Development and Characterization of Buccal Bilayer Tablets containing Microparticles with Ibuprofen

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2. Materials and Methods

2.1. Materials

Ibuprofen (Roig Farma, Spain), hydrogenated castor oil (Cutina^® HR) (José M. Vaz Pereira SA, Portugal), monosodium phosphate (José M. Vaz Pereira SA, Portugal), disodium phosphate anhydrous (José M. Vaz Pereira SA, Portugal), propylene glycol (José M. Vaz Pereira SA, Portugal), Tween^® 80 (Sigma-Aldrich, United States of America), chloroform (José M. Vaz Pereira SA, Portugal), Noveon^® AA-1 Polycarbophil USP (Lubrizol, Brussels), Carbopol^® 980 NF Polymer (Lubrizol, Brussels), and Carbopol^® 974 NF Polymer (Lubrizol, Brussels) were used.

2.2. Preparation of Lipid Microparticles

Lipid microparticles of 1:2 ibuprofen/hydrogenated castor oil (Cutina^® HR) ratio were prepared using the emulsion/chilling method ^[17]. The lipophilic excipient was melted on a hot plate (85-88°C) under stirring at 600 rpm and ibuprofen was added ^[17]. The oil phase was slowly added to a Tween^® 80 solution (1.5%, w/w) at the same temperature, followed by the quick addition of a mixture of water:propylene glycol (75:25) at 0°C, maintaining the agitation at 600 rpm ^[17]. The obtained lipid microparticles were filtered and washed with water ^[17].

2.3. Determination of Drug Encapsulation Efficiency (EE%)

For the determination of ibuprofen content in lipid microparticles, 75 mg of sample was dissolved in chloroform (50 mL) and analyzed using a UV-VIS spectrophotometer (Jasco, model V-650, Japan) at 272 nm. Drug calibration curve was previously prepared (y = 0.989x + 0.029; R² = 0.999). EE% was calculated using the following equation:

(1)

where W_m is the amount of ibuprofen in lipid microparticles and W_iis the amount of ibuprofen used.

2.4. Particle Size Analysis and Morphological Characteristics

Particle size measurements were determined using a laser diffraction particle size analyzer (Mastersizer 3000, Malvern Instruments, United Kingdom) with a range from 0.01 to 3500 µm. The determination was performed at room temperature using 1.6 for the refractive index, 0.1 for the absorption index, laser obscuration around 6% and scattering model mie. The dispersant was water with Tween^® 80, and each sample was tested five times at 2000 rpm. The results were, respectively, expressed using volume distributions by the volume weighted mean (D [4,3]), surface weighted mean (D [3,2]), 10% percentile (Dv [10]), median (Dv [50]) and 90% percentile (Dv [90]).

The particle morphologies were also observed and captured by the inverted microscope (Motic^®, model AE2000, China).

2.5. Manufacture of Tablets

Three types of bilayer tablets containing three bioadhesive polymers, namely Noveon^® AA-1 Polycarbophil USP, Carbopol^®974 and Carbopol^® 980 were prepared using a single-punch compression machine (Korsh 9048-71, Maschinenfabrik, Germany) with 13 mm diameter punches as follows: the first layer with a weight of 300 mg, responsible for the tablet retention on the mucosa, was obtained by compression of each one of the bioadhesive polymers; the second layer with a weight of 338 mg, responsible for buccal drug delivery, containing the lipid microparticles corresponding to 100 mg of ibuprofen, was then added to the first layer and tablets were obtained by compaction of the two layers.

2.6. Weight Uniformity, Friability and Hardness of Tablets

To study tablet weight uniformity, 20 tablets of each formulation were weighed using an analytical balance (Mettler Toledo, Mettler AE 200, Switzerland). For each formulation the hardness of 10 tablets was also evaluated using a tablet hardness tester (Erweka GmbH, Erweka TBH 28, Germany).

Friability was determined by submitting 10 previously weighed tablets to falling shocks for 4 min in a friabilator (Electrolab, EF-1W, India), set at 25 rpm/min. After 4 min, the tablets were reweighed and the percentage of friability was calculated.

2.7. In Vitro Release Studies

The in vitro drug release study was performed using a dissolution apparatus (Sotax, model AT7, Switzerland) according to the paddle method at 50 rpm. The dissolution medium consisted of 1000 mL of phosphate buffer pH 7.4 ^[29] at 37.0±0.5°C. The collection times were 30, 60, 120, 180, 240, 360, 480 minutes, and the volume of sample collected was 10.0 mL (without volume replacement and with the same adjustment in calculations).

The dissolution tests were performed by two different methods: A and B. In the method B the tablets were attached at a height of 7.0 cm to the inside of the dissolution vessel ^[30], and in method A, the tablets were positioned on the bottom of the dissolution vessel ^[31].

The samples, collected at established times, were filtered and the drug concentration was determined by a UV-VIS spectrophotometer (Jasco, model V-650, Japan). Drug calibration curve was previously prepared (λ_max = 272.0 nm; y = 1.459x + 0.004; R² = 0.996). Dissolution studies were made in triplicate and results were registered as the average ± standard deviation (SD).

The dissolution profiles of tablets were compared using the ƒ₂ similarity factor as follows ^{[32, 33]}:

(2)

where n is the number of time points, R_j is the mean percent reference drug dissolved at time j after initiation of the study, and T_j is the mean percent test drug dissolved at time j after initiation of the study.

2.8. Evaluation of Firmness and Adhesiveness of the Bioadhesive Layer of Tablets and Gels

Firmness and adhesiveness were assessed at 20°C in the bioadhesive layer of tablets after 6 h and 16 h of hydration in phosphate buffer pH 7.4 ^[29]. In addition, three gels (0.5%, w/w) were prepared with the same bioadhesive polymers and the same textural parameters were also evaluated.

Firmness and adhesiveness measurements were performed using a texture analyzer (Stable Micro Systems, TA-XT2i, United Kingdom) by carrying out a penetration test using a load cell of 5 Kg, a cylindrical probe (6 mm diameter for tablets and 25 mm in the case of gels), a penetration depth of 2 mm and velocities of 3 mm/s and a trigger force of 0.049 N. After penetrating the sample, the probe returned to a position 90 mm above the platform surface. The maximum force (firmness) and the negative area (adhesiveness) were obtained from the graphic force (N) versus distance (mm) ^[34]. All the measurements were performed in triplicate and data were statistically analyzed by one-way ANOVA followed by Tukey post hoc test (IBM^® SPSS^® Statistics, version 22). A value of p < 0.05 was considered significant.

3. Results

Lipid microparticles with ibuprofen, a BCS class II drug, through emulsion/chilling method were prepared (Figure 2). The result of the drug encapsulation efficiency was 87.4%.

The median size of lipid microparticles (Dv [50]) was 75.90 ± 0.55 μm. The particle size range can be represented as mean (Dv ^[10]) and mean (Dv [90]) which were, respectively, 6.30 ± 0.08 μm and 167.00 ± 1.26 μm. The volume weighted mean (D [4,3] and the surface weighted mean (D [3,2]) were, respectively, 83.3 μm and 14.8 μm.

The buccal bilayer tablets presented suitable physical properties (Figure 3) and Table 1 shows the obtained results for weight uniformity, hardness and friability.

Figure 2. Lipid microparticles with ibuprofen (A - macroscopic aspect, scale in millimeters; B - microscopic aspect, magnification of 40x)

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Figure 3. Appearance of the buccal bilayer tablets before and after 16 h of hydration in phosphate buffer pH 7.4. (A - tablets with Carbopol^®974; B - tablets with Polycarbophil; C - tablets with Carbopol^®980; D - tablets with Carbopol^® 974 after 16 h of hydration; E - tablets with Polycarbophil after 16 h of hydration; F - tablets with Carbopol^® 980 after 16 h of hydration)

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Table 1. Results of weight uniformity (mean ± SD, n = 20), hardness (mean ± SD, n = 10) and friability (mean ± SD, n = 10) of the buccal bilayer tablets

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Tables index

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Figure 4 shows the dissolution profiles of buccal bilayer tablets by two different methods: A and B. The results of firmness and adhesiveness of the bioadhesive layer of tablets, after 6 h and 16 h of hydration in phosphate buffer pH 7.4, and gels are illustrated in Figures 5 and 6, respectively.

Figure 4. In vitro release profiles of buccal bilayer tablets (n = 3, mean ± SD). (A - dissolution performed positioning the tablet on vessel bottom (method A); B - dissolution performed positioning the tablet on internal vessel surface at 7 cm from the bottom (method B)

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Figure 5. Box plot of firmness and adhesiveness of bioadhesive layer of tablets after 6 h and 16 h of hydration in phosphate buffer pH 7.4. (TC974 - tablets with Carbopol^® 974; TC980 - tablets with Carbopol^® 980; TP - tablets with Polycarbophil)

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Figure 6. Box plot of firmness and adhesiveness of gels. (G C974 - gel with Carbopol^® 974; G C980 - gel with Carbopol^® 980; G P - gel with Polycarbophil)

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