Formulation and evaluation of sustained released buccoadhesive tablets of Itraconazole

 

Swapnil Gupta, Ajazuddin*, Pooja Yadav, Hemlata Thapa, Tripti Banjare, Palak Agrawal, Akansha Bhandarkar, Aditi Bhatt, Hemlata Sahu, Shradha Devi Diwedi, Pankaj Sahu, Siddharth Kumar Sahu, Kailash Sahu, Deeksha Dewangan, Deepika, Mukesh Sharma,

D. K. Tripathi, Amit Alexander

Rungta College of Pharmaceutical Sciences and Research, Kohka-kurud road, Bhilai, Chhattisgarh, 4900024

 

ABSTRACT:

The aim of present research was to report the buccoadhesive tablet of itraconazole to provide localized delivery of drug for the treatment of oral thrush and maintain the drug concentration in the mouth for prolonged period of time thereby improving the oral bioavailability of drug. Buccoadhesive tablet is a sustained release of itraconazole for easy permeation across buccal mucosa and provide a local delivery concentration that may or may not be sufficient to maintain MIC to kill the microorganism. Solid dispersion of itraconazole was prepared by solvent evaporation technique using silica gel act as adsorbent and drug was soluble in chloroform to obtain a slurry or uniform mixture. The buccoadhesive tablet was prepared by direct compression method using different polymers such as Carbopol(C934P),HPMC K4M, Eudragit E100. Five formulations of different concentrations were prepared. Itraconazole strength were kept constant at 30mg and target was fixed at 120mg. After examine the moisture content, bulk density, tapped density, Angle of repose of powder blend get the result were found to be prescribed limit and indicated good flow property. Then the tablets were evaluated for hardness, thickness, weight variation, drug content, friability, swelling index, In-vitro drug release.

 

 

 

INTRODUCTION:

Itraconzole act as a anti-fungal drug which is used for the treatment of oral cavity for prolonged of time. It improves the oral bioavailability of drug. Itraconazole is considered as a azole anti-fungal drug for treating mucosal and systemic infection caused by fungus which can invade in the oral cavity such as mouth. It inhibits membrane component ergosterol synthesis.^[1-5] It shows poor bioavailability of drug through buccal route and extensive hepatic first pass metabolism because of its low aqueous solubility and molecular weight.^[6-9] The solubility of itraconazole can also be improved by Solid Dispersion using Adsorbent like Colloidal silica, porous calcium silicate, silica gel. Silica gel is the best adsorbent for solid dispersion.^[9-14]

 

The main objective of the present investigation has to formulate solid dispersion of itraconazole using silica gel as adsorbent was evaluated. The present study of sustained release buccoadhesive tablet were prepared by Direct compression technique. Excipients like C934P, HPMCK4M, Eudragit E100 used. The sustained release formulation of itrconazole were formulated by using Silica Gel in different ratio and buccoadhesive tablet provides a permeation across buccal mucosa to achieve a salivary drug concentration that may ensure prolonged drug delivery towards the oral cavity.

 

MATERIAL AND METHOD:

Chemicals

Itraconazole API, Carbopol (C934P), HPMCK4M, EudragitE100, Solid Dispersion of Itraconazole and all other excipients were obtained from Pharmaceutics laboratory of RCPSR, Kohkakurud Road, Bhilai.

 

Instrumentation

UV-Visible Spectrophotometer (Shimadzu UV-1800), Tablet Compression machine (Shakti), Dissolution apparatus (Electrolab TDT- 08L)

 

Preparation of Calibration curve of Itraconazole in Methanol

Selection of Solvent

Methanol was selected as ideal solvent for spectrophotometer analysis of itraconazole.

 

Preparation of Standard Stock Solution

Standard drug solution of itraconazole was prepared by dissolving 5mg of pure drug in 50mL Methanol a concentration of 100µg/ml was obtained from which desired Concentration solution was prepared.

 

Determination of λmax

10µg/ml solution of itraconazole was prepared and scanned in UV-range 200-400nm and Photometric spectrum was obtained. The λ max was found to be 262nm.

 

Preparation of Calibration curve

From the stock solution of itraconazole a series of dilution ranging from 4-14µg/ml were prepared. Absorbance of these solution was measured at 262nm wavelength and calibration curve was plotted between concentration and absorbance.

 

Preparation of Calibraton Curve of itraconazole in 6.8 pH phosphate buffer.

Preparation of buffer solution

The medium, 6.8 pH phosphate buffer was prepared by mixing 250ml of 0.2M potassium dihydrogen phosphate along with 112ml of 0.2M NaOH distilled water was added to adjust the volume and make up the volume to 1000ml.

 

Preparation of Standard stock solution

Standard drug solution of itraconazole was prepared by dissolving 5mg pure drug in 50ml 6.8 pH phosphate buffer. A concentration of 100µg/ml was obtained, from which desired concentration solutions were prepared.

 

Determination of λmax

10µg/ml solution of itraconazole was prepared and scanned in UV range 200-400nm spectrum was obtained. The λmax was found to be 262nm.

 

Preparation of Calibration curve

From the stock solution of itraconazole, a series of dilutions ranging from 4-14µg/ml were prepared. Absorbance of these solution were measured at 262nm wavelength and calibration curve was plotted between concentration and absorbance.

Preparation of Itraconazole sustained release tablet by Direct Compression Method.

The sustained release tablet of Itraconazole were prepared by Direct compression method as per formula given in Table 1. Five different formulation were prepared for Itraconazole sustained release tablet with different component of polymer and excipient ratio.

 

All the ingredients were passed initially through sieve #80 and then accurately weighed, mixed thoroughly and then passed through sieve no.80.The powder blend were then dried in Hot air oven at 50°C for 20-30min, in a multi tooling lab based punching machine(SHAKTI) in a slow and steady speed with high compression power to avoid capping.

 

Table 1. Formulation ofBuccoadhesive tablets.

Contents	F1	F2	F3	F4	F5
C934P	5mg	7.5mg	10mg	12.5mg	15mg
HPMC K4M	15mg	12.5mg	10mg	7.5mg	5mg
Solid dispersion of Itraconazole and Eudragit E100(1:2)	60mg	60mg	60mg	60mg	60mg
CP934P HPMC K4M(1:1)	20mg	20mg	20mg	20mg	20mg
C934P	5mg	7.5mg	10mg	7.5mg	15mg
HPMC K4M	15mg	12.5mg	10mg	7.5mg	5mg
TOTAL	120mg	120mg	120mg	120mg	120mg

 

EVALUATION OF POWDER BLENDS

Powders were evaluated for all pre-compression parameters like angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index. The evaluations were done using all the methods as per specified in pharmacopoeias.⁴

 

Angle of repose:

It is defined as “the maximum angle between surface of the pile and horizontal plane”. It is measured using fixed funnel method. The funnel is kept vertically attacked to a stand at a specific height, below which a paper is kept on a horizontal surface. The funnel is first filled with the powder and then opened to release the same in a form of conical heap, the height of heap is measured with scale and then angle of repose is calculated using formula below:

 

θ = tan^-1 h/r

Where h = height of heap, r = radius of heap

 

Tapped density:

It was determined by placing the powder in a measuring cylinder and tapping it 100times, the total mass of powder was determined and density was calculated using the formula:

 

Tapped density = Vb/Vf

Where Vb = initial volume, Vf = tapped volume

 

Bulk density:

A known quantity of powder blend is putted into a measuring cylinder and levelled, note the bulk volume and calculate the bulk density using formula below:

 

Bulk density = m/Vo

Where m = unsettled, Vo = apparent volume

 

Compressibility index:

It was calculated using measured values of bulk and tapped density as:

 

Carr’s index = [(Vt-Vb)/Vt] x 100

Where Vt = tapped volume and Vb = bulk volume

 

It is also calculated from using measured values of bulk and tapped density as:

Hausner’s ratio = Dt/Do

Where Dt = tapped density, Do = bulk density

 

EVALUATION OF TABLETS

Tablets were evaluated for certain properties like weight variation, Hardness, Friability, Swelling index, In-vitro dissolution study.

 

Assay

Tablets containing 120mgItraconazole were weighed; powdered and average weight was calculated. Powder equivalent to 10mg itraconazole was dissolved in 30ml of buffer solution with the help of sonication. This was further diluted with the mark up to the mark with same solvent. The solution was filtered with 5ml of filtrate was discarded. This solution was further diluted to obtain 10µg/ml solution with same solvent and subjected for UV analysis.

 

Tablet weight variation

Each individual tablet in a batch should be uniform and weight variation within permissible limits. Twenty tablets were randomly selected and accurately weighed using an electronic balance. The results are expressed as mean values of 20 determinations.

 

Hardness

The hardness of tablets is defined as “the force required in breaking a tablet” and it is determined using Monsatto hardness testing apparatus. The tablet is placed vertically in the tester and force required to break the tablet is measured. The unit of hardness of tablet is Kg/cm2.

 

Friability

The friability of tablets was measured in a Roche Friabilator. 20 tablets of known weight (Wo) were taken in a plastic chamber for a fixed time (100 revolutions) and weight(W) again. % Percentage friability was calculated from the loss in weight as given in equation below.

 

NOTE: % friability should not exceed 1.0%.

 

Percent drug content

Accurately weighed 10 tablets , crushed and powder wt. Equivalent  with 50mg of drug was mixed with 5ml phosphate buffer pH 6.8 and filtered through Whatmann filter. The solution was diluted with phosphate buffer, and analysed spectrophotometer at 262 nm.

 

Swelling Index

Buccal tablets were weighed individual (W1) and placed separately in 5ml phosphate buffer pH 6.8 and incubated at 37degree celcius ±1degree celcius temperature. At regular time intervals 1hr, 2hr, 4hr, 8hr tablets were removed from petridish and excess buffer was removed carefully using filter paper. The swollen tablet was then reweighed (W2) and swelling index(SI) was determined using the equation.

Swelling Index= (Wo-W)/Wo X 100

Where,

W2= Weight of tablet after time t

W1=Weight of tablet before placing in the petridish

 

In-vitro dissolution study

Invitro drug release of the tablets was conducted for a period of 6hours using a six station USP type II (paddle) apparatus at 37°C ±0.5°C and 50rpm speed (Fig. 1). The dissolution studies were carried out in acid buffer pH 1.2 for first 2 hours and further in phosphate buffer 6.8 pH. 1ml sample were withdrawn in 10ml volumetric flask at specific interval of time from dissolution medium and replaced with fresh medium to maintain constant volume. The withdrawn sample was made up to the mark with same medium and was analysed at 262nm Itraconazole in UV-Spectrophotometer. The amount of drug was calculated^{, 4}

Fig.1. Dissolution Apparatus

 

RESULT AND DISCUSSION

Table 2.Calibration curve of Methanol         

 

Table 3. Calibration curve of Phosphate buffer pH6.8

 

Fig. 2.Standard calibration curve of Itraconazole in Methanol

 

Fig. 3. Standard calibration curve of Itraconazole in Phosphate bufferpH6.8

 

Calibration curve of Itraconazole was prepared in Methanol (Table 2, Fig. 2) and 6.8pH Phosphate buffer (Table 3, Fig. 3). In Methanol the slope ofthe graph was found to be 0.042 and intercept with 0.047 with regression coefficient R² =0.998 while in 6.8pH phosphate buffer the slope of the graph was found to be 0.050 and intercept with 0.030 with regression coefficient R² =0.990.

 

Table 4.Evaluation of powder blends of different compositions of itraconazole tablet.

Formulation	Moisture content	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Angle of repose
F1	1.2%	0.18	0.23	22.32
F2	1.2%	0.20	0.25	24.38
F3	1.2%	0.25	0.50	24.38
F4	1.2%	0.25	0.58	26.40
F5	1.2%	0.50	0.55	27.60

 

Table5.Formulation of Solid Dispersion of Itraconazole with different Adsorbent.

Name of adsorbent (solid dispersion)	Product name assigned	Drug (mg)	Adsorbent (mg)	Ratio of Drug to Adsorbent	Nature of product
Silica Gel	Gl 1	30	15	2:1	Solid dispersion
	Gl 2	30	30	1:1	Solid dispersion
	Gl 3	30	60	1:2	Solid dispersion
	Gl 4	30	120	1:4	Solid dispersion
	Gpm	30	60	1:2	Physical Mixture

 

 

Table 6. Evaluation of different formulation of sustained release Itraconazole tablet.

Formulation	Average wt(mg)	Thickness (mm)	Hardness (kg/cm2)	% Friability	Swelling Index	% Drug Content
F1	Silica Gel	4	3.0	0.44%	79.12	85.84%
F2	120.6	3	3.0	0.36%	78.14	90.95%
F3	120.5	4	4.0	0.22%	78.14	92.85%
F4	120.7	4	4.0	0.19%	76.13	94.87%
F5	120.7	4	4.0	0.15%	76.13	97.91%

 

Table 7. Evaluation ofthe drug release time

Time	F1	F2	F3	F4	F5
5min	20.24	15.22	20.28	25.29	30.38
15min	25.25	20.24	30.42	28.45	35.42
30min	50.35	30.35	35.45	32.47	38.55
60min	54.48	45.48	40.52	45.53	45.48
120min	56.53	50.54	45.63	55.58	55.62
300min	69.62	68.64	58.59	68.74	68.72
480min	75.81	76.79	78.79	77.79	75.78
540min	77.82	78.82	78.78	76.78	85.88
600min	82.83	85.87	86.87	75.78	78.82
660min	90.86	93.88	95.85	94.82	93.85
720min	90.86	93.88	95.85	94.82	93.85

 

 

Fig 4.Percent In vitro drug release of buccoadhesive formulation

 

 

The Angle of Repose from formulation F1 to F5 varied between 22.32° to 27.60° showing very good flow properties. The tapped density varied from 0.23 to 0.55 while bulk density ranged from 0.18 to 0.50 both indicating good ability of powder blends among which F1 to F5 have very good flow property (Table 4). Itraconazole tablets were formulated by using Solid dispersion of Adsorbent like Silica gel (Table 5). These were also formulated by Direct Compression Method using different polymers like C934P, HPMCK4M, Eudragit100. The granules were subjected to various pre-formulation study tests before compression.

 

The punched tablet of different formulations were also subjected to different evaluation parameters like average weight, Thickness, Hardness, Friability, %drug content, Swelling index, In-vitro dissolution study which is shown in Table 6. All the tablets passed weight variation tests as all of them are weighed within given pharmacopoeial limits. The Hardness of tablet ranged between 3.0 to 4.0, which indicated good strength. The friability was between 0.44 to 0.15 within a limit. The percent drug content of tablets was within limits 85.84% to 97.91%. The drug release profile of all the formulation release in 6 hrs (Table 7, Fig. 4).According to USP dissolution criteria for sustained release Itraconazole tablet. The data was in accordance with previous reports.^[15-18]

 

 

CONCLUSION:

The overall study was done to formulate and evaluated Itraconazole sustained released tablet using different polymer ratio and the present study showed that it could be easily formulated using direct compression technique for slow release, improved bioavailability, patient compliance with effective therapy. All the formulation showed acceptable release among which F4 was best selected out. The study revealed that solid dispersion of itraconazole and Eudragit (E100) could be used in different ratios for a better-sustained release profile. More the concentration of polymer increase in release profile was observed.

 

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

 

 

 

 

 

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Received on 14.08.2017         Modified on 14.10.2017

Accepted on 21.11.2017      © RJPT All right reserved