INTRODUCTION:

Buccal delivery of medication provides an alternative strategy to systemic drug administration this is often as a result of the buccal tissue layer incorporating a rich blood supply that facilitates direct entry of drug molecules into the blood circulation. Extensive research efforts have recently been focused on placing a drug delivery system in a particular region of the body for maximizing biological drug availability and minimizing dose-dependent side effects.

Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Since buccal mucosa is relatively permeable with rich blood supply and acts as an excellent site for the absorption of drugs.^[1,2] Hence buccal drug delivery is a highly effective way to improve bioavailability.

The administration of medication via buccal route facilitates an instantaneous entry of drug molecules into the blood circulation, avoiding the first-pass metabolism and drug degradation within the gastrointestinal surroundings that are often related to oral administration.^[3–5] So for various route of administrated tried in the novel drug delivery systems, localized drug delivery to tissues of the oral cavity has been investigated for the treatment of periodontal disease, bacterial and fungal infection, therefore localized drug delivery, by retaining a dosage form at the site of action (e.g. within the gastrointestinal environment) or systemic delivery by holding the formulation in intimate contact with the absorption site (e.g. buccal cavity).^[6]

Buccal drug delivery is well accepted by patients as the buccal cavity is easily accessible for self-medication. In addition, buccal dosage forms allow drug absorption to be rapidly terminated in case of an adverse reaction. The use of mucoadhesive polymers in buccal drug delivery which includes adhesive tablets^[7] gels and patches of which patches are preferable in terms of flexibility and comfort.^[8,9]

In the recent years the interest in developing a drug delivery system with the employment of a mucoadhesive chemical compound which will attach to connected tissue or to the surface coating of the tissue for targeting numerous absorptive mucosal membrane like ocular, nasal, pulmonary, buccal, vaginal, etc. This method of drug delivery is named as mucoadhesive drug delivery system.^[10]

Other advantages includes excellent accessibility, low enzymatic activity, suitability for medication or excipients that directly and reversibly harm or irritate the mucosal membrane, painless administration, easy withdrawal, facility to incorporate permeation enhancer/ enzyme inhibitor or pH modifier within the formulation, versatility in designing as multidirectional or unidirectional release system for local or systemic action.^[11]

ORAL MUCOSA:

Anatomy of the oral mucosa:

The oral cavity is lined with the epithelium, below which lies the supporting basement membrane. The basement membrane is, in turn, supported by connective tissues ie lamina propria followed by the sub mucosa as the innermost layer.

MUCOADHESIVE POLYMERS:

Mucoadhesive polymers are the important component in the development of buccal delivery systems. The first step in the development of mucoadhesive dosage forms is the selection and characterization of appropriate bioadhesive polymers in the formulation. Bioadhesive polymers play a significant role in mucoadhesive drug delivery systems of drugs. Bioadhesive polymers have properties to get induced to the biological membrane and thus capable of prolonging the contact time of the drug with a body tissue. The utilization of bioadhesive polymers will considerably improve the performance of many medications. This improvement ranges from higher treatment of local pathologies to improved bioavailability and controlled release to enhance patient compliance.^[12-13]

GINGIVITIS:

Gingivitis is a bacterial infection of the gums. The precise reason why gingivitis develops has not been acknowledged, however many theories exist. Gingivitis describes inflammation of the gingivae, which is a reversible form of periodontal disease characterized by inflammation of the gingivae in response to a mature dental plaque biofilm which includes swelling, redness, influx of inflammatory cells, edema in the tissue, change of normal contours and bleeding. Gingival pockets from tissue swelling and loss of attachment not involving bone are usually present.^[14,15]

This disease happens once a microorganism from bacterial plaque invades encompassing tissues and accumulation of plaque at the gingival margin induces inflammatory response. The result is the formation of pockets between gingival tissue and tooth that causes gingival margin retraction and also the development of a perfect atmosphere for anaerobic bacterial growth responsible for the disease. This, in turn, will cause destruction of the gingival tissues, which may progress to destruction of the periodontal attachment apparatus.^[16]

The most common type of gingivitis involves the marginal gingiva and is brought on by the accumulation of microbial plaques in persons with inadequate oral hygiene.

Gingivitis proceeds through an initial stage to produce early lesions, which then progress to advanced disease. The initial stage of an acute exudative inflammatory response begins at an interval of 4 or 5 days of plaque accumulation. Both gingival tissue fluid and transmigration of neutrophils increase. Deposition of fibrin and destruction of collagen may be noted within the initial stage.^[17]]

NSAID is preferable in local formulations such as mouth wash, gels, to treat oral inflammatory conditions e.g. gingivitis. A relatively large number of studies have been carried out to formulate different dosage forms of aceclofenac, such as tablets, soft capsules, particulate systems and topical systems. Aceclofenac is the example of biopharmaceutical classification system (BCS) Class II compound.

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID'S) belongs to class phenyl acetic acid and possess good anti-inflammatory, analgesics and anti-pyretic and it is widely used for treating condition like osteoarthritis, rheumatoid arthritis, management of dental pain and post-operative pain.^[18] It directly blocks the prostaglandin synthesis and has less gastrointestinal complications since it is highly protein bound and possess short biological half-life of 4-5 hours, volume of distribution 25l, 99% of protein binding and 60-70% of bioavailability after oral administration.^[19]

The aim of this work is to design the formlation and evaluation of buccal patches of aceclofenac (non-steroidal anti-inflammatory drugs) for gingivitis using using various combination of hydrophilic and hydrophobic polymer in different ratio.

MATERIALS AND METHODS:

Drugs and chemicals:

Aceclofenac was obtained from (R. K. Enterprises, Meerut), HPMC (5cps) was obtained from (CDH Laboratory New Delhi), eudragit rl 100 Complimentary sample from (Qualigens Fine Chemicals, Mumbai), Carbopol 934 P, peg 400, glycerine, sodium hydroxide pellet, potassium dihydrogen phosphate, menthol, dichloromethane, was obtained from (R.K. Enterprises, Meerut), ethanol (Changshu yangyuan chemical, china), calcium chloride (Priya Fine Chem Ltd, Bangalore).

Instruments:

Digital Vernier Caliper (R. K Industries, Mumbai), Electronic weighing balance (Shimadzu, Japan), UV Visible spectrophotometer (Shimadzu (UV-1800), Japan.), Hot air oven (Narang Scientific Works Pvt. Ltd, New Delhi), pH meter (Elico, Bangalore, India), Fourier Transform IR Spectroscopy (Perkin Elmer, USA), Magnetic Stirrer (Remi Equipment Pvt.Ltd), Stability Chamber (Analytical Technologies, Bangalore), Dissolution apparatus (Electrolab TDT-08L) Franz Diffusion Cell (Neutron Scientific, Kolkata).

METHOD:

Analytical Method Used in the Determination of Aceclofenac:

The UV spectrophotometry method was developed for the analysis of drug using double beam spectrophotometer (Shimadzu 1601).

Determination of λ max:

Aceclofenac (20mg) was dissolved in 25ml of distilled water and 10ml of the resulting solution was diluted to 100ml and 1ml was withdrawn from that and diluted to 10ml i.e. 10µg/ml solution. The drug solution was scanned for maximum absorbance in UV double beam spectrophotometer (Shimadzu 1601) in the range from 200 to 400 nm. The λmax of the drug was found to be 274nm.

Calibration curve of Aceclofenac by UV-Spectroscopic Method:

Preparation of Phosphate buffer (pH 6.8):

Sodium hydroxide (0.94g) and Potassium Di hydrogen phosphate (6.8g) were dissolved and made up to 1000ml with distilled water.^[20]

Preparation of Stock-I Solution of Aceclofenac:

Standard stock solution were prepared by weighing out 50 mg of drug in 50 ml volumetric flask which was dissolved and made up to the mark using phosphate buffer (pH 6.8) to get 1000 µg/ml solution and was used as a standard solution (SS).

Preparation of Stock-II Solution of Aceclofenac:

5mL of Stock-I solution was withdrawn and made up to 50mL with Phosphate buffer (pH 6.8) to give 100 µg/mL solution.

Preparation of working standard:

From Stock-II solution 0.5,1,1.5, 2, 2.5, 3 ml were taken in different 10 ml volumetric flask and were diluted up to the mark with phosphate buffer (pH 6.8) to get a concentration of 5,10,15,20,25, 30µg/ml respectively. These solutions were scanned and the absorbance was measured at 274nm against blank. The absorbance values thus obtained were plotted in graph of concentration on X-axis versus absorbance on Y-axis.

Drug – Excipients Interaction Study:

FT-Infrared spectroscopy:

Fourier transform infrared spectroscopy (FT-IR) study was conducted using Perkin Elmer, USA to identify the purity of the drug and test the compatibility of the drug with the excipients.

Formulation of buccal patches of Aceclofenac:

The patches were prepared by the solvent casting method by using hydrophilic and hydrophobic polymers for the patches mentioned in table 1. Predetermined amount of Carbopol 934 P and Eudragit RL100 were dispersed in required quantity of ethanol under stirring and HPMC 5cps were dispersed in required quantity of ethanol and dichloromethane (1:1) ratio. The polymer solution in the different proportions was mixed until the homogenous clear solution was obtained and kept aside for 5 minutes. The drug was dissolved in ethanol and one drop of (0.0294 g) glycerine and followed by specified quantity of PEG 400 was added to the polymeric solution. The drug solution was added to the polymer solution and the whole solution was mixed thoroughly for 30min. The solution was then transferred quantitatively to petri-dish covered with inverted funnels to allow controlled evaporation of the solvents. These were lefts undisturbed upon temperature (20-25⁰C) for one to two days depending upon the solvent system used. Small patches of size 0.2 to 0.3 mm thick were carefully pull out from the petri-dishes.^[20-21]

Table 1: Formulation chart

Formulation	F1	F2	F3	F4	F5	F6	F7	F8	F9
HPMC 5cps (mg)	450	400	350	300	250	450	400	350	300
CARBOPOL 934 P (mg)	150	200	250	300	350	-	-	-	-
EUDRAGIT RL 100 (mg)	-	-	-	-	-	150	200	250	300
Plasticizer (PEG 400) % of polymer wt	46%	46%	46%	46%	46%	46%	46%	46%	46%
Drug (mg)	160	160	160	160	160	160	160	160	160
Glycerine (% of polymer wt)	12%	12%	12%	12%	12%	12%	12%	12%	12%
Menthol (%)	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05
Solvent	E:D	E:D	E:D	E:D	E:D	E:D	E:D	E:D	E:D

Evaluation of tablets:

The tablets were tested for its physical appearance, thickness and diameter using vernier callipers; weight variation using Digital weighing balance; Hardness using Pfizer hardness tester; Friability using Roche friabilator. Drug content; and dissolution time were also determined.

RESULTS:

Table 2: Thickness and Weight Variation of F1 to F9.

Sl . No	Formulation	Thickness (mm)		Weight Variation
Sl . No	code	± SD		(mg) ± SD
1	F1	0.22 ± 0.015		82.51 ± 0.215
2	F2	0.252 ± 0.020		76.73 ± 1.00
3	F3	0.243	± 0.068	80.75 ± 0.35
4	F4	0.25	± 0.02	68.38 ± 0.45
5	F5	0.193 ± 0.015		78.76 ± 0.62
6	F6	0.22 ± 0016		79.47 ± 0.15
7	F7	0.230	± 0.026	82.33 ± 0.16
8	F8	0.216 ± 0.005		82.92 ± 0.52

9	F9	0.123	± 0.02	79.16 ± 0.16

Table 3: Swelling Index and Folding Endurance for F1 to F9.

Sl. No	Formulation code	Swelling index ± SD	Folding Endurance
1	F1	44.334 ± 0.06	>200
2	F2	35.33 ± 0.95	>200
3	F3	43.33 ± 0.191	>200
4	F4	43.79 ± 0.070	>200
5	F5	42.33 ± 2.81	>200
6	F6	38.79 ± 1.134	>200
7	F7	42.414 ± 0.06	>200
8	F8	34.68 ± 3.332	>200
9	F9	36.43 ± 1.24	>200

Table 4: Percentage drug content and Surface pH of F1 to F9.

Sl. No	Formulation	% drug content		Surface pH
Sl. No	code	± SD		± SD
1	F1	94.385	± 0.065	6.403 ± 0.2112
2	F2	83.24 ± 0.0655		6.316 ± 0.0092
3	F3	92.668	± 0.339	6.472 ± 0.0201
4	F4	91.866	± 0.0550	6.336 ± 0.2059
5	F5	87.369 ± 0.0550		6.516 ± 0.2650
6	F6	92.916	± 0.339	6.723 ± 0.049
7	F7	89.054	± 0.196	6.823 ± 0.1457
8	F8	96.546 ± 0.0550		6.21 ± 0.2389
9	F9	93.974 ± 0.1961		6.440 ± 0.016

Table 5: In vitro drug release of formulation F1 –F9.

SL. NO.	Tim (Min)				In vitro drug release studies
		F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0	0
1	5	11.346	9.987	8.052	7.26	6.359	17.81	19.569	14.1	11.217
2	10	21.868	15.098	12.810	11.349	9.647	34.404	35.837	34.04	22.336
3	15	30.184	27.562	22.660	15.646	14.060	43.188	44.603	37.71	32.042
4	20	44.560	36.066	24.941	21.438	17.583	48.739	49.682	46.81	40.711
5	25	52.490	43.889	37.887	29.475	25.067	54.869	59.932	51.69	48.983
6	30	63.501	52.155	39.467	36.508	35.932	57.828	61.213	52.62	50.118
7	35	66.215	55.550	53.527	43.889	42.730	66.673	69.115	65.97	57.894
8	40	69.052	66.215	64.629	52.155	45.869	75.731	77.451	69.69	62.001
9	45	72.346	69.052	66.429	59.745	49.654	79.361	81.373	71.09	67.113
10	50	78.542	75.731	71.327	64.507	57.584	85.369	88.018	78.56	75.021

Ex-Vivo Studies:

Ex vivo permeation study were carried out for 60 min in Phosphate buffer pH 6.8. The samples were analysed using UV spectrophotometer at 274nm and results are shown below:

Table 7: Ex-vivo Permeation study for selected formulation F6 and F7.

Sl no	Time In min	Ex vivo permeation studies

		F6	F7
0	0	0	0
1	05	15.275	16.826
2	10	19.846	20.329
3	15	26.216	28.803
4	20	32.565	35.550
5	25	37.245	40.137
6	30	44.485	46.818
7	35	51.317	56.217
8	40	59.929	63.633
9	45	66.154	70.510
10	50	75.221	79.131
11	55	81.240	87.927
12	60	87.212	95.125

DISCUSSION:

Formulations F1, F2, F7, F9 exhibited a higher swelling rate than other formulations. Formulation F5 shown minimum drug release and formulation F7 showed the maximum drug release. The selected formulation F6 and F7 were subjected to ex-vivo permeation studies through the sheep buccal mucosa. Among the all the formulations F1 to F10, the formulations F7 was selected as the best formulation after considering its surface PH, Swelling index, good drug content, maximum drug release and maximum permeation through the sheep buccal mucosa.

CONCLUSION:

Aceclofenac buccal patches were prepared by solvent casting technique. It was shown that with the developed formulations, the release and mucoadhesion properties of buccal patches can be controlled by changing the polymer type and concentration. It was concluded that development of mucoadhesive buccal drug delivery of aceclofenac as buccal patches was one of the alternative routes of administration for local effect by immediate drug release and to improve the bioavailability.

REFERENCES:

1. Cristina Cavallari, Adamo F B, Francesca O C. Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine. European Journal of Pharmaceutics and Bio Pharmaceutics, 2013; 83: 405–414.

2. Gowthamarajan, Sachin Kumar Singh, Dev Prakash, Somashekhar. Dissolution Enhancement of Poorly Soluble Aceclofenac by Solid Dispersion Technique and Its Comparison with Marketed Formulations, International Journal of Pharm Tech Research (IJPRI)., 2010; 2(4): 2347-2356.

3. Harris D, Robinson J.R. Drug delivery via the mucous membranes of the oral cavity, J Pharm Sci., 1992; 18: 1-10.

4. Humes, H. David, et al., Kelley's Textbook of Internal Medicine. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins., 2000.

5. Patel VM, Prajapati BG, Patel MM. Design and characterization of chitosan containing mucoadhesive buccal patches of propranolol hydrochloride. Acta Pharm., 2007; 57: 61–72.

6. Khairnar A, Jain P, Baviskar D, Jain D. Development of mucoadhesive buccal patch containing aceclofenac: in-vitro evaluation. Int J Pharm Sci., 2009; 1(1): 91–5.

7. Shah Viral A, Shah Jimish, Upadhyay UM. Formulation development and evaluation of buccal bilyer patch using thiocolchicoside and diclofenac sodium, Int. J. Inv. Pharm. Sci., 2013; 1(3): 190-211.

8. Dhagla Ram Choudhary, Vishnu A Patel, Usmangani K Chhalotiya, Harsha V Patel, Aliasgar J Kundawala. Natural Polysaccharides As Film Former: A Feasibility Study For Development Of Rapid Dissolving Films of Ondansetron Hydrochloride, Int J Pharm Pharm Sci., 2001; 3: 78-85.

9. Tej Pratap Singh, Rakesh Kumar Singh, et al. Mucoadhesive bilayer buccal patches of verapamil hydrochloride: formulation development and characterization. Int J Pharm Pharm Sci., 2014; 6(4): 234;241.

10. Burgalassi S A, Panichi L A et al. Development and in vitro/in vivo testing of mucoadhesive buccal patches releasing benzydamine and lidocaine, Int. J. Pharm., 1996; 133: 1-7.

11. Faiyaz Shakeel, Mohammed S Faisal, Sheikh Shafiq. Comparative Pharmacokinetic Profile of Aceclofenac from Oral and Transdermal Application Journal of Bioequivalence and Bioavailability(JBB)., 2009; 1.

12. Shivhare U D, Suruse P S, Varvandkar S S. Formulation and evaluation of buccal patch containing aceclofenac. J App Pharm., 2014: 6(1): 65-76.

13. Mohamed S. Pendekaln, Pramod K, Tegginamat. Formulation and evaluation of a bioadhesive patch for buccal delivery of tizanidine. Acta Pharmaceutica Sinica B., 2012; 2(3): 318–324.

14. Owens TS, Dansereau RJ, Sakr A. Development and evaluation of extended release bioadhesive sodium fluoride tablets, Int J Pharm., 2005; 288: 109–22.

15. Lee VHL, Lee VHK, Robinson JR. Controlled Drug Delivery New York: Marcel Dekker Inc., 1987; 29(2): 4.

16. Amir Shojaei H. Buccal mucosa as a route for systemic drug delivery. J Pharm Pharm Sci., 1998; 1(1): 15-30.

17. Parthasarathy G, Bhaskar R Kesavan, Jayaveera K Narasimha, Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa. Asian Pac J Trop Biomed, 2013; 3(12): 995-1002.

18. Pendekaln M S, Tegginamat P K. Formulation and evaluation of a bioadhesive patch for buccal delivery of tizanidine. Acta Pharmaceutica Sinica B., 2(3): 318–24.

19. K Balamurugan, J K Pandit, P K Choudary, J Balasubramaniam. Ind. J. Pharm. Sci., 2001; 63: 473-480.

20. Schatzle M, Loe H, Burgin W, Anerud A, Boysen H, et al. Clinical course of chronic periodontitis. I. Role of gingivitis. J Clin Periodontol., 2003; 30: 887–901.

21. Vashmi Vishnu Y, Chandrasekhar K, Ramesh G, Madhusudan Rao Y. Development of mucoadhesive patches for buccal administration of carvedilol. Curr Drug Deliv., 2007; 4: 27–39.

Received on 27.11.2017 Modified on 22.12.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(4): 163-167.

DOI: 10.5958/0975-4377.2017.00026.X