INTRODUCTION:

The taste of the drug in oral dosage forms, especially which release the drug within the oral cavity, plays an influencing role in the patient compliance and hence therapeutic outcomes. Thus, masking the unpleasant taste of drugs considers crucial to the therapeutic success and commercial value of these forms^1-5.

Various taste masking techniques have been investigated to deal with the problem of patient compliance such as using flavours and/or sweeteners, microencapsulation, granulation, complexation with ion exchangers or cyclodextrins, and solid dispersion. Furthermore, new taste masking excipients and techniques are still appearing^1,6-8.

Paracetamol (PAR), which is commonly indicated as an analgesic and antipyretic for pediatric and geriatric patients who suffer difficulty of swallow, has an extremely bitter taste. Therefore, the development of a palatable oral dosage form easy to swallow of this drug is requisite to achieve appropriate patient compliance^9-14.

In this study, microencapsulation was chosen to mask the bitter taste of paracetamol as it is the most common and effective technique and the resultant microparticles can be incorporated into different oral dosage forms that are easy to swallow^10,15,16. Microencapsulation is a process that involves surrounding the small particles of solids, droplets of liquids, dispersions of solids in liquids or gasses with the matrix or shell to give microparticles, microcapsules or microspheres, ranging in size from 1 to 1000 µm^17-21. Taste masking by microencapsulation including minimizing contact between the drug particles and the taste buds by forming a physical barrier^15,22. Microencapsulation should ideally mask the drug taste without adversely affecting the drug release profile. To achieve that balance, pH-sensitive polymers such as Eudragits^® (acrylic derivatives) or combinations of water-insoluble polymers and water-soluble polymers or pore formers are often employed^6,23.

EC has been extensively investigated as an encapsulating agent to mask the taste of several drugs due to its properties such as safety, biocompatible, non-biodegradable, tasteless, water-insoluble but soluble in a wide range of organic solvents and flexible thus prevent microparticles fracturing during compression^24-28. Among the various microencapsulation techniques, temperature-induced phase separation was the most commonly used as it is a simple and well-established technique²⁹.

The evaluation of taste-masking is still a major hurdle because of absence definition of taste-masking and standardized protocol. So far, human taste panel is the most common method for taste-masking evaluation. Moreover, this method can be considered as a gold standard for any other method used in the taste-masking evaluation, but it is subject to ethical concerns and inter-subject variability. Therefore, in vitro taste evaluations (dissolution testing and electronic tongue) are becoming increasingly popular, as it offers safe and objective results. However, there are many attempts to develop specific methods, which their data can be correlated with the in vivo data^2,30,31. The mini-column method, a novel continuous flow system developed by Thia et al. (2012) to evaluate taste-masked particles, might be one of the more reproducible and physiologically representative in vitro dissolution models of the oral cavity²³.

In this study, paracetamol microcapsules were prepared by temperature-induced phase separation technique using ethyl cellulose and calcium carbonate, which is just soluble in the acidic medium, to ensure the retard release of PAR at saliva and the rapid release in the stomach, hence mask the bitter taste of PAR without adversely affecting its release profile. The effect of drug/polymer ratio and calcium carbonate addition on the drug release behavior and further on taste masking efficiency were investigated.

MATERIALS AND METHODS:

Materials:

Paracetamol was received as a gift sample from Hama Pharma, Syria. Ethylcellulose 45 cp (Sigma–Aldrich, USA), Cyclohexane (Chem–Lab nv, Belgium), Calcium carbonate (Titan Biotech Ltd, India), Methanol (Riedel–de Haen, Germany), Hydrochloric acid (Merck, Germany), All other materials used were of analytical grade.

Methods:

Preparation of microcapsules:

Microcapsules were prepared by temperature-induced phase separation technique: 1g of ethylcellulose was dissolved in 50 ml cyclohexane containing 3% w/v of liquid paraffin by heating to 80°C with vigorous stirring (700 rpm). Paracetamol was then dispersed in the solution by stirring for 15 min. With continued stirring, phase separation was induced by gradually cooling the mixture to 40°C within 60min. However, at the temperature of 50_60°C different amounts of calcium carbonate were added. The microcapsules were hardened by cooling the solution quickly to 10°C by immersing the beaker in an ice bath. The separated microcapsules were washed with water then filtered and dried to a constant weight in the oven at 45 ºC. The dried microcapsules are stored in a desiccator for further investigations.

Encapsulation Efficiency:

An accurately weighed amount of microcapsules, equivalent to 10 mg paracetamol, from each formulation was dissolved in a small amount of methanol then a sufficient amount of 0.1N HCL (pH 1.2) was added. The mixture was stirred and heated to evaporate methanol and then filtered. After suitable dilution with 0.1N HCL (pH 1.2), the resultant solution was analyzed spectrophotometrically at 243 nm (Jasco V-530, Jaban). The encapsulation efficiency was calculated by the following equation:

Actual PAR content in microcapsules

Encapsulation efficiency (EE) (%) =--------------------------------- ×100

Theoretical PAR content

Particle size and size distribution:

The particle size and size distribution of microcapsules were determined by an optical microscopy (Olympus CH20) at 10× magnification. The particle size of 150 microcapsules from each of the prepared formulations were determine using ImageJ image processing program.

The shape and surface morphology:

the shape and surface morphology of the microcapsules (F8) were examined by scanning electron microscopy (Tescan Vega II XMU, USA). The samples were observed under different magnifications.

Fourier transform infrared spectroscopy (FTIR):

FTIR spectra of PAR, EC, CaCO3 and PAR microcapsules (F8) were recorded over the range of 4000-500 cm^-1 using Shimadzu’s FTIR spectrometer (Japan). The samples were prepared by KBr disk method.

In vitro drug release studies:

The in vitro release of PAR from microcapsules were performed using USP dissolution apparatus type I (Erweka DH 2000, Germany) in 900 ml of 0.1N HCL (pH 1.2) at 37±0.5°C. The rotation speed was 100 rpm. 5 ml of aliquot were withdrawn at 5, 10, 15, 20, 30 and 45min, filtered and analyzed spectrophotometrically at 243 nm. Each time samples were withdrawn, an equal volume of the fresh dissolution medium was added to compensate the loss in the dissolution medium.

Taste-masking evaluation:

Determination of bitterness threshold of paracetamol

The bitterness threshold value of PAR was determined using the series of aqueous solutions of PAR, ranging in concentrations from 0.6 to 1.2 mg/ml. A group of 6 healthy volunteers, age 20–28 years, were selected. Volunteers were asked to hold 10 ml of each solution in the mouth for 30 s, then spit it out and wait for 1 min. A gap of 10 min was between each solution tasting. After each sample tasting, volunteers rinsed the mouth with distilled water and rated the bitterness of the test solution as follows: -, did not detect any difference in test between the distilled water and the test solution; +, detected some difference but was not able to be specific about the taste; ++, detected a bitter taste. The threshold of bitterness of PAR was defined as the concentration at which more than half of the volunteers detected bitterness¹¹.

- In vitro taste-masking evaluation for microcapsules

The test was carried out using a dissolution model mimicking the mini-column method developed by Thia et el. (2012). The pure drug or microcapsules, equivalent to 120 mg of PAR, were put into an unpacked column tube (4.6 mm × 5 cm). Then phosphate saline buffer pH 7.4 was pumped through the column inlet at 1 mL/min by a syringe pump to mimic the saliva flow rate in human. The column and buffer temperature was 37 ◦C. The solution was collecting at the outlet of tubing during the first 2 min. Then PAR concentration in the filtrate was determined by UV spectrophotometer and compared to the bitterness threshold of PAR³².

Statistical Analysis:

Statistical analysis of data was evaluated using Two-way ANOVA and T-test, and A p value of less than 0.05 was considered statistically significant. IBM SPSS version 21.0 was used for analyses.

RESULTS AND DISCUSSION:

The optimum conditions for preparing paracetamol microcapsules (e.g. the stirring speed, the cooling rate, the concentration of EC, the type of coacervation-inducing agent) were determined through several initial experiments. Ethylcellulose, a water-insoluble polymer, in combination with carbonate calcium (CaCO3), a gastro-soluble pore former, were used in order to achieve both taste-masking and rapid drug release. Liquid paraffin was used as a coacervation-inducing agent. Calcium carbonate was added at the temperature of (50-60°C) during formulation when the ethyl cellulose wall had already been formed and became highly adhesive but had not hardened. Although the microencapsulation process was critical concerning the addition of carbonate calcium, the method was reproducible. Eight different formulations of PAR microcapsules were prepared (listed in Table 1) with different drug/polymer ratios and proportions of carbonate calcium in the wall at the same ratio. The encapsulation efficiency of all microencapsulation formulations was between 97-98%, indicating that almost all the drug amount was dispersed in the polymer matrix. There was no significant effect (P> 0.05) for the drug/polymer ratio or the proportion of carbonate calcium on the encapsulation efficiency.

Particle size and size distribution:

The mean particle size of microcapsules ranged between 268.38 µm and 541.59 µm. The results of the size distribution analysis of each formulation, (figure 1), show that the size distribution of microcapsules shifts toward smaller sizes with a decrease in the polymer ratio, which was also observed with previous studies^33,34. This can be explained that as the polymer ratio was decreased, microcapsules with thinner walls and consequently with smaller sizes were formed. Another probable reason was suggested is that at lower paracetamol ratios, an excessive amount of ethylcellulose is present in the preparation medium, which could result in increased frequency of adhesives between the microcapsules^35-37. Furthermore, the increase of the carbonate calcium proportion in the wall led to a decrease in the particle size of microcapsules. As the calcium carbonate particles are deposited on and in the wall of the microcapsules, this could reduce the potential adhesives between the microcapsules during the formulation

Figure 1. Particle size-frequency distribution bar diagram of various formulations of taste-masked PAR microcapsules.

The shape and surface morphology:

The SEM images showed, (figure 2), that the microcapsules (F8) were oblong with a rough surface having many circular-shaped pores which may extend through the wall. The calcium carbonate particles were also observed at the surface of microcapsules.

Fig 2. SEM micrographs of PAR microcapsules (F8) at magnifications 600× (a), 1000× (b), 5000× (c).

Fourier transform infrared spectroscopy (FTIR):

The FT-IR spectrum of PAR showed absorption peaks for O-H and CH3 stretching at 3321 and 3162-3035 cm^-1, respectively. The peaks at 1654, 1565 cm-¹ were assigned to C=O stretching and N–H amide II bending, respectively. The absorption peaks at 1368-1328 and 1260-1227 cm^-1 were assigned to symmetrical bending in C-H and C-N (aryl) stretching. Further, the peaks at 965 and 838 cm^-1 were assigned to C-N (amide) stretching and para-disubstituted aromatic ring, respectively.

The FT-IR spectrum of EC showed absorption peaks for OH and CH3 stretching at 3485 and 2872-2976 cm⁻¹, respectively. The peak at 1052 cm^–1 was assigned to –C–O–C– stretching.

The FT-IR spectrum of CaCO3 showed a weak peak for C–H bending at 2512 cm⁻¹. The absorption peak at 1425 cm⁻¹ was assigned to the asymmetric C-O stretching vibration. The peaks at 718 and 876 cm⁻¹ were correspond to the in-plane bending and out-of plane bending modes of CO3^-2.

FTIR spectra of PAR, EC, CaCO3 and PAR microcapsules (F8) are presented in (figure 3). The spectrum of microcapsules corresponds to the superimposition of PAR, EC, CaCO3 with no significant shift of major peaks or new peaks, indicating that the presence of drug in the microcapsule matrix without interaction with other components of the microcapsules.

Figure 3. FTIR spectra of PAR (a), EC (b), CaCO3 (c) and PAR microcapsules F8 (d).

In vitro drug release studies:

In vitro release studies from all prepared microcapsule formulations into 0.1HCL (pH 1.2) were estimated to assess the effect of the taste masking technique on the dissolution profile. The cumulative dissolution profiles are shown in (figure 4). By comparing the dissolution profile of each formulation. The release rate increases with decreasing the polymer ratio (P-value <0.05). The reasons for that enhance of PAR release could be explained that a higher surface area being exposed to the dissolution medium with a decrease in the microcapsule size, as well as decreasing thickness of EC matrix and increasing the intensity and size of surface pores, as the polymer ratio was decreased^33-38. In addition, the release rate was accelerated as a function of carbonate calcium concentration in the wall. According to previous studies, the drug release from ethylcellulose microcapsules is achieved mainly by diffusion through the pores existing in the microcapsule wall because of the hydrophobic character of ethylcellulose; thus, the incorporation of a pore inducer to the microcapsules may induce new pores in the surface and channels in the matrix of the microcapsules or/and increased The extent of surface pores, hence enhanced the drug release^33-35,39,40. Zaki Rizkalla, CM et al. (2013) have reported that using sucrose and pre-gelatinized starch as pore induces in ethylcellulose wall of microcapsule increased the release rate of drug⁴¹.

Figure 4. Drug release profile of various formulation of taste-masked PAR microcapsule in 0.1N HCL pH 1.2.

Taste masking evaluation:

The bitterness threshold value of PAR was selected from different concentrations of paracetamol. The concentration of 0.9mg/ml was the lowest paracetamol concentration which most of the volunteers detected a bitter taste, as shown in Table 2. Therefore, the bitterness threshold of paracetamol was considered to be 0.9 mg/ml, which is similar to the determined value by Drašković et al (2017).

As a substance needs to be dissolved for perception by the receptors located in taste buds, In vitro dissolution testing is employed to predict the taste masking effects by measuring the amount of drug released or dissolved in simulated oral cavity conditions and comparing it to bitterness threshold. Taste masking considers successful if the concentration of the drug is less than the bitterness threshold at a specific time^2,7,42.

Table 2. Determination of the bitterness threshold of PAR

Volunteers						Concentration (µg/ml)
6	5	4	3	2	1	Concentration (µg/ml)
-	-	-	-	-	-	600
+	-	-	+	+	-	700
-	+	-	+	+	-	800
++	++	+	++	++	-	900
++	++	++	++	+	+	1000
++	++	++	++	++	++	1100
++	++	++	++	++	++	1200

Based on the results obtained from in vitro release study, the formulation F8 showing the highest percent drug release (more than 75% at 30min) was investigated for in vitro taste masking evaluation. It was observed that the released concentration of PAR after 2 min from formulation F8 was 0.335mg/mL, below the bitterness threshold of PAR, while it was 17.87 mg/mL in the case of the pure drug (P-value<0.05), indicating the significant effect of EC in reducing the release of drug despite its low ratio.

CONCLUSION:

Microencapsulation by temperature-induced phase separation technique using ethylcellulose as a wall polymer and calcium carbonate as a gastro-soluble pore former can be an appropriate technique to mask the bitter taste of paracetamol. Moreover, it is a simple process and can be easily scaled up. According to the results of in vitro release and in vitro taste-masking studies, Formulation F8 was the optimal formulation as it successfully achieved taste-masking without adversely affecting the drug release profile. As well as, the characterization of optimal formulation showed that the drug is well encapsulated. Therefore, this formulation seems to be promising to investigate in designing palatable oral dosage forms easy to swallow of PAR.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 30.10.2021 Modified on 02.12.2021

Research J. Pharm. and Tech. 2022; 15(8):3703-3708.

DOI: 10.52711/0974-360X.2022.00621

Formulation	PAR: EC	EC: CaCO3	EE^{(n = 3)} (%)	Mean particle size (µm)	Drug release in 0.1N HCL (%) at 30 min ⁽ⁿ⁼⁶⁾
F1	1:1	2:1	98.20 ± 0.09	541.593	16.189 ± 0.9
F2	1:1	1:1	98.68 ± 0.04	463.358	21.506 ± 1.09
F3	2:1	2:1	98.39 ± 0.19	523.500	25.801 ± 3.77
F4	2:1	1:1	98.27 ± 0.11	445.265	30.921 ± 4.39
F5	4:1	2:1	98.20 ± 0.13	474.744	41.389 ± 3.45
F6	4:1	1:1	98.16 ± 0.22	396.509	45.504 ± 2.53
F7	8:1	2:1	97.08 ± 0.51	346.617	68.877 ± 3.11
F8	8:1	1:1	97.01 ± 0.40	268.383	76.463 ± 3.75