INTRODUCTION:

The incidence of allergic diseases such as allergic rhinitis, allergic asthma, chronic idiopathic urticaria and atopic dermatitis has steadily increased over the past decades and affects a large number of people worldwide. Symptoms such as itching, sneezing, rhinorrhea and rhinobyon caused by allergic diseases usually reduce the quality of life. Millions of people have been reported to experience physical impairments and reduced quality of life and economic burden stemming from allergic diseases, and their associated comorbidities^1,2,3

Chlorpheniramine maleate (CTM) is commonly used in the treatment of asthma and other respiratory allergies.

CTM is the most widely used antihistamine and is available in various dosage forms, namely oral solution, tablet, and injection, as well as a global multi-source compound drug². CTM is used as monotherapy or in combination, with the adult dose for oral administration of 4 mg every 4-6 hours³. Approximately 70% of circulating chlorpheniramine is bound to plasma proteins, consequently being widely distributed throughout the body with peak plasma concentrations being 2.5-6.0 hours after oral administration⁴.

The frequent administration of CTM (3-4x a day) supported by a short half-life can result in reduced patient compliance, so alternative preparations are needed that are comfortable for consumption by patients such as Orally Disintegrating Film (ODF). Jelvehgari, et al reported that the bitter taste of CTM was felt when it came into direct contact with the mucous membrane of the tongue and taste buds, thereby reducing patient compliance and feeling dissatisfied. Therefore, it can be seen that taste plays an important role in drug acceptance and patient compliance. Taste masking is an appropriate way to mask the bitter taste of drugs with several applications and methodologies, including microencapsulation, formation of inclusion complexes with cyclodextrins, liposomes, prodrug approach, salt formation and solid dispersion⁵.

There are many polymers can be used in the microencapsulation process using a spray drier such as hydroxypropylmethylcellulose (HPMC), Sodium carboxymethylcellulose (Na-CMC), ethylcellulose and eudragit. We used Eudragit E PO in this study because eudragit E is a pH sensitive polymer. Eudragit E PO is soluble in acid and insoluble in water and saliva. Therefore eudragit E PO is suitable to be used as a polymer to cover the bitter taste of CTM^6,7.

Microencapsulation is a process in which very small solid or liquid particles are surrounded by a continuous layer of polymeric material. The microencapsulation method has advantages when compared to other methods such as liposomes, where liposomes have a constituent component in the form of phospholipids that are easily oxidized and easily hydrolyzed. Microencapsulation provides many benefits, including covering uncomfortable tastes and odors, thereby increasing patient compliance^8,9.

Spray-drying method was one of the various methods to prepare the microcapsules. Spray-drying method could produce microcapsules quickly in very large quantities^9,10. The ODF preparation was chosen because it is one of the preparations with a good drug release system, capable of releasing CTM microcapsules in the mouth and then immediately absorbed. Variations of the three formulas were carried out on the spray-drying method in the manufacture of microcapsules to produce greater efficiency and entanglement values, so it is hoped that this study can produce CTM microcapsules with a masked bitter taste to improve patient comfort and compliance.

The formulations achieved through the microencapsulation process differ in terms of size, from one to 1000μm. The success of this process is highly dependent on the shape of the encapsulated core material (solid, liquid, gas), stability to temperature and pH, the type of coating material used, physicochemical properties (solubility, hydrophobic or hydrophilic), the microencapsulation medium used (water solvent or others), the microencapsulation principle used (physical or chemical), and the size of the microencapsulation made. The coating materials that can be used in this process also have several conditions, including being able to provide a thin layer that is cohesive with the core material, stable with the core material, not hygroscopic and reacts with the core material, being able to coat the core material strongly, hard and flexible, able to be released under certain conditions, as well as economical^11,12,13,14.

MATERIALS AND METHODS:

Materials:

Chlorpheniramine maleate BPFI (BPOM, Indonesia), eudragit E PO (PT Evonik Indonesia), acetone (p.a), magnesium (Mg) stearate, distilled water, sodium chloride (NaCl) (p.a), hydrochloric acid (HCl) (p.a), aluminum foil, Whatman filter paper.

Methods of making microcapsules:

CTM microcapsules were made with 3 types of ratio CTM:eudragit E PO, namely F1 (1:1), F2 (1:2), and F3 (1:3). The first step was eudragit E PO dissolved in acetone solvent using a glass beaker, then stirred homogeneously. After that, CTM and magnesium stearate¹⁵ was added, dispersed, and homogenized in eudragit E PO solution with a homogenizer at 3000rpm for approximately 5 minutes then put the mixed solution into the spray drying apparatus and sprayed with the conditions of inlet temperature 80ºC, outlet temperature 60ºC, spraying speed of 3mL/min, and nozzle of 30µm. The formed microcapsules were then stored in an airtight container. The system formed is a matrix because the mixing of polymer, active substance, and solvent produces a homogeneous solution so that the active substance will be evenly distributed in the coating material¹².

Table 1: Formulation of microcapsules

Materials	F1 (1:1)	F2 (1:2)	F3 (1:3)
CTM (g)	1	1	1
Eudragit E PO (g)	1	2	3
Magnesium stearate (g)	2	2	2
Acetone (mL)	50	50	50

Microcapsules evaluation:

a) SEM study:

The evaluation of the morphology and structure of the microcapsules was carried out using Scanning Electron Microscopy (SEM). The microcapsules were placed in an aluminum SEM specimen holder and coated with palladium with a thickness of 10 mm. The sample was then observed with various magnifications of the SEM (Hitachi S-3400 N, Tokyo, Japan) tool. Voltage is measured at 20 kV and the current is 12mA¹⁶.

b) Particle size distribution:

The particle size distribution of CTM microcapsules was analyzed using a Particle Size Analyzer (Shimadzu SALD-2300, Tokyo, Japan). Several microcapsules were dispersed in distilled water and then shaken using a vortex mixer for ±1 minute. Then put into the cuvette, the cuvette is inserted into the tool and closed with a sensor. The expected microcapsule size is 1-1000μm¹².

c) IR-spectroscopy:

Evaluation of the interaction of the active substance and polymer was carried out using IR spectrometry (Shimadzu IR Tracer-100 AH, Tokyo, Japan). An evaluation was carried out by placing the sample on top of the ATR crystal so that it covered all the crystal surfaces. The results of this evaluation are not expected to form new functional groups which indicate an interaction between the active substance chlorpheniramine maleate and the eudragit E PO coating¹⁷.

d) Microcapsules weight and drug content:

The weight of microcapsules obtained from each formula was weighed with an analytical balance (Ohaus PA323). Determination of CTM content in microcapsules using UV-Vis spectrophotometer (Shimadzu UV-1900, Tokyo, Japan). The microcapsules were crushed and dissolved in 0.1 N HCl solvent, then the concentration of CTM maleate in microcapsules was calculated using a linear regression equation at a maximum absorption wavelength of 264.4nm¹⁸.

e) Encapsulation efficiency and drug loading:

The calculation of the percent adsorption is useful to determine the efficiency of the microencapsulation method used. The percentage of adsorption was obtained by comparing the amount of drug content (nuclear substance) in the microcapsules with the amount of drug (nuclear substance) that should be (theoretical)¹⁹. Drug loading is calculated from the weight of the active substance contained in each microcapsule weight²⁰.

f) Leak test:

Microcapsule leakage test was carried out using artificial saliva with a pH of 6.8. The manufacture of artificial saliva was carried out using 0.9% physiological NaCl as much as 500mL. Then the pH of the artificial saliva was balanced and controlled using HCl until it reached the specified pH of 6.8^21. The drug concentration was measured with a wavelength of 261.4nm^18.

RESULT:

The physical appearance of the microcapsules could be seen in Figure 1. The particles were irregular and the surface was rough. Then the results of SEM could be seen in Figure 2.

SEM study:

Microcapsules evaluation was carried out microscopically with SEM (Scanning Electron Microscope) photos using a magnification of 100x and a scale of 500µm. The three forms of the microcapsules formula were irregular (irregular) and the surface was rough (Figure 2).

Figure 1. Photograph of physical appearance of F1 (1:1), F2 (1:2) and F3 (1:3)

Figure 2: Results of SEM analysis with 100x magnification (a) Microcapsules F1, (b) Microcapsules F2 (c) Microcapsules F3, (d) CTM, (e) Eudragit E PO.

Particle size distribution:

The results of the particle size distribution test using a particle size analyzer showed that the size of the microcapsules was in the range of 60-200μm (Table 2). In each formula, it was shown that the smallest CTM microcapsule size was obtained in formula 1 compared to formulas 2 and 3. Measurement of the number and size of particles can be made into a graph that describes the relationship between the number of particles with the particle size of each formula (Figure 3). From the graph obtained, each formula has a bell-shaped curve/normal distribution curve. Formula 3 has a sharper curve than formulas 1 and 2. This indicates that the particle size distribution in formulas 1 and 2 is less even, because the sharper the normal distribution curve, the more homogeneous the particle distribution²².

Figure 3: Microcapsule size distribution chart.

Table 2: Microcapsules particle size results

Microcapsules	Median (µm)	Mean (µm) ± SD
Formula 1	60.348	60.319 ± 0.625
Formula 2	84.523	84.506 ± 0.410
Formula 3	200.759	200.734 ± 0.270

IR-spectroscopy:

The three formulas still detected functional groups from CTM, namely halide groups (C-Cl) and C=N bonds (Figure 4.), because the coating formed was thin. From the results of the FT-IR analysis at F1, F2, and F3 there is no wave number indicating the presence of a new functional group (Table 3). The results of the CTM spectrum showed that the C=N group appeared in the 1675-1500 cm-1 range and the C-Cl (halide) group appeared in the 600-800 cm^-1 range and fulfilled the requirements when compared to the BPFI CTM spectrum.

Figure 4. Infrared spectrum

Table 3: FT-IR check wavenumber

Functional groups	Wavenumber (cm^-1)	CTM	Eudragit E PO	Mg Stearate	F1	F2	F3
C-H	3300-2700	3012	2949, 2769	2916, 2848	2914, 2850	2914, 2850	2914, 2850
C=O	1900-1650	-	1722	-	1732	1724	1724
C=N	1675-1500	1583	-	-	1539	1558	1541
C-H	1475-1300	1355,1471	1386, 1456	1463	1471	1456	1456
C-N	1360-1180	1205	1238	-	1238	1238	1238
C-O	1000-800	-	-	945, 877	970	966	966
C=C-H	1000-650	995, 864, 763	964, 844, 748	723, 667	864, 752	866, 717	866, 748
C-Cl	800-600	650	-	-	651	619	650

Microcapsules weight and drug content:

The regression equation was obtained by y= 0.0256 x + 0.0024, with r= 0.999. The yield percentage resulted in quite a large difference between the three formulas (Table 4). The highest percentage of yield is in formula 3, which is 84%. While the least is in formula 1, which is 71%. From the results of the percentage weight of the drug calculated based on its theoretical weight, there are differences in the percentage weight of each formula (Table 5). Formula 3 produces a higher percentage of drug weight, which is 3.8mg from 4mg (95%).

Table 4: Microcapsules weight yield and percent yield

Weight of Microcapsules Obtained (g)	Actual Microcapsules Weight (g)	Yield (%)
2.85	4	71.25
3.61	5	72.20
5.07	6	84.18

Table 5: Results of drug content calculation

Microcapsules	Average of Weight CTM in Microcapsules (mg) ± SD	Rate (%)
F1	3.473 ± 0.039	86.82
F2	3.634 ± 0.071	90.85
F3	3.827 ± 0.047	95.67

Encapsulation efficiency and drug loading:

From the encapsulation efficiency data in (Table 6), it can be seen that the efficiency of formula 3 reaches the highest efficiency, which is 95% compared to formulas 1 and 2. The results of determining the weight of the drug in microcapsules, it was found that the encapsulation efficiency was relatively large when compared to previous studies with results of only 2-3%. In the literature, the encapsulation efficiency of microcapsules ranges from 70-100%, so it can be concluded that the efficiency of the three formulas above meets the requirements²³. The results of % drug loading from microcapsules in the three formulas showed results that were following the weight of the drug contained in each microcapsule which was weighed as a sample. The result of the largest drug loading is in F1, which is 21%.

Table 6: Calculation of encapsulation efficiency and drug loading

Microcapsules	Encapsulation Efficiency (%)	Drug Loading (%)
F1	86.82	21.71
F2	90.85	18.17
F3	95.67	15.94

Leak test:

The regression equation was obtained by y= 0.0135x + 0.0178, with r= 0.999. The microcapsules leak test obtained (Table 7), resulted in the percentage of leakage in F1, F2, and F3 of 91%, 74%, and 67%, respectively. The microcapsules produced in this study should be completely encapsulated so that there is no leakage when dispersed in artificial saliva because eudragit E PO is practically insoluble in water.

Table 7: Calculation results of microcapsules leakage test

Microcapsules	Average CTM in Saliva (mg) ± SD	Leakage (%)
F1	3.663 ± 0.039	91.57
F2	2.960 ± 0.021	74.00
F3	2.709 ± 0.081	67.72

DISCUSSION:

The three forms of the microcapsules formula were irregular and the surface was rough. This is due to the polymer used, namely eudragit E PO which has sticky properties and produces microcapsules in the form of plates in acetone²⁴. The expected shape of the microcapsules is spherical because if the core material is a liquid, the microcapsules formed will be spherical, and if the core material is a solid or crystalline substance, the resulting microcapsules are irregular in shape²⁵.

The average particle size increased with increasing polymer concentration. This is because high polymer concentration results in a significant increase in polymer viscosity in solution and a reduced agitation efficiency, thereby causing an increase in particle size²⁶. Stirring speed will also affect the shape and size of the resulting microcapsules, slow stirring will produce microcapsules with larger particle sizes. On the other hand, stirring at high speed can cause the formation of microcapsules of smaller sizes. The completeness of the coating on the microcapsules was also affected by the duration of stirring²⁷. The uneven distribution of particle size in formulas 1 and 2 can be caused by the formation of agglomerates so that the microcapsules form non-uniform droplets.

The wave numbers obtained only show the functional groups present in the structure of eudragit E PO and CTM. The interaction between the active substance and the polymer is indicated by the presence of a new peak or a shifting peak or a shift in wave number²⁸. It can be concluded that there is no substance interaction between the active substance CTM, eudragit E PO coating, and additives Mg-stearate. In the literature, the yield obtained is at least ±70% and the yield in the three formulas meets the requirements^29,30,31. The weight of the microcapsules obtained from the three formulas was reduced from the actual weight of the microcapsules, so the percentage of recovery did not reach 100%. The results that do not reach 100% can be caused by several factors such as the active substance being not completely encapsulated^32,33. The difference in the percentage weight of each formula occurs because the evaporation rate of the solvent affects the amount of active substance that is entangled, the faster the solvent evaporates, the more the entangled active substance increases³⁴.

The value of encapsulation efficiency can be an illustration of the efficiency of the method used. The more polymers used, the more active substances will be adsorbed. The less polymer used, the less active substance will be absorbed because the coating material is not optimal in protecting the active substance³⁵.

The microcapsules leakage was caused by the active substance not being completely encapsulated as shown in (Figure 2), where the microcapsules formed had a non-smooth surface and could be the cause of microcapsules leakage.

CONCLUSION:

Based on the evaluation results, it can be concluded that the spray-drying method has an inlet temperature of 80ºC, an outlet temperature of 60ºC, a spraying speed of 3 mL/min, and a nozzle of 30 μm were not very effective in the manufacture of CTM microcapsules with eudragit E PO coating, proven from the results of an examination of the high leakage percentage, shape, and surface of the microcapsules that are not smooth (irregular) despite having high encapsulation efficiency.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

Thanks to the research team who have assisted in the completion of this research, the head of the laboratory and, analyst at the Faculty of Pharmacy, Universitas Andalas.

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Received on 25.10.2022 Modified on 29.12.2022

Research J. Pharm. and Tech 2023; 16(11):5279-5284

DOI: 10.52711/0974-360X.2023.00855