INTRODUCTION:

Buccal drug delivery has lately started representing an important route of drug administration. This route has recently been extensively reviewed. Delivery of various therapeutic agents via the buccal route using conventional matrix tablets, disks, gel, films, patches, strips, ointment, laminated systems and buccal cups systems has been studied and reported by several research groups. The use of polymeric patches for buccal delivery has not yet been widely investigated, although they have been extensively employed in the modification of the drug release and their protection by way of coating and matrix formation in various solids like tablets, pellets, granules and powders. An ideal buccal patch should be flexible, elastic and soft yet adequately strong to withstand breakage due to stress from mouth activities. Moreover, it must also exhibit good mucoadhesive strength so that it can be retained in the mouth for a desired duration. As such, the mechanical, mucoadhesive, and swelling properties of buccal patches are critical and essential to be evaluated.^1-3

The buccal route has high acceptance due to avoidance of first pass metabolism and possibility of being accessible for controlled drug release. Various bioadhesive mucosal dosage forms have been developed which include adhesive tablets, gels, ointments, patches and more recently patches. Buccal patches are preferred over adhesive tablets in terms of flexibility and patients comforts. Now day’s bioadhesive polymers received considerable attention as platforms for buccal controlled delivery due to their ability to localize the dosage form in specific regions to enhance drug bioavailability.^4-5

Buccal delivery of drugs provides an attractive alternate to the oral route of drug administration, particularly in overcoming deficiencies associated with the latter mode of dosing. Problems such as high first - pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering the drug via the buccal route. Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer drugs to patients who cannot be dosed orally.^6-7

Nifedipine is chemically 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine -3,5-dicarboxylate. It is a dihydropyridine calcium channel blocker. Its main uses are as an antianginal (especially in Prinzmetal's angina) and antihypertensive. It is used as antihypertensive, calcium channel blocker, coronary vasodialator. Its half life is 2 hrs. It is having bioavailability 45-56%. Its protein binding is 92-98%.The metabolism of nifedipine occurs in gastrointestinal, hepatic region. Its excretion occurs by renal route ( >50%) and by biliary route (5-15%).⁸

HPMC K4M and Carbapol 974 are non toxic, biocompatible and biodegradable polymer. These polymers are known for their film as well as matrix forming abilities.

A suitable buccal drug delivery system should be flexible and possess good bioadhesive properties, so that it can be retained in the oral cavity for the desired duration. In addition, it should release the drug in a predictable manner to elicit the required therapeutic response. In the present study, flexible buccal patches were developed using water swellable polymer, hydroxypropyl methylcellulose (HPMC K4M) and Carbapol 974. The in vitro release characteristics of the prepared systems were evaluated using Keshery - Chien type diffusion cell.^9-15

EXPERIMENTAL:

MATERIALS:

Nifedipine was a generous gift from Nicholas Piramal, Pithampur. HPMC K4M was gifted by Colorcon and Carbapol 974 was gifted by Oxford chemicals, Mumbai. All reagents were of analytical reagents grade. Double distilled water was used for all the experiments.

METHOD:

Preparation of polymer films:

For preparation of the buccal patch solvent casting method was used. HPMC K4M and Propylene glycol in water were mixed together in a predetermined ratio and stirred continuously until a clear solution was obtained. This was then poured in a mould and allowed to dry in an oven maintained at 40°C till a flexible film was formed. The dried patches were carefully removed from the mould, checked for any imperfections or air bubbles and cut into pieces squares of 1cm x 1cm. The samples were packaged in aluminum foil and stored in a glass container maintained at room temperature and 58 % relative humidity. This condition maintained the integrity and elasticity of the patches. For the medicated patches, calculated amount of drug was incorporated in polymeric solution before addition of plasticizer and casting was performed in the same way as mentioned above. The same method was repeated for the formulation by using the polymer carbapol 974. For the medicated patches, calculated amount of drug was incorporated in polymeric solution before addition of plasticizer and casting was performed.

The variables used while formulating the patch (table-2) were concentrations of HPMC K4M, Carbapol 974 and plasticizer (Propylene glycol). The concentration of HPMC K4M was varied from 1% to 4%. The concentration of Carbapol 974 was varied from 2% to 5%. The concentration of plasticizer was finalized differently for the two polymers from the plasticity of the film. It is varied from 10% to 15% for the patch.

The batches of patches (table-1) were prepared from that the batch which is showing proper results were selected. Thus, the concentration of HPMC K4M and Carbapol 974 were finalized as 2.5% and 3.5% respectively, as it showed proper results. The concentration of plasticizer was finalized as 10% and 13% for the patch of HPMC K4M and Carbapol 974, respectively.

EVALUATION:

Evaluation of polymer films:

Patch thickness –

Assessment of thickness was done on 5 patches from every batch by using micrometer screw gauge.

Surface PH –

Agar plate, prepared by dissolving 2% (w/v) agar in warmed isotonic phosphate buffer of pH 7.4 under stirring and then pouring the solution in a petri dish and cooling till gelling at room temperature. Buccal patches were left to swell for 2 hr on the surface of these plates. The surface pH was measured by means of a pH paper placed on the surface of the swollen patch. A mean of three reading was recorded.

Folding endurance test –

This test was done by repeatedly folding the patch at the same place up to maximum 300 times or till it broke.

Swelling index –

After determination of original film weight and diameter, the samples were allowed to swell on the surface of agar plate kept in an incubator maintained at 37⁰ C. Increase in the weight or diameter was calculated after the preset time interval. The measurement of diameter of patch were done by using microscope after one hour interval for 5 hrs The percentage swelling %S, was calculated using the following equation:

%S = (Wt-W₀/W₀)*100

Where, Wt is weight of the patch after time t and W₀is the initial weight at zero time.

In vitro drug release study –

The release study was done in the Keshery - Chien diffusion cell using 6.8 buffer medium. The cellophane membrane was carefully mounted in between the two compartments of a Keshery - Chien diffusion cell with internal diameter of 2.1 cm (3.46cm² area) with a receptor compartment volume of 12.0 ml. 12 ml of solution containing phosphate buffer pH (6.8) was placed in the receptor compartment. The donor compartment contained a solution of 3ml of phosphate buffer pH 6.8. The entire set up was placed over magnetic stirrer and temperature was maintained at 37°C by placing the diffusion cell in a water bath. 1 ml sample was collected at predetermined time intervals upto 8 hrs from receptor compartment and filtered using Whatman filter paper. The withdrawals were compensated using equal volumes of phosphate buffer pH 6.8 kept at the same temperature. The concentration of drug released in the medium was assayed spectrophotometrically at 350 nm after suitable dilution with the diffusion medium phosphate buffer pH 6.8 whenever necessary. The experiment was carried out continuous up to 8 hrs. All the experiments were conducted in 3 replicates.

Content uniformity: –

The medicated patch was allowed to dissolve in 100 ml phosphate buffer, pH 6.8. The amount of drug in the solution was measured spectrophotometrically at λ max of 350 nm.

FTIR Studies: –

The formulations containing a physical mixture of nifedipine and hydroxypropyl methylcellulose HPMC K4M and nifedipine and Carbapol 974 were prepared. The physical mixtures of Nifedipine and hydroxypropyl methylcellulose were prepared by simple blending. The IR spectra for the test samples were obtained using KBr disk method using an FTIR spectrometer (FTIR-Varian).

RESULTS AND DISCUSSION:

The concentrations of polymers were decided by varying the concentration. The films showing good results were selected. Thus, the concentrations of the polymer were finalized. Similarly, the concentration of propylene glycol was also finalized.

The concentration of HPMC K4M and Carbapol 974 were finalized as 2.5% and 3.5% respectively, as it showed good results. The concentration of plasticizer was finalized differently for the two polymers from the plasticity of the film. It is 10% and 13% for the patch of HPMC K4M and Carbapol 974, respectively.

Physical characteristics of plain patches and patches containing drug are shown in table 3.

The patches were 10 mm in diameter and 1.06 ± 0.023 mm in thickness. The mass ranged from 27 to 29 mg for medicated patch. The surface pH of all formulations was within the desirable 6–7 units which are near to neutral pH and hence no mucosal irritation would be expected.

The recorded folding endurance of the patches was > 300 times. This might be due to adequate content of propylene glycol which provides it with high mechanical strength and good elasticity.

Assessment of the swelling behavior was done by measuring radial swelling. In the case of buccal patches, the contact area should be large enough to meet a requirement that must be balanced with patient compliance; excessive increase in patch diameter might cause discomfort and/or dislodgment of the swollen patch. The medicated patches showed higher radial swelling compared to plain patches. The swelling index values after 5 h were 31± 2.4 % and 29.8± 2.2 % respectively. Higher swelling values would result in excessively increased surface area which could result in unmanageable faster release of the drug. Also, higher swelling may cause patient discomfort due to occupying of larger space in the oral cavity and chances of dislodgement.

The drug content in the patches was found 98.42 ± 0.5% for HPMC K4M and 99.05 ± 0.5% for Carbapol 974 of the labeled value.

The in vitro drug release was carried out in Keshery - Chien diffusion cell. The drug release was studied upto 8 hrs from medicated patch. The patch of HPMC K4M and Carbapol 974 showed 89.58% and 91.45% drug release, respectively. Both the release profile follows peppas model. The release profile of nifedipine from HPMC K4M and Carbapol 974 patch was shown in Fig. 1 and 2, respectively.

Fig 1: Release profile of Nifedipine from patch of HPMC K4M.

Table 1 : Patch formulae

Constituents	Identity	Plain patch		Medicated Patch
Polymer	HPMC K4M	2.5%	-	2.5%	-
	Carbapol 974	-	3.5%	-	3.5%
Plasticizer	Propylene glycol	10%	10%	13%	13%
Drug	Nifedipine	-	-	50 mg	50 mg

Table 2: Formulation ingredients of Nifedipine buccal patch

Formulation batch	Nifedipine (mg)	HPMC K4M (%)	Carbapol 974 (%)	Propylene glycol (%)
AH 1	50	1	-	10
AH 2	50	1.5	-	10
AH 3	50	2	-	10
AH 4	50	2.5	-	10
AH 5	50	3	-	10
AH 6	50	3.5	-	10
AH 7	50	4	-	10
AC 1	50	-	2	13
AC 2	50	-	2.5	13
AC 3	50	-	3	13
AC 4	50	-	3.5	13
AC 5	50	-	4	13
AC 6	50	-	4.5	13
AC 7	50	-	5	13

Table 3: Characteristics of plain and medicated mucoadhesive buccal patches.

Sr. no.	Characteristics	Plain patches	Medicated patches
Sr. no.	Characteristics	Plain patches	HPMC K4M (2.5%)	Carbapol 974 (3.5%)
1	Thickness (mm)	1.06 ± 0.05	1.07 ± 0.03	1.08 ± 0.02
2	Mass(mg)	27.49 ± 0.3	28.62 ± 0.5	28.53 ± 0.4
3	Surface pH	6-7	6-7	6-7
4	Folding endurance	More than 300	More than 300	More than 300
5	Swelling index	252 (5 hrs)	249 (5 hrs)	250 (5 hrs)
6	In vitro release time after 8 hr	-	89.58%	91.45%
7	Drug content %	-	98.42 ± 0.5%	99.05 ± 0.5%

Fig 2: Release profile of Nifedipine from patch of Carbapol 974.

Fig.2 . FTIR Spectra of Nifedipine, HPMC K4M, Carbapol, Nifedipine + HPMC K4M and Nifedipine + Carbapol

FTIR Studies: –

To study any interaction between drug and polymers used in the preparation of patches IR spectroscopy was carried out for the test preparations. The IR spectra of the patch showed the same absorption bands as the physical mixtures, illustrating absence of interaction between nifedipine and HPMC and Carbapol 974. It presumably suggests that the drug molecule is present in an unchanged state in the patch.

CONCLUSION:

It may be concluded that the development of bioadhesive buccal formulation for Nifedipine may be a promising one as it avoids first pass metabolism and give release of drug upto 8 hrs. The polymers Carbapol 974 and HPMC K4M showed good mucoadhesive and swelling characteristics. Medicated patches maintained a good residence in the buccal cavity and demonstrated peppas release of the drug over a relatively long period (8 hr).

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Received on 22.02.2011 Modified on 16.03.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 944-948