by filtration and dried until the weight was constant. 2.3. Microparticle preparation EuS and EuL sodium salts (EuSNa and EuLNa) were obtained by adding NaOH pellets to a polymer suspension in acetone/water (60/40%, m/m) until complete salification was achieved. The solution was spray-dried as described below. Two series of microparticulate systems made of piroxicam/EuLNa (series 1) and piroxicam/EuSNa (series 2) were designed. For each series, the ratio of drug to copolymer salt was fixed at the following values: 15/85, 30/70, 50/50, 70/30, 85/15% (m/m) (Table 1). Microparticles were prepared by a spray-drying technique (Lab-Plant model SD04, UK). The feed was prepared by dissolving the piroxicam in acetone and the copolymer salt in water. The final solution concentrations were set in order to obtain the desired piroxicam/copolymer salt ratio and a clear 2% (w/v) feed. The microparticles were obtained by spraying the feed through a standard nozzle with an inner diameter of 1 mm. The process parameters were set as follows: inlet temperature, 80 ◦ C; outlet temperature, 48–50 ◦ C; and feed flow rate, 6 ml/min.
2. Materials and methods 2.1. Materials Micronized piroxicam in cubic form was obtained from Dipharma (I). Eudragit® S100 (EuS), poly(methacrylic acid, methyl methacrylate), molar proportions of the monomer units 1:2, molecular weight 135,000 Da (R¨ohm, G), and Eudragit® L100 (EuL), poly(methacrylic acid, methyl methacrylate), molar proportions of the monomer units 1:1, molecular weight 135,000 Da (R¨ohm, G), were kindly donated by Rofarma (I). Crude (type II) mucin from porcine stomach was purchased from Sigma Chemical Co. (USA). All substances were used as received. All solvents were of analytical grade.
2.4. Particle size measurement Particle size distribution was determined using a Malvern 2600c laser diffraction particle sizer (Malvern Instrument, UK). The microspheres were suspended in pre-filtered isopropanol and a 63-mm focal length lens (for a size range of
2.2. Preparation of polymorphic forms of piroxicam The polymorphic forms of piroxicam were obtained according to the methods described by Vrecer et al. (2003). Table 1 Microparticles composition (%, m/m) and size distribution (m) Series
Formulation no.
Microparticle composition (%, m/m)
Size distribution (m)
Piroxicam
EuLNa
Diameter 10%a
Diameter 50%b
Diameter 90%c
Mean volume diameter
EuSNa
1
1 2 3 6
85 70 50 0
15 30 50 100
– – – –
2.4 4.1 3.7 7.2
3.1 7.2 7.1 14.3
4.0 12.7 13.8 7.15
3.12 7.22 7.13 4.24
2
7 8 9 10 11 12
85 70 50 30 15 0
– – – – – –
15 30 50 70 85 100
7.2 2.7 3.2 2.9 2.5 2.5
6.1 4.0 5.2 4.9 4.2 4.5
12.5 5.9 8.4 8.3 7.1 8.3
6.08 4.00 5.15 4.95 4.24 4.53
a b c
10% of particles were smaller than that number. 50% of particles were smaller than that number. 90% of particles were smaller than that number.
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0.5–118 m) was employed to determine particle size. Particle size was expressed as volume median diameters in microns. 2.5. Scanning electron microscopy The surface morphology and shape of series 1 and series 2 placebo and drug-loaded microspheres were analyzed by SEM (JSM-T 800-JEOL, I). The samples were sputtered with an Au/Pd coating in an argon atmosphere. 2.6. Thermogravimetric analysis The formation of monohydrated form of piroxicam and the water content of microparticles was determined by thermogravimetric analyses using a TGA 2050 thermogravimetrical analyzer (TA Instruments, USA). Samples of approximately 20 mg were heated in a platinum crucible at 10 K/min under a nitrogen atmosphere and the loss of weight was recorded. 2.7. ATR–FTIR spectroscopy ATR–FTIR spectra were recorded with an ATR-FTIR spectrometer (Perkin Elmer, USA) equipped with a diamond crystal. Sixty-four scans were collected for each sample at a resolution of 2 cm−1 over the wavenumber region 4000–650 cm−1 . The experiments were conducted on piroxicam polymorphs, placebo and drug-loaded microparticles of both series and the corresponding physical mixtures.
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2.10. In vitro mucoadhesion test The texture analysis was performed as previously described (Cilurzo et al., 2003) using mucin as the adherent substrate (Jabbari et al., 1993; Tamburic and Craig, 1997; Llabot et al., 2004). Briefly, piroxicam-loaded microparticle compacts weighing 130 mg were obtained by applying a compression force of 10 tons for 30 s by means of a hydraulic press (Glenrothes, UK) equipped with flat-faced punches (11.28 mm die diameter). The test material compacts were attached to the mobile steel punch by cyanoacrylate glue. Mucin compacts of 130 mg were obtained by applying a compression force of 10 tons for 60 s. Such a compact was attached by cyanoacrylate glue to a steel plate fixed at the bottom of the tensile apparatus and hydrated with 80 l water for 5 min, in order to obtain a jelly surface layer. Upon making contact between the polymeric compact and the hydrated mucin, a constant force of 1.3 N was imposed for 360 s. The mucoadhesive performance was measured as the detachment force required to separate a bioadhesive compact from the mucin (maximum detachment force) upon an elongation of 10 mm at a constant rate of 0.1 mm/s. The area under the curve of the detachment force versus the elongation was also determined to represent the work or energy required to detach the two compacts. The stainless steel punch was used as negative control. A software-controlled dynamometer (AG/MCL, Acquati, I) with a 5 Da N force cell was used.
3. Result and discussion 3.1. Microparticle morphological and physicochemical characterization
2.8. X-ray diffraction Powder X-ray diffraction spectra of the four piroxicam polymorphs, EuLNa, EuSNa and drug-loaded microparticles were collected using a Rigaku DMAX powder diffractometer (J) with Cu K␣ radiation and a monochromator on the diffracted beam. 2.9. In vitro drug release In order to discriminate the different features in the dissolution rate and apparent solubility of raw piroxicam and the drug-loaded microparticles, a dissolution test was carried out in oversaturation condition using USP 26 paddle dissolution apparatus. Samples of loaded microparticles were weighed exactly in order to obtain the amount of drug corresponding to twice the solubility of piroxicam in cubic form (35 mg/l). Experimental conditions. Dissolution medium: 350 ml of purified water, temperature: 37 ± 0.5 ◦ C, paddle speed: 50 rpm, wavelength: 285 nm. The results are expressed as the mean of the results from three samples. The dissolution profile of piroxicam in cubic form was also determined using the same conditions.
The selected conditions enable the preparation of microparticles of all the formulations from the series 2 and formulation numbers 1–3 from series 1 (Table 1). When the piroxicam/EuLNa ratios were lower than 50/50% (m/m), EuLNa precipitated after mixing of the two phases. The differing behavior of the two copolymers during the feed preparation could be justified by considering that both materials are soluble in water and that a larger amount of water molecules are required to solubilize EuLNa because of the higher number of salified carboxylic groups. The moisture content of microparticles was less than 10% (m/m) and the size distribution ranged from 2 to 15 m (Table 1). As expected, maintaining the same process conditions, the particle size distribution of the different types of microparticles overlapped. According to the technical sheet of the micronized piroxicam, its mean diameter was 4.12 m and therefore comparable to that of the microparticles. Electron microphotographies of representative samples of placebo and drug-loaded microparticles are shown in Fig. 1a–d. The placebo microparticles from both series (formulation nos. 6 and 12, Table 1) displayed well-shaped spherical morphologies and smooth surfaces independent of the
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Fig. 1. Electron microphotographies of (a) formulation no. 12, (b) formulation no. 6, (c) formulation no. 9 and (d) formulation no. 3.
copolymer used (Fig. 1a and b). By contrast, the morphology of microparticles containing piroxicam was modified depending on the amount of drug loaded. In series 2, the shape of microparticles of formulation no. 11 which contained the lowest amount of drug, appeared irregular with a smooth surface. When the amount of loaded drug was increased, modifications in the surface morphology became more evident. In formulation no. 9, containing a piroxicam/EuSNa ratio of 50/50% (m/m) several peeling features were evident on the surface (Fig. 1c). The morphology of series 1 microparticles was more significantly affected by the feed composition than that of series 2. Formulation no. 3, containing a piroxicam/EuLNa ratio of 50/50% (m/m), exhibited a very irregular and dimpled surface (Fig. 1d). This modification of microparticle morphology may be ascribed to a change in the permeability of the crust to the solvents according to the amount of piroxicam in the feed. During drying of the slurry droplets, the pressure built up and the solvent mixture inflated the microparticles in formation (Kawashima et al., 1972). As a consequence of this, at the end of the drying process the micromatrices displayed an irregular structure. The thermogravimetric analysis of the microparticles did not give evidence of the characteristic loss of water from
piroxicam in monohydrate form (data not shown), ruling out the formation of a solvate in the microparticles. The ATR–FTIR spectra of the piroxicam polymorphs, EuLNa and EuSNa were similar to FTIR spectra described in the literature (Vrecer et al., 2003; Cilurzo et al., 2003). The main differences in the ATR–FTIR spectra of the piroxicam polymorphs can be observed in the –NH stretching vibration region (Table 2). In particular, different positions of the –NH absorption band are attributed to the differences in H-bonding (inter- and intra-molecular) in piroxicam crystals (Vrecer et al., 2003). In all the physical mixtures, the main bands of the drug and the copolymer were detectable independent of the polymorphs used. The intensity of the bands depended on the drug/copolymer ratios (data not shown). In spectra from drug-loaded microparticles, several relevant modifications of the main piroxicam bands were noticed (Table 2). The –NH stretching vibration was detected as a broad band at 3382 cm−1 only when the piroxicam/copolymer ratio was higher than 50/50% (m/m). The wavenumber of the –NH stretching band differed from those of the three polymorphs of piroxicam. The microparticle piroxicam amide C O vibration band and amide II stretching band, detected at about 1635
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Table 2 ATR–FTIR transmission band (cm−1 ) of piroxicam polymorphs, placebo and piroxicam-loaded microparticles Piroxicam
EuLNa/EuSNa
NH
Amide I
Amide II
C O
Piroxicam cubic form Piroxicam needle form Piroxicam form III
3337 3392 3323–3342
1628 1639 1639
1524 1527 1519
– – –
Series 1
Formulation no. 1 Formulation no. 2 Formulation no. 3 Formulation no. 6
3379 3380 –a –
1634 1634 1634 –
1520 1520 1520 –
–a 1719 1717 1712
Series 2
Formulation no. 7 Formulation no. 8 Formulation no. 9 Formulation no. 10 Formulation no. 11 Formulation no. 12
3382 3382 3382 –a –a –
1634 1636 1635 1635 1636 –
1520 1520 1519 –a –a –
1728 1726 1724 1723 1723 1721
a
Not detectable.
and 1520 cm−1 , respectively, did not correspond to those of the three polymorphs. The shift of the piroxicam bands correlated with a variation in the geometry and wavenumber of the C O stretching band of the copolymer, which became broader and slightly shifted toward higher wavenumber as the piroxicam/EuSNa and piroxicam/EuLNa ratios were increased. The modifications of the spectra obtained from the microparticles indicated that a new H-bond was formed between the piroxicam NH moiety and the C O of the copolymer. The hydrogen bonding interaction between piroxicam and EuLNa or EuSNa gave rise to the formation of a solid solution in the microparticles. The X-ray diffraction patterns of the placebo and piroxicam-loaded microparticles are shown in Fig. 2a and b. Both EuLNa and EuSNa are amorphous powders displaying no crystalline structure. No characteristic diffraction peaks of the different crystalline forms of piroxicam were detected in all the microparticles, independent of the weight fraction of piroxicam. The absence of diffraction peaks indicated that the piroxicam was in the amorphous form at all the drug/polymer ratios. The piroxicam/polymer interaction may be responsible for the formation of the amorphous form of piroxicam. This feature was consistent with the infrared measurements. 3.2. Technological characterization of microparticles As expected, as the piroxicam/copolymer ratio was increased, both the work of adhesion and maximum detachment force decreased (Table 3). In series 2, no mucoadhesive properties were detected when the piroxicam/copolymer salt ratio was greater than 50/50% (m/m). The microparticles made of EuSNa (series 2) exhibited lower value of work of adhesion and maximum detachment force than those of the microparticles made of EuLNa at the same piroxicam/copolymer salt ratio. This behavior can be explained by considering that the
Table 3 In vitro mucoadhesive performances of placebo and piroxicam-loaded microparticles (mean ± S.D., n = 5) Series
Formulation no.
Work of adhesion (mJ)
MDFa (N)
1
1 2 3 6
1.82 ± 0.20 2.67 ± 0.29 3.34 ± 0.83 6.72 ± 0.64
2.50 ± 0.59 3.26 ± 0.49 5.45 ± 0.56 5.38 ± 0.47
2
7 8 9 10 11 12
0.66 ± 0.08 0.67 ± 0.07 1.51 ± 0.38 3.14 ± 0.51 5.12 ± 0.80 6.81 ± 1.01
2.32 ± 0.34 2.78 ± 0.14 3.34 ± 0.22 4.27 ± 0.84 5.05 ± 0.86 5.02 ± 0.36
0.65 ± 0.01
2.01 ± 0.11
Steel punchb a b
Maximum detachment force. Negative control.
mucoadhesive properties of these polymethacrylate salts, and in particular the work of adhesion, are influenced by the ester group/carboxylic group ratio (Cilurzo et al., 2003). The formation of a solid solution made of piroxicam and the copolymer improved the piroxicam dissolution rate in comparison with that of micronized piroxicam in cubic form (Fig. 3a and b). The piroxicam released from all the microparticles reached a plateau value within 12 min and the concentrations were always higher than the maximum solubility of piroxicam in cubic form. When microparticles were made of EuLNa (series 1), the degree of supersaturation was at least 1.5-fold that of solubility increasing with decreasing piroxicam/EuLNa ratio (Fig. 3a). In the case of series 2, a degree of supersaturation of at least 1.5-fold that of solubility was reached when the piroxicam/EuSNa ratio was 85/15 or 70/30% (m/m) and about two-fold that of solubility when piroxicam/EuLNa ratio was equal to or lower than 50/50% (m/m) (Fig. 3b). The stabilization of the supersatured systems formed in the dissolution medium may be justified by
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Fig. 2. X-ray diffraction patterns of piroxicam-loaded and placebo microparticles of series 1 (a) and series 2 (b).
considering that the piroxicam/copolymer interaction, identified in the solid microparticles could remain even when the copolymer salt dissolves. In both series, piroxicam loaded into the microparticles remained in the amorphous form after 6 months of storage. The dissolution profile of microparticles of formulation no. 9 did not show any significant modification upon storage (data not shown). These preliminary results suggest that solid solutions of piroxicam and copolymer are stable for at least 6 months. Piroxicam solid dispersions prepared by using other carriers, such as polyethylene glycol 4000 and polyvinylpyrrolidones, were studied previously (Pan et al., 2000; Tantishaiyakul et al., 1996, 1999) but their efficiency in promoting the drug dissolution rate and producing supersatured solutions was lower than that obtained by using EuSNa and EuLNa. When polyethylene glycol 4000 was used, the dissolution rate was faster in the case of solid dispersions than in the case of physical mixtures. However, piroxicam was in the cu-
bic form and thus supersatured systems could not be achieved (Pan et al., 2000). An inhibitory effect of polyvinylpyrrolidones on piroxicam crystallization was observed previously (Tantishaiyakul et al., 1996, 1999). This effect was attributed to H-bond formation, but was dependent on the polymer molecular weight and the drug/polymer ratio, which had to be at least 1:4 (Tantishaiyakul et al., 1996). This ratio is approximately 20 times lower than that of piroxicam/EuSNa or piroxicam/EuLNa, which was 85/15% (m/m). This implies that a remarkably lower amount of carrier is needed to obtain piroxicam in amorphous form when using EuSNa or EuLNa. In conclusion, we have shown that EuLNa and EuSNa are suitable materials for preparation of fast-dissolving mucoadhesive microparticles containing piroxicam. The microparticles made of piroxicam and EuLNa in the ratio 70/30% (m/m) appear to be the best delivery system because they contain the lowest amount of polymer able to confer mucoadhesive performance and increase the apparent solubility of piroxicam by at least two-fold.
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Fig. 3. Dissolution profile of piroxicam in cubic form (PRX) and loaded microparticles of series 1 (a) and series 2 (b).
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