Formulation and Evaluation of Fexofenadine Buccal Mucoadhesive Patches

 

Arifa Begum Sk1*, Sravya AHLB2, Deepika BGD2, Naga Manasa G2, Srujana M2, Uma V2, Lakshmi Tejeswari S2, Padmalatha K2

1Chalapathi Institute of Pharmaceutical Sciences, Chalapathi Nagar, Lam, Guntur – 522034, Andhra Pradesh, India.

2Vijaya Institute of Pharmaceutical Sciences for Women, Enikepadu, Vijayawada – 521108, Andhra Pradesh, India.

*Corresponding Author E-mail: arifashaik2007@gmail.com

 

ABSTRACT:

Mucoadhesive buccal patches for the delivery of fexofenadine using various polyvinyl alcohol, hydroxypropyl methyl cellulose K4M and K15M and Eudragit L100 were developed using solvent casting technique. The fabricated formulations were evaluated for different physicochemical as well as mechanical parameters such as thickness, surface pH, weight uniformity, swelling index, folding endurance, drug content, percentage moisture loss, in vitro dispersion and in vitro residence time. An in vitro drug release study was designed and performed using freshly prepared egg membrane as semi-permeable membrane. The optimized formulation (F1) showed maximum percentage of drug release 96.18% ± 0.53% by the end of 8 h. The sustained release of the drug was achieved up to 8 h.

 

KEYWORDS: Buccal delivery, mucoadhesivde patches, polyvinyl alcohol, hydroxypropyl methyl cellulose, folding endurance.

 

 


INTRODUCTION:

Currently, immense research efforts have been focused on introducing a drug delivery system at a specific site of the body in order to maximize bioavailability of drug as well as minimize side effects that are dose dependent. As buccal mucosa is relatively permeable with a rich blood supply, buccal delivery of drugs can be an attractive alternative to other conventional methods of systemic delivery of drugs1,2. Buccal drug delivery bypasses the first pass hepatic metabolism of drugs and avoids pre-systemic elimination in the gastro intestinal tract. Thus, the oral mucosa is considered as a feasible site for systemic drug absorption. Fexofenadine is a second generation, long lasting H1-receptor antagonist (antihistamine) and has a selective and peripheral H1-antagonist action used for management of seasonal allergic rhinitis.

 

The drug is absorbed rapidly after oral administration and 60% - 70% bound to the plasma proteins, mainly albumin and a1-acid glycoprotein3. The metabolism of fexofenadine is insignificant4,5. About 5% of the total fexofenadine oral dose gets metabolized. The drug is

un-metabolized by liver6. Elmination half life is 13 h - 16 h7. Around, 90% of fexofenadine drug is found to be unchanged in feces and urine8. Fexofenadine belongs to BCS class III with high solubility and low permeability. Fexofenadine oral bioavailability is only 33% due to less absorption and metabolism to some extent because of cytochrome P450 3A4 and by microflora present in the intestine. After oral administration, Tmax of fexofenadine is 1.35 h - 1.52 h, i.e., long and variable. The effective dose of fexofenadine is approx. 30 mg. Since fexofenadine belongs to BCS Class III, having high aqueous solubility and low permeability, there is a need to improve the permeability of the drug. Taking into consideration the physicochemical properties and pharmacokinetics of the drug, it was inferred that the drug has a need to be formulated into mucoadhesive buccal patches and the drug fexofenadine was appropriate for it.

The present research was mainly focused on the development and evaluation an oral patient friendly mucoadhesive buccal patches of fexofenadine. Various batches of fexofenadine buccal patches were developed by solvent casting method using different polymers in different proportions in order to improve permeability, bioavailability and therapeutic efficacy of drug.

 

MATERIALS AND METHODS:

Fexofenadine was a gift sample (Aurobindo Pharma Ltd., Hyderabad, India); poly vinyl alcohol, HPMC K4M and Eudragit L100 were obtained from Triveni Chemicals, Rolex Chemicals and Hetero Drugs Ltd, Hyderabad respectively. Ethanol, propylene glycol, oleic acid were purchased from Swasthick Pharmaceuticals, Aman Enterprises and Acid India, Chennai respectively. Other chemicals used in the research investigation were of analytical grade and purchased from Loba Chemie (Mumbai, India).

 

PREFORMULATION STUDIES:

Pre-formulation studies on fexofenadine include colour, taste, solubility analysis, melting point determination and drug-excipient compatability studies.

 

Solubility Study:

Pre-formulation solubility study was carried out, which include the selection of appropriate solvent systems in order to dissolve fexofenadine drug and different excipients.

 

Melting Point Determination:

The purity of the drug sample was assessed by the determination of melting point. Lowering and widening in the melting point range is indicative of the presence of trace amount of impurity.

 

Drug – Excipients Compatibility Testing:

Fourier Transform Infra - Red (FT-IR) Analysis:

IR analysis of samples was performed using an FT-IR spectrophotometer. Approx. 4 to 5 mg of fexofenadine was mixed with dry KBr and prepared sample was tested over the range of 4000 - 400 cm-1 wave number at transmission mode 9.

 

FORMULATION DEVELOPMENT:

Calibration of standard curve of fexofenadine:

100 mg of fexofenadine was accurately weighed and dissolved in 100 ml of phosphate buffer solution (PBS), pH 6.8 in 100 ml of volumetric flask. The resulting solution had a concentration of 1 mg/ml (1000 µg/ml). From the prepared stock solution, 10 ml was further diluted to make up to 100 ml using PBS, pH 6.8 with concentration of 100 µg/ml. Different aliquots of 1 ml,

 2 ml, 3 ml, 4 ml, 5 ml were diluted up to 10 ml with buffer to give concentrations in the range of 10 µg/ml, 20 µg/ml, 30 µg/ml, 40 µg/ml and 50 µg/ml respectively. The absorbance of each solution was measured by UV-Visible spectrophotometer at 259 nm using PBS, pH 6.8 as blank. The graph of concentration versus absorbance was plotted.

 

FORMULATION OF MUCOADHESIVE BUCCAL PATCHES:

Method of preparation of buccal patches:

Fexofenadine mucoadhesive buccal patches were fabricated by solvent casting method. Accurately weighed amount of fexofenadine was dissolved in 1 ml of ethanol; followed by addition of polymer dissolved in 2 ml of ethanol. Further, to the same solution, 1 drop of oleic acid as permeation enhancer and 3 ml of propylene glycol as plasticizer were added with continuous stirring. The stirring process was continued on a magnetic stirrer (Remi) at 50 rpm and 40 oC after final make up of the solution to 20 ml with ethanol till the solution attains viscous and pourable consistency. The solution was poured into a dry and clean petridish followed by drying at RT for 24 h by placing the funnel inverted on the petridishes. The patch was peeled carefully with the help of a surgical scalpel by making a small cut in the patch at one side of petridish. Patches of 4 cm2 were cut from each patch, packed in aluminium foil and such foils were placed in a self- sealing polythene cover to ensure negligible moisture penetration Finally, the patches obtained were evaluated. Total 4 formulations were prepared and the composition of formulations was mentioned in Table 1.

 

Determination of dose of drug:

Dose to be incorporated in each 4 cm2 film = 30 mg of fexofenadine . Area of petri plate (Пr2) = 3.14*4.5*4.5 = 63.5 cm2 . No. of 4 cm2 films obtained from main film = 9 films each with area 4 cm2 . Area of the main film considered (9 films) = l*b =6*6 = 36 cm2 . Area not considered = total area - area considered = 63.5 - 36 = 27.5 cm2 . Amount of drug in the area considered = 9*30 = 270 mg  Amount of drug in area not considered = 27.5*30/4 = 206.25 mg .

 

Total amount of drug to be incorporated into a film of 63.5 cm2 = amount of fexofenadine in area considered + amount of fexofenadine in area not considered = 270 + 206.25 = 476.25 mg of fexofenadine.


 

Table 1: Formulation of fexofenadine mucoadhesive buccal patches

Formula code

Drug

(mg)

PVA

(g)

HPMC

K4M (g)

HPMC K15M (g)

Eudragit L100 (g)

Oleic acid (ml)

Propylene glycol (ml)

Ethanol (ml)

F1

476.25

1.5

-

-

-

0.036

3.0

20.0

F2

476.25

-

1.3

1.0

-

0.036

3.0

20.0

F3

476.25

-

-

-

1.5

0.036

3.0

20.0

F4

476.25

-

-

-

-

0.036

3.0

20.0


EVALUATION OF FEXOFENADINE BUCCAL PATCHES:

Physical characterization of patches:

Physical characterization of the developed patches was done by checking the patches visually for their thickness, peeling ability, brittleness, surface texture, transparency and tackiness.

 

Weight variation:

Three patches of each developed formulation were selected at random and individual weight of each 4 cm2 patch was checked on digital balance. The average weight of patches was determined.

 

Patch thickness:

Thickness of patches was determined using a screw gauge (with a least count of 0.01 mm) at three different places on the patches and the average of thickness was calculated 10.

 

Surface pH:

Three patches of each prepared formulation were allowed to come in contact with 1 ml of purified water. For the determination of surface pH, a combined glass electrode or pH paper was brought near surface of patches and equilibrated for 1 min. The mean of 3 readings was noted.

 

Folding endurance:

It was measured by repeated folding a patch at the same place until it breaks. The test was done to prove good film characteristics. The number of times of patches can be folded at the same place without any breakage gives folding endurance value. Folding endurance test was performed upon three films which were selected randomly from each developed formulation11.

 

Drug content uniformity:

Drug content uniformity was assessed by dissolving patch of 4 cm2 area consisting of fexofenadine in 50 ml PBS, pH 6.8 with occasional shaking. In order to remove any insoluble reisdue, filtration was done. 1 ml of filtrate was further diluted to 10 ml with PBS, pH 6.8 and absorbance was measured at a wave length of 259 nm using UV - Visible spectrophotometer. The test was conducted three times for the patches of all formulations12.

 

Swelling study:

Buccal mucoadhesive patches were weighted (W1) individually and kept in 2% agar gel petriplates separately, The plates were incubated at a temperature of 37 oC ± 1 oC and checked for any changes in physical characteristics. The patches were taken off from the gel plates at periodic 1 h time intervals until 3 h. With the use of filter paper, excess surface water was cleared carefully13. The swollen patches were subsequently  reweighed (W2) and the swelling index (SI) was determined using the below mentioned formula, 

                                    W2- W1                    

Swelling Index (SI) =------------------- X 100

                                            W1

 

Determination of % moisture loss:

The patches were accurately weighed and placed in desiccators consisting of anhydrous CaCl2. The patches were taken out after 3 days and then weighed. The % moisture content was determined by using formula14.

                             (Intial Weight – Final Weight)

% Moisture Content =  -------------------------------- X 100

                                         Intial Weight

 

In vitro residence / mucoadhesion time:

The in vitro residence time of patches was assessed by determining the time taken for the patch to get detached from the buccal mucosa of goat in a thoroughly agitated beaker containing 500 ml of PBS, pH 6.8 at a temperature of 37 oC. Using cyanoacrylate glue, the mucosal membrane was fixed on the side of beaker. Patch was fixed to mucosal membrane by pressing with finger tip for 1 min. Furhter, the beaker was subjected to magnetic stirring at 150 rpm. The time taken for the complete erosion or separation of patch from the mucosal membrane was considered as a measure of in vitro mucoadhesion or residence time15.

 

Dispersion test:

In dispersion test, a patch equivalent to 30 mg of fexofenadine was placed in 200 ml of PBS, pH 6.8 and agitated for 3 min. The obtained solution was filtered using # 22 sieves. Absence of any residue on sieve is an indication that the patch has passed the dispersion test16.

 

In vitro drug dissolution studies:

In vitro dissolution studies were performed using Franz diffusion cell. Freshly prepared egg membrane was used as semi permeable membrane and was placed at one end of the open cylinder that acted as donor compartment. The developed patches consisting of fexofenadine was kept inside donor compartment. Receptor compartment filled with 100 ml of PBS, pH 6.8 was stirred continuously with the help of magnetic stirrer and maintained at temperature of 37 oC ± 1 oC. From receptor compartment, 2 ml of samples were withdrawn at regular intervals and subsequently replaced with fresh PBS, pH 6.8. Samples were filtered using filter paper, and further assayed by UV - Visible spectrophotometer (Lab India) at the wave length of 259 nm.

 

RESULTS AND DISCUSSION:

Pre-formulation studies of fexofenadine:

The drug and the excipients interaction studies were evaluated by checking the physical appearance                   and by FT-IR analytical methods. The following pre-formulation tests were carried out on fexofenadine and excipients.

Table 2: Analytical report for fexofenadine:

Test

Results

Description

Colourless

Odour

Odourless

Nature

Crystalline Powder

Solubility

Very soluble in water,  ethanol and methanol, freely soluble        in acetone and soluble in phosphate buffers within pH range of 6.0 - 7.5

Category

Antihistaminic drug

Melting Point

196 oC

 

 

 

 

 

 

Table 3: Fexofenadine characterization

Test

Result

Particle Size (μm)

8.47

Bulk Density (g/cm3)

0.362

Tapped Density (g/cm3)

0.415

Carr’s Index

12.77

Hausner’s Ratio

1.14

Angle of Repose (o)

28.54

 

Drug - excipient compatability Tests:

The compatibility studies were done in order to check any kind of interaction of fexofenadine, polymers and other excipients used in the formulation of mucoadhesive buccal patches.

 


Interpretation of fexofenadine:

 

Fig. 1: FT-IR spectra for fexofenadine

 

 

Fig. 2: FT-IR spectra for optimized buccal patch formulation (Fexofenadine - PVA patch):

 


FT-IR spectra of fexofenadine showed the following major peaks at 1706 cm-1 indicating -C-O stretching, a peak at 1279 cm-1 representing C-N stretching of tertiary amine and a peak at 3297.90 cm-1 representing -OH stretching. The optimized formulation (F1) clearly showed the retention of these characteristic peaks of fexofenadine thus the results proved the absence of any interaction between the selected drug i.e., fexofenadine, polymers as well as other additives.

 

FORMULATION DEVELOPMENT:

Standard curve of fexofenadine:

In this study at 259 nm in pH phosphate buffer had good reproducibility in the concentration between 10 - 50 µg/ml. Correlation (R2 = 0.999) between concentration and absorbance was found to be closer to 1 indicating that the method obeyed Beer - Lambert's law.

 

Table 4: Standard calibration curve of fexofenadine

Concentration (µg/ml)

Absorbance at  259 nm (in PBS, pH 6.8)

0

0.000

10

0.225

20

0.454

30

0.689

40

0.945

50

1.195

 

 

Fig. 3: Fexofenadine calibration curve in PBS, pH 6.8 at 259 nm

 

EVALUATION OF FEXOFENADINE MUCOADHESVE BUCCAL PATCHES:

Total four formulations of fexofenadine mucoadhesive buccal patches with the dose of 30 mg per 4 cm2 patches were developed by solvent casting method using mucoadhesive polymers like PVA, HPMC K4M, HPMC K15M and Eudragit L100 and the resulting patches were shown in Fig. 4.

 

 

Fig. 4: Buccal mucoadhesive patches of fexofenadine

 

The developed patches were tested for physical characteristics, thickness, uniformity of weight, surface pH, drug content uniformity, folding endurance, swelling index, water absorption capacity, dispersion test, in vitro residence / mucoadhesion time, % moisture content and drug release in vitro.

 

Physical characterization:

It was done for patches by visual inspection and the following results were observed as given in Table 5 and 6.

 

Weight uniformity and patch thickness:

The weight of 4cm2 patches of all prepared formulations was observed to be within the range of                   150.82 mg ± 0.02 to 152.02 mg ± 0.08, which was acceptable. Thickness of all patches was measured with Vernier calliper and thickness values for all formulations was from 0.19 mm ± 0.005 to 0.21 mm ± 0.005     (Table 6). The optimized patch (PVA) has thickness of 0.19 mm ± 0.005.

 

Surface PH:

The surface pH of all prepared patches was observed in the range between 6.76 ± 0.01 and 6.94 ± 0.005 as shown in Table 6. As the pH values were close to the neutral pH, the patches may be less irritating to the sublingual mucosa, and therefore, the patches would be more preferred by patients.

 

 

Folding endurance:

The folding endurance was determined manually by folding the patch repeatedly until it broke, and it was taken as the end point. The values of folding endurance for the prepared buccal patches were found within 165 to 334 ranges as shown in Table 6. The folding endurance of the patches (F1) was more than 300 which proved that the patches were having high mechanical strength as well as good elasticity. F2 showed minimum folding endurance. However, all prepared patch formulations showed satisfactory flexibility.

 

Table 5: Physicochemical characteristics of various buccal mucoadhesive patches

Formulation code

Film forming property

Tackiness property

Ease of handling

Texture

F1

Excellent

Non-tacky

Thin, flexible, easy to peel and handle

Smooth

F2

Good

Non-tacky and slightly brittle

Thick and easy to peel

Rough

F3

Good

Non-tacky

Thick and easy to peel

Rough

F4

Good

Tacky

Thick, easy to peel and easy to handle

Smooth

 

Table 6: Physicochemical and mechanical parameters of buccal patches

Formulation

code

Thickness

(mm)

Weight            uniformity (mg)

Surface pH

Folding Endurance

F1

0.19 ± 0.005

150.82 ± 0.02

6.87 ± 0.005

334 ± 1.0

F2

0.20 ± 0.007

151.18 ± 0.04

6.76 ± 0.01

165 ± 1.6

F3

0.21 ± 0.005

152.02 ± 0.08

6.81 ± 0.01

171 ± 1.6

F4

0.20 ± 0.007

151.35 ± 0.06

6.94 ± 0.005

302 ± 1.2

Note: Mean ± SD of three determinations

 

Uniformity of drug content:

Based on results of drug content uniformity, it was found that fexofenadine was dispersed uniformly and the values ranged between 91.61% ± 0.08 to 95.47% ± 0.02.

 

Swelling Index:

The swelling behaviour of the mucoadhesive polymers was studied and results were given in Table 7.            Percent swelling index for the patches was found between 47.28% ± 0.06 to 65.82% ± 0.02. The comparative swelling of polymer in the prepared formulations was shown in Fig. 5. The swelling index was found in the order of F4 < F2 < F3 < F1. The void space is supposed to be filled by the external solvent which diffused into the patch and thereby increasing the dissolution of gels. In case of all prepared formulations, the standard deviation values obtained were found to be very low indicating that the developed patches showed uniform swelling index.

 

Table 7: Drug content and swelling index of developed formulations

Formulation code

Drug content  (%)

Swelling Index (%)

F1

95.47 ± 0.02

65.82 ± 0.02

F2

92.39 ± 0.04

54.18 ± 0.04

F3

91.61 ± 0.08

59.02 ± 0.08

F4

93.82 ± 0.06

47.28 ± 0.06

Note: Mean ± SD of three determinations

 

 

Fig. 5: Swelling studies of buccal patch formulations

 

Percentage moisture loss:

The % moisture loss study of different patches was done for a period of 3 days. The results of the % moisture loss were depicted in Table 8. Less moisture content in developed formulations was found to be favourable in order to protect from microbial contamination due to its hygroscopic nature.

 

In vitro residence time:

The in vitro mucoadhesion time of mucoadhesive polymers were found as given in Table 8. In vitro mucoadhesion time shown by all the patch formulations was observed to be good. Formulation F1 showed highest in-vitro mucoadhesion time where as formulation F2 showed lowest in-vitro mucoadhesion time. In-vitro mucoadhesion time for the patches was in between 3.22 h ± 0.25 and 6.89 h ± 0.24. As the particle swells, the matrix experiences intra matrix swelling force which further promotes disintegration as well as leaching of drug leaving behind a highly porous matrix. The in-vitro residence time increases with increase in polymer concentration.

 

Table 8: Percentage moisture loss and in vitro residence time of patches

Formulation code

Moisture loss

(%)

In vitro residence time (h)

F1

2.94 ± 0.02

6.89 ± 0.24

F2

1.48 ± 0.01

3.22 ± 0.25

F3

1.83 ± 0.04

4.16 ± 0.12

F4

2.09 ± 0.02

5.12 ± 0.16

Note: Mean ± SD of three determinations

Dispersion test:

All the formulations passed the dispersion test and observed that there was no residue left on the sieve #22 after 3 min.

 

In vitro dissolution studies:

The cumulative percent drug release for developed formulations was tabulated in Table 9 and Fig. 6. Formulation F1, F2, F3 and F4 showed drug release up to 96.18% ± 0.53, 87.26% ± 1.50 , 85.94% ± 1.24 and 89.51% ± 0.96 respectively at the end of 8 h. The optimized formulation (F1) showed highest % of drug release 96.18% ± 0.53% by the end of 8 h. The sustained release of the drug was achieved up to 8 h. The polymer, PVA in F1 caused the initial burst release within 4 h. Based on the results obtained; F1 was observed to be the best formulation in order to release the drug in sustained manner. For a buccal drug delivery, the preferable drug release pattern is slow and steady release as exhibited by F1.

 

Table 9: In vitro drug release data for developed mucoadhesive buccal patches of fexofenadine

Time (h)

% Cumulative drug release

F1

F2

F3

F4

0

0

0

0

0

0.5

17.25 ± 1.21

11.82 ± 0.92

10.69 ± 0.85

13.45 ±1.69

1

25.49 ± 0.97

22.96 ± 0.75

21.74 ± 0.51

23.16 ± 0.72

2

30.92 ± 0.68

34.45 ± 1.52

31.52 ± 1.06

32.40 ± 0.94

4

67.36 ± 1.02

52.01 ± 0.86

50.18 ± 0.68

51.72 ± 1.28

6

82.27 ± 0.74

70.47 ± 0.59

72.07 ± 1.92

72.46 ± 1.54

8

96.18 ± 0.53

87.26 ± 1.50

85.94± 1.24

89.51 ± 0.96

Note: Mean ± SD of three determinations

 

 

Fig. 6: In vitro drug release profiles of developed buccal patch formulations

 

CONCLUSION:

Mucoadhesive buccal patches of fexofenadine fabricated using polymers such as PVA, HPMC K4M, HPMC K15M and Eudragit L100 showed satisfactory physicochemical and mucoadhesive properties. From the present research study, it can be concluded that mucoadhesive buccal patches of fexofenadine may provide sustained buccal delivery for 8 h with improved permeability, bioavailability and therapeutic efficacy. Further, the investigation needs to be extended for kinetics of drug release, ex vivo permeation studies and in vivo drug release studies.

 

ACKNOWLEDGEMENTS:

The authors are grateful to the principal and management of Vijaya Institute of Pharmaceutical Sciences for Women, Enikepadu, Vijayawada for providing the necessary research facilities.

 

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Received on 01.06.2018            Modified on 22.07.2018

Accepted on 20.08.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(11): 4892-4898.

DOI: 10.5958/0974-360X.2018.00891.0