INTRODUCTION:

Conventional routes of drug administration such as oral, intramuscular and intravenous have, in many cases, been supplanted by the advent of new, novel drug delivery systems. The systemic delivery of drugs through novel methods of administration is one area in which significant changes and improvements have been made. Consequently, precise control of drug input into the body by a variety of routes is now possible. Controlled and sustained release formulations have been developed and are gaining in popularity and medical acceptance[1]. Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over both injectables and enterable methods[2].

Not all drugs, however, can be administered through the oral mucosa because of the characteristics of the oral mucosa and the physicochemical properties of the drug. Primary bond arises due to chemisorptions and secondary bond due to and Vander waals forces, hydrophobic interaction and hydrogen bonding between dosage form and mucosal membrane[3]. The adhesive properties of such drug delivery platforms can reduce the enzymatic degradation due to the increased intimacy between the delivery vehicle and the absorbing membrane[4]. Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, this presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and thehepatic “first-pass” effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption. Chitosan has been used in a wide variety of biomedical applications like sustained release of drugs[5-7].

Buccoadhesive buccal film of isosorbide using different combination of Carbopol 934 P, Eudragit RL100 and PVP K- 30 had been made[8]. The buccoadhesive patch of carvedilol using HPMC, Carbopol, and Eudrahgit-RS100 has been made[9]. Buccoadhesive film and its evaluation for ex vivo buccal permeation, mechanical strength and in vivo buccal permeation of atenolol have also done[10]. Mucoadhesive buccal patches containing cetylpyridinium chloride, characterized by Fatma et al., 2003[11]. The work on buccoadhesive patch containing Amlodipine besylate, yet not found, hence this is an area of our interest. Being a non-toxic, biocompatible and biodegradable polymer, chitosan has been widely used for pharmaceutical and medical applications. A wide variety of pharmaceutical applications for chitosan have been reported over the last two decades due to its preservative and haemostatic properties[12-14]. It has also been used as a pharmaceutical excipient in conventional dosage forms as well as in novel applications involving bioadhesion and transmucosal drug transport.

Amlodipine besylate(AMB) is a calcium channel blocker and a class IV antiarrhythmic agent. The oral absorption of the drug from oral dosage forms is about 90% but it is subjected to a very extensive first-pass metabolism in the liver and its bioavailability is only about 20%. Since this drug has a short elimination half-life of 2 - 4 hours and is eliminated rapidly. Repeated daily administration is required to maintain effective plasma levels[15]. The short half life and extensive first pass metabolism of AMB makes it a suitable candidate for administration via a buccal delivery system that provides sustained drug delivery without pre-systemic metabolism. For the sustained action of AMB through oral mucosal route, 10 mg drug had incorporated. The mucoadhesive, natural and unique polymer, chitosan was the base of dosage form.

MATERIAL AND METHODS:

Amlodipine besylate obtained from commercial purchase. Chitosan (pH = 4.0–6.0, 1 w/v aqueous solution) was provided by Central Institute of Fisheries Technology, Cochin as gift sample; Polyvinyl Pyrrolidone K-30 was obtained from Alkem labs, Navi Mumbai, India. The other chemicals were used are of analytical grade. The compatibility study of drug and polymers were carried out with FT-IR spectroscopic study, there was no chemical interaction found.

Preparation of mucoadhesive buccal patch:

The buccal mucoadhesive patches from chitosan polymer were prepared by solvent casting technique [7] in different concentration. Table 1 contains the composition of prepared buccal patch. The polymeric solution of chitosan was prepared using 1.5% (V/V) acetic acid in distilled water under occasional stirring for 48 h. The resulting viscous chitosan solution was filtered through nylon gauze to remove debris and suspended particles. The drug release characteristic was increased on use of a water-soluble hydrophilic additive polyvinylpyrrolidone (PVP K-30) into the chitosan solution under constant stirring. Propylene glycol (5%, V/V) was added as plasticizer under constant stirring. The resultant solution was left overnight at room temperature to ensure a clear, bubble-free solution. The solution was poured into a glass petri dish having 6 cm diameter. The amount of drug required to dissolve in petri dish, so patch of 10 mm diameter size containing 10 mg of Amlodepine Besylate was calculated by the ratio of surface area of petridish and buccal patch (10 mm). The dummy patch without drug was also prepared. The Petri dishes were kept on leveled surface and covered by inverted funnel to allow controlled evaporation of solvent at room temperature till a flexible film was formed. Dried films were carefully removed, checked for any imperfections or air bubbles and cut into patches of 10 mm in diameter by using fabricated punch. The patch containing10 mg of AMB drug was packed in aluminum foil and stored in an airtight glass container to maintain the integrity and elasticity of the patches.

Table 1: Composition of Amlodepine Besylate buccal mucoadhesive patches

Formulation Code	Chiostan ^a (20 ml)	PVP K-30 (mg)	Propylene glycol	Drug ^b (mg/28.26 cm² area)
Placebo	1%	50	5%	----
C-01	1%	50	5%	1800
C-02	1%	100	5%	1800
C-03	1%	150	5%	1800
C-04	1.5%	50	5%	1800
C-05	1.5%	100	5%	1800
C-06	1.5%	150	5%	1800
C-07	2%	50	5%	1800
C-08	2%	100	5%	1800
C-09	2%	150	5%	1800
C-10	2%	200	5%	1800

^aChiostan solution made with 1.5 % acetic acid

^b10 mg drug per1×1 cm² patch

Evaluation of Buccal Patches:

Thickness and weight uniformity the thickness of three randomly selected buccal patches from every batch was determined using a standard screw gauge. Weight uniformity of patch determined by taking weight of ten patches of sizes 10 mm diameter from every batch and weigh individually on electronic balance.

Surface pH study:

The surface pH of the buccal patches was determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may cause irritation to the buccal mucosa, it was determined to keep the surface pH as close to neutral as possible [16]. A combined glass electrode was used for this purpose. The buccal patch was allowed to swell by keeping it in contact with 1 ml of distilled water for 1 hour at room temperature. The pH was measured by bringing the electrode in contact with the surface of the patch and allowing it to equilibrate for 1 minute. The experiments performed in triplicate, and average values were reported.

Content uniformity:

Drug content uniformity was determined by dissolving the buccal patch (10 mm in diameter) rom each batch by homogenization in 100 ml of an isotonic phosphate buffer (pH 6.6) for 6 h under occasional shaking. The 5 ml solution was taken and diluted with isotonic phosphate buffer pH 6.6 up to 20 ml, and the resulting solution was filtered through a 0.45 mm Whatman filter paper. The drug content was then determined after proper dilution at 365 nm using a UVspectrophotometer.

Folding endurance:

Folding endurance of the patch was determined[17] by repeatedly folding one patch at the same place till it broke or folded upto 300 times manually, which was considered satisfactory to reveal good patch properties. The number of times of patch could be folded at the same place without breaking gave the value of the folding endurance. This test was done on randomly selected three patches from each.

Swelling percentage study:

Swelling study of prepared buccal patch was calculated by function of weight and area increase due to swelling, which was measured for each formulation as follows [9]

Weight increase due to swelling:

A patch of 10 mm size (1 x 1 cm²) diameter from every batch was weighed on a preweighed cover slip. It was kept in a petridish and 10 ml of phosphate buffer, pH 6.6 was added. After one hour, the cover slip was removed and weighed. The difference in the weights gives the weight increase due to absorption of water and swelling of patch. Area increase due to swelling: similarly patch of 10 mm diameter from each batch was place on cover slip and this cover slip was placed in a petridish. Ten ml of phosphate buffer, pH 6.6, was poured into the petridish. A calibrated measuring scale was used to measure the increase in the area of each patch. An increase in the area in diameter of the patch was noted at one hour intervals for 6 hour and the area was calculated. The percentage weight and area swelling ratios was calculated from the average of three measurements using the following equation:

% S = (Xt – Xo / Xo) ×100

Where, Xt - weight or area of the swollen patch after time t and Xo - is the original patch weight or area at zero time.

Tensile strength:

A tensile strength study of patch is total weight, which is necessary to break or rupture the dosage form and this was done by a device has rectangular frame with two plates made up of Plexiglas’s [18, 19]. The one plate is in front and is movable part of device and can be pulled by loading weights on the string, which is connected to movable part. The 1x1 cm2 buccal patch equivalent to 50 mg drug from each formulation was fixed between the stationary and movable plate. The force needed to fracture the film was determined by measuring the total weight loaded in the string. The weight corresponds to break the patches were taken as tensile strength and the values were shown in table 3.

The following equation was used to calculate the tensile strength (TS).

TS (g/cm2) = Force at break (g) / Initial cross sectional area of patch.

Determination of In vitro residence time:

The in vitro residence time was determined using a locally modified USP disintegration apparatus, based on the apparatus applied by Nakamura et al[20]. The disintegration medium was composed of 800 ml pH 6.6 isotonic phosphate buffer (IPB) maintained at 37 ± 0.5°C. A porcine buccal mucosa, 3 cm length, was glued to the surface of a glass slab, vertically attached to the apparatus. The mucoadhesive patch was hydrated from one surface using 15μl pH 6.6 IPB and then the hydrated surface was brought into contact with the mucosal membrane. The glass slab was vertically fixed to the apparatus and allowed to move up and down so that the patch was completely immersed in the buffer solution at the lowest point and was out at the highest point. The time necessary for complete erosion or detachment of the patch of each batch from the mucosal surface was recorded in table 3.

Vapour transmission test (VTR):

Vapour transmission method [21] was employed for the determination of vapor transmission from the patch. Glass-bottle (length= 5 cm, narrow mouth with internal diameter =0.8 cm) filled with 2 g anhydrous calcium chloride and an adhesive (Feviquick®) spread across its rim, was used in the study. The patch was fixed over the adhesive and the assembly was placed in a constant humidity chamber, prepared using saturated solution of ammonium chloride and maintained at 37±2 °C. The difference in weight after 24 h, 3rd day and 1 week was calculated [18.] The experiments were carried out in triplicate and vapor transmission rate was obtained as follow:

Amount of moisture transmitted

VTR =-------------------------------------

Area x Time

Measurement of mucoadhesive strength:

The strength of bond formed between the formulation and mucosa membrane excised from porcine buccal mucosa was determined using two-arm balance method[22]. Fresh porcine buccal mucosa was obtained from a local slaughterhouse and used within 2 h of slaughter. The mucosal membrane was separated by removing the underlying fat and loose tissues. The membrane was washed with distilled water and then with isotonic phosphate buffer pH 6.6 (IPB) as moistening fluid. Briefly, buccal mucosa section (2.4 mm thick, 3×5 cm) was fixed on the plane surface of glass slide (3×5 cm) attached (with adhesive tape) to bottom of smaller beaker, kept inverted in 500 ml beaker attached to the bigger beaker. Isotonic phosphate buffer pH 6.6 was added to the beaker up to the upper surface inverted beaker with buccal mucosa. The buccal patch of size 10 mm in diameter (1x1 cm2) was stuck to the lower side of the upper clamp with cyanoacrylate adhesive. The exposed patch surface was moistened with 15 μl of IPB and left for 30 s for initial hydration and swelling. Then the platform was slowly raised until the patch surface came in contact with mucosa. Two sides of the balance were made equal before study. After a preload (50 g) time of 2 minutes, water was added to the polypropylene bottle present in another arm, until the patch was detached from the buccal mucosa. The water collected in the bottle was measured and expressed as weight (g) required for the detachment (table 5). The force measurement was repeated 3 times for each formulation. The following parameters were calculated from the bioadhesive strength:

Force of adhesion (N) =

(Bioadhesive strength (g) × 9.81)/1000

Bond strength (N m–2) =

Force of adhesion / Disk surface area

In vitro release study:

The USP 23 (1995) [23] rotating paddle method was used to study the drug release from buccal patches. The dissolution medium consisted of 400 ml of isotonic phosphate buffer pH 6.6. The release was performed at 37 ± 0.5°C, at a rotation speed of 50 rpm. One side of the buccal patch was attached to a glass disk with instant adhesive (cyanoacrylate). The disk was put in the bottom of the dissolution vessel so that the patch remained on the upper side of the disk. Samples (1 ml) were withdrawn by using calibrated pipette at pre-determined time (1 hour) intervals and replaced with fresh medium. The samples were filtered through 0.45 μm Whatman filter paper with appropriate dilutions with phosphate buffer pH 6.6 and were assayed spectrophotometrically at 365nm.

Ex vivo buccal permeation study:

The buccal permeation test planned for optimized batch only. The test was carried out using porcine buccal mucosa because of nonkeratinized buccal mucosa similar to that of human and their inexpensive handling and maintenance cost. The buccal epithelium was used within two hour upon removal [24]. The modified Franz diffusion cell was used to permeation studies, it consists of two compartments, one is donor compartment and another is receptor compartment of 25 ml capacity [25. The receptor compartment was cover with water jacket to maintain temperature 37°C. The separated buccal epithelium was mounted between the chamber, and in receptor chamber phosphate buffer solution having pH 7.4 was filled and buccal epithelium was allow to stabilized for the period of 1 h. after stabilization, patch was kept on epithelium and periodically (for 6 h) samples were withdraw and maintain sink condition. The aliquot were analyzed spectrophotometrically at 365 nm. The drug permeation was correlated with cumulative drug released.

RESULTS:

The thickness (Table 2) of formulated patches was ranges from 0.66 ± 0.04 to 1.22 ± 0.02 mm, while the average weight of patch from each batch ranges from 63.17 ± 0.52 to 93.79 ± 0.07. The surface pH of patches was ranges from 5.50 ± 0.12to 6.03 ± 0.091 were found around neutral pH. The content uniformity recovery was possible to the tune of 93.18 to 101.5 %. Films did not show any cracks even after folding for more than 200 for all batches.

Table 2: Physicochemical characteristics of prepared buccal patches of ABD

Formulation Code	Thickness ^a (mm)	Weight^b uniformity	Surface pHa	Content uniformity (%)	Drug ^b (mg/28.26 cm² area)
Placebo	0.66 ± 0.015	25.694 ±0.58	6.23 ± 0.075	---	> 200
C-01	0.84 ± 0.04	63.726 ±0.55	5.53 ± 0.30	94.77	> 200
C-02	0.83 ± 0.03	63.172 ±0.52	5.50 ± 0.12	93.18	> 200
C-03	0.86 ± 0.03	68.674 ±0.41	5.73 ± 0.068	95.12	> 200
C-04	0.99 ± 0.02	67.474 ±0.33	5.91 ± 0.057	98.51	> 200
C-05	1.08 ± 0.07	68.644 ±0.15	6.03 ± 0.091	100.2	> 200
C-06	1.05 ± 0.81	74.845 ±0.55	5.98 ± 0.077	101.5	> 200
C-07	1.11 ± 0.01	68.656 ±0.44	5.83 ± 0.11	99.56	> 200
C-08	1.16 ± 0.02	86.266 ±0.11	6.02 ± 0.023	98.53	> 200
C-09	1.33 ± 0.01	89.832 ±0.05	6.04 ± 0.098	97.33	> 200
C-10	1.22 ± 0.02	93.796 ±0.07	5.95 ± 0.071	96.66	> 200

a n=3; standard deviation for three determinations.

b n=10; standard deviation for ten determinations.

Table 4:Vapour transmission rate through the patches at different time intervals

Formulation Code	Moisture vapour transmission, gcm^-2h^-1(mean±SD^a)
	Day-1	Day-2	Day-3
Placebo	8.68×10⁻³±1.41×10⁻³	3.65×10⁻³±0.97×10⁻³	1.61×10⁻³±0.44×10⁻³
C-01	7.60×10⁻³±0.80×10⁻³	3.18×10⁻³±0.46×10⁻³	1.64×10⁻³±0.45×10⁻³
C-02	7.07×10⁻³±0.93×10⁻³	1.91×10⁻³±0.98×10⁻³	0.90×10⁻³±0.50×10⁻³
C-03	10.67×10⁻³±1.64×10⁻³	4.0×10⁻³±0.97×10⁻³	1.81×10⁻³±0.30×10⁻³
C-04	4.41×10⁻³±1.33×10⁻³	1.82×10⁻³±0.41×10⁻³	0.80×10⁻³±0.15×10⁻³
C-05	7.43×10⁻³±0.53×10⁻³	3.0×10⁻³±0.53×10⁻³	1.51×10⁻³±0.07×10⁻³
C-06	6.07×10⁻³±1.37×10⁻³	2.83×10⁻³±0.10×10⁻³	1.33×10⁻³±0.15×10⁻³
C-07	3.35×10⁻³±2.33×10⁻³	1.41×10⁻³±0.63×10⁻³	0.65×10⁻³±0.26×10⁻³
C-08	3.71×10⁻³±0.53×10⁻³	1.58×10⁻³±0.17×10⁻³	0.73×10⁻³±0.08×10⁻³
C-09	7.42×10⁻³±3.22×10⁻³	2.65×10⁻³±0.81×10⁻³	1.31×10⁻³±0.41×10⁻³
C-10	7.60×10⁻³±1.33×10⁻³	2.82×10⁻³±0.47×10⁻³	1.28×10⁻³±0.22×10⁻³

^an=3; standard deviation fo rthree determinations

Table5: Bioadhesive parameters of Amlodipine Besylate buccal patches

Formulation Code	Bioadhesive Strength(g)^a	Forceof Adhesion(N)		Bond Strength(Nm-2)
Placebo	5.51±1.27		0.052		642.4
C01	3.30±0.93		0.030		342.1
C02	3.61±0.67		0.034		463.1
C03	1.58±1.31		0.017		236.5
C04	2.64±2.37		0.020		284.7
C05	3.66±0.74		0.034		463.1
C06	4.42±2.97		0.042		565
C07	7.22±1.11		0.067		843.5
C08	6.84±0.55		0.062		749.8
C09	5.93±0.31		0.056		723.3
C10	4.86±2.21		0.043		567.7

^an=3; standard deviation for three determinations

DISCUSSION:

The thickness and weight variation might be due to increasing concentration of chitosan and PVP K-30. The surface pH study indicates no mucosal irritation was expected between the pH reported in table 2 for each batch. Folding endurance did not vary when the comparison was made between plain films and drug loaded patches (Table 2). Due to poor aqueous solubility of chitosan the placebo chitosan base matrix shown less swelling index. The results mentioned cleared that; the increasing concentration of PVP K- 30 increases the swelling percentage. Also the swelling percentage of placebo batch was found less, might be due to absence of water soluble drug. PVP K-30 increased the surface wettability and consequently water penetration within the matrix, hence increased weight and area. In residence time, the increasing concentrations of PVP-K30 allow swelling the buccal patch and made hydrogen bonding weaker. The buccal patch from group-I C07 has highest 4.95 ± 0.39 hour and batch C01 has less 3.08 ± 0.46 hour residence time. The tensile strength of buccal patch was stronger in absence of drug, while increasing the concentration of chitosan base with increasing PVP K-30 concentration has less but acceptable tensile strength. Vapour transmission from day first to third the vapour transmission through patches given the idea of good permeability, but after that patch became saturated and no more moisture absorbed or transmitted. This kind of result gave the idea of presence of less concentration of PVP K-30. During mucoadhesive study, we conclude that the Chitosan base has good bioadhesion properties in appropriate concentration, and good bond strength forming capacity with mucin (Fig.2). But as the concentration of PVP K-30 increases, the bioadhesive strength was found very less, may be due to hydrophilic natures which loosen the bond strength with mucosal area. So patch might be detached as it absorbed water molecule. Mean while some formulation batches had shown less mucoadhesion. The reason might be due to increasing concentration of both Chitosan and PVP K-30, while placebo shows highest mucoadhesion may be due to absence of drug. The drug release finding was also supported by the reported swelling studies where the highest swelling index was also exhibited by batch C06, indicating that the increase in water-soluble polymer PVP K-30 content result in faster swelling and release from patches. In ex vivo permeation study, the cationic chitosan with negative charge of epithelium, creates the strong bonding with mucus layer and on hydration of the patch with buffer 6.6, the drug get diffused 82.42 % into the accepter compartment.

A new buccoadhesive patches for sustained released of Amlodipine besylate was developed by chitosan in appropriate ratio. Chitosan has not only film forming but also good bioadhesion properties with drug AMB. The drug release rate increases on inclusion of PVP K-30 into the chitosan base matrix system and can be modifying for kinetic study. So lastly we conclude that, chitosan with PVP K-30 can meet the ideal requirement for buccal devices, which can be good way to bypass the extensive hepatic first pass metabolism and increase bioavailability.

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Received on 08.05.2017 Accepted on 15.06.2017

Asian J. Res. Pharm. Sci. 2017; 7(2): 97-104.

DOI: 10.5958/2231-5659.2017.00015.7

Formulation Code	Swelling index ^a		Tensile strength (g/cm²)	In -Vitro ^b Residence Time (Hour)
Formulation Code	% Weight increase after 1 hr	% Area increases after 1 hr	Tensile strength (g/cm²)	In -Vitro ^b Residence Time (Hour)
Placebo	13.37±0.37	33±6.08	277.90	3.13±0.49
C-01	15.96±3.96	46.33±4.04	252.48	3.08±0.46
C-02	15.43±2.30	56.66±5.50	261.14	3.10±0.1
C-03	22.06±1.34	67.33±4.61	256.19	2.73±0.66
C-04	15.24±2.20	48.33±3.05	275.92	3.95±0.39
C-05	16.99±1.16	58±5.0	228.02	3.42±0.11
C-06	34.96±2.81	61±2.0	246.75	3.39±0.11
C-07	24.18±4.26	41.66±4.04	231.21	4.95±0.39
C-08	18.58±5.09	47±4.35	270.70	3.67±0.37
C-09	26.49±6.57	52.66±1.52	215.28	3.17±0.11
C-10	36.15±2.66	59.33±2.88	212.99	2.25±0.21

ABSTRACT:

Table5: Bioadhesive parameters of Amlodipine Besylate buccal patches

Fig 2: Comparative dissolution profile of batches C01toC10

Fig.4: Drug released profile for batchC06