Formulation, Optimization and Evaluation of Amlodipine Besylate Sublingual Films

 

Mayur V. Chinchore*,  Pankaj D. Kothawade, Rajendra K. Surwase, Avish D. Maru

Department of Pharmaceutics, Loknete Dr. J. D. Pawar College of Pharmacy,

Manur, Tal- Kalwan, Dist- Nashik (423501), Maharashtra, India.

 

ABSTRACT:

Amlodipine is widely used in the treatment of Hypertension, Angina pectoris and Cardiac arrhythmia. The present study is deals with formulation, optimization evaluation of Amlodipine sublingual films. Hypertension, Angina pectoris and Cardiac arrhythmia are the conditions where instance effect of drug is required. Amlodipine is one of the drug which is used in the treatment of above three disease conditions. The sublingual films was prepared by using solvent casting method. The concentration of polyvinyl alcohol (PVA), glycerin, sodium lauryl sulphate (SLS) were kept constant in all formulations (F1-F9) and varying concentration of hydroxy propyl methyl cellulose(HPMC). All the formulations were evaluated for surface pH, weight uniformity, folding endurance, drug content, disintegration time, in-vitro dissolution studies. The formulation ‘F5’ was found to be optimized formulation. It shows results for all evaluation parameters such as weight variation 90.10±0.16 mg, surface pH 6.75±0.60, folding endurance > 100, drug content 98.60±0.60%, disintegration time 17±0.30 sec, and in-vitro dissolution study 98.78 % at the end of 5 min.

 

 

 

INTRODUCTION:

The oral route is most popular route for the administration of various drugs. The ease of administration leads to high levels of patient compliance. Approximately one-third part of the population, primarily the geriatric and pediatric patients has a problem of swallowing it leads to cause poor patient compliance with oral tablets/capsules drug therapy which reduces the therapy effectiveness. To overcome such difficulties the sublingual films are one of best drug delivery system.

 

The sublingual films contain active drug material incarporated into polymeric film. The various film forming polymers are available in the market which have wide range of compatibility with most of drug. The sublingual films contain such film forming polymer which can be disintegrate rapidly in mouth due to presence of saliva. By giving the drug from sublingual route the first pass metabolism of drug can be avoided.

 

MATERIALS AND METHODS:

Material:

Amlodipine besylate was received as a gift sample from Blue Cross Laboratories Pvt. Ltd. Nashik, HPMC- E5 was obtained from Space Lab. Nashik, all other chemicals used were obtained from commercial sources and were of analytical grade.

 

Method:

Films were prepared by using solvent casting method. Polymer was weighed and dissolved in alcohol (solution A). In another beaker the drug solution was prepared (solution B) and mix both this solution (A and B) with the help of magnetic stirrer. The glycerin, vanillin and SLS were added to above solution and stir continuously for 30 minutes. After stirring kept this solution in sonicator for complete removal of air bubbles and then transfer the solution in petridish and allowed to dry at room temperature for 24 hours. After drying, these films were removed from the petridish and cut into definite shapes and size. For further evaluation films are packed in aluminium foil and placed in desicator. 

 

 

Table 1: Composition of Amlodipine besylate  sublingual films.

Sr. No.	Ingredients	F1(mg)	F2(mg)	F3(mg)	F4(mg)	F5(mg)	F6(mg)	F7(mg)	F8(mg)	F9(mg)
1	Amlodipine besylate	8	8	8	8	8	8	8	8	8
2	HPMC	100	200	300	100	200	300	100	200	300
3	PVA	5%	5%	5%	5%	5%	5%	5%	5%	5%
4	Glycerin	10%	10%	10%	10%	10%	10%	10%	10%	10%
5	SLS	2%	2%	2%	2%	2%	2%	2%	2%	2%
6	Citric acid	20	20	20	20	20	20	20	20	20
7	Flavour	QS	QS	QS	QS	QS	QS	QS	QS	QS
8	Methanol	QS	QS	QS	QS	QS	QS	QS	QS	QS
9	Water	QS	QS	QS	QS	QS	QS	QS	QS	QS

 

 

Evaluation of Amlodipine besylate sublingual films ^{[2, 6-8 ]}

Appearance, Shape and Thickness:

The formulated films of Amlodipine besylate were checked for their appearance, shape and thickness. The thickness of randomly selected 5 test films was determined at five different places using a micrometer and mean value was calculated.

 

Weight variation:

Weight variation test was performed by taking weight of five films of every formulation individually and then average weight was calculated.

 

Surface pH:

The surface pH of films was determined by placing film in petridish and moistened with few drops of distilled water and allowed to moisten for 1 hrs. After that bring a electrode of pH meter in contact with surface of film and pH were noted.

 

Folding endurance:

It was determined by repeatedly folding one film at the same place till it broke. The number of times that film can be folded at the same place without breaking gives the value of the folding endurance.

 

Drug content:

The film (area 2x2 cm²) was placed in beaker and to this add sufficient volume of phosphate buffer pH 6.8 and dissolved the film with the help of magnetic stirrer. Filter this solution and transfered into 100ml volumetric flask make up final volume (100ml) with phosphate buffer pH 6.8 solution. The absorbance of solution was measured at ג max 237 nm using UV spectrophotometer (LABINDIA 3000+ UV-VIS spectrophotometer). The experiment was performed in triplicate.

 

Disintegration time: 

In vitro disintegration time was determined by placing the film (area 2x2 cm²) in beaker containing 10 ml of phosphate buffer pH 6.8 and swirling at interval of 5 sec. The time at which films start to disintegrate considered as disintegration time.

 

Preparation of calibration curve of Amlodipine besylate:

Weigh quantity of Amlodipine besylate (100mg) place in 100 ml of standard volumetric flask and make up the volume with simulated saliva pH 6.8. The stock solution obtained is 1000 µg/ml solution. Aliquots of 0.5, 1, 1.5, 2, 2.5 and 3 ml of stock solution pipette out into 100 ml standard volumetric flasks and final volume adjust up to 100 ml with simulated saliva pH 6.8 to give the concentration of 5, 10, 15, 20, 25 and 30µg/ml. The absorbance measure at 238 nm in UV spectrophotometer against reagent blank with simulated saliva pH 6.8 (Table 3 and Figure 1).

 

In-vitro dissolution study: 

The in-vitro drug release study was carried out using USP dissolution test apparatus (USP type II) at temperature 37±0.5ºc and 50 rpm. The phosphate buffer pH 6.8 was used as the medium. During study 5ml of test sample was withdraw at 15sec. intervals and the absorbance of sample taken at ג at 237 with the help of UV spectrophotometer (LABINDIA 3000+ UV-VIS spectrophotometer). The values were transformed into concentration using standard calibration curve. The results are shown in table no. 4.

 

RESULT AND DISCUSSION:

Amlodipine sublingual films were prepared and evaluated for appearance, size, shape, thickness, surface pH, weight variation, folding endurance, drug content, disintegration and dissolution study.

 

All the films were transparent. Thickness was varies between 0.300±0.001 mm to 0.320±0.001 mm. The formulation ‘F5’ shows thickness 0.300±0.001mm, there was no significant difference in S.D.

 

The weight of films (formulation F1-F9) were found to be in range of 90.10±0.11mg to 92.10±0.16 mg, the weight of formulation ‘F5’ was 90.10±0.11 mg. The S.D. value was not significantly varies and meet the criteria for the weight variation as shown in table no. 2.

 

Surface pH was varies in the range of 6.12±0.47 to 6.75±0.60. The formulation ‘F5’ was shows the pH 6.75±0.60 since this value was nearest to the pH of saliva i.e. 6.8.

 

Folding endurance for all the formulations was found to be more than 100 folds. It shows that all formulations had good plasticity.

 

All the formulation were evaluated for the drug content. The result obtained was shown in table no. 2. The formulation ‘F5’ shows maximum amount of drug 98.60±0.60.

 

Table No.2: Results of evaluation of Amlodipine besylate sublingual films.

Formulation Code	Thickness (mm)	Mean weight (mg)	Drug content (%)	Disintegration time (sec.)	Surface pH	Folding endurance
F1	0.300±0.001	90.10±0.11	95.05±1.30	20±1.10	6.40±0.10	>100
F2	0.310±0.002	91.10±0.20	97.03±0.50	17±1.60	6.35±0.25	>100
F3	0.316±0.001	90.20±0.35	94.20±1.20	19±0.50	6.12±0.47	>100
F4	0.320±0.002	91.10±0.15	98.50±1.05	21±0.40	6.40±0.56	>100
F5	0.300±0.001	90.10±0.20	98.65±0.60	17±0.30	6.75±0.60	>100
F6	0.318±0.002	91.05±0.13	94.40±1.40	18±1.30	6.30±0.30	>100
F7	0.306±0.001	92.10±0.16	86.35±1.35	20±1.50	6.15±0.35	>100
F8	0.320±0.001	91.10±0.34	88.36±0.68	17±1.40	6.20±0.41	>100
F9	0.315±0.002	91.20±0.50	94.20±1.35	21±0.56	6.40±0.20	>100

*values are Mean value of 3 observations

 

Disintegration time of each formulation was determined. It was varies in range between 17±0.30 sec. to 21±0.40 sec. The disintegration time for the formulation ‘F5’ was found to be 17±0.30 sec.

 

The in-vitro drug release study was carried out using USP dissolution test apparatus type-II. The results obtained was shown in table no. 4. The formulation ‘F5’ shows 98.78% drug release at the end of 5 minutes.

 

Table No. 3: Absorbance- Concentration data for standard curve of Amlodipine besylate.

Concentration (µg/ml)	Absorbance
	I	II	III	Average (± S.D.)
0	0.000	0.000	0.000	0.000±0.000
5	0.220	0.222	0.218	0.220±0.002
10	0.323	0.325	0.320	0.322±0.003
15	0.430	0.431	0.429	0.430±0.001
20	0.570	0.565	0.570	0.568±0.003
25	0.710	0.708	0.711	0.709±0.002
30	0.843	0.845	0.842	0.843±0.002

 

 

Figure 1: Standard calibration curve of Amlodipine besylate.

 

Table No. 4: In-vitro drug release study of Amlodipine besylate sublingual films.

Sr. No.	Time(sec)	%Drug release
		F1	F2	F3	F4	F5	F6	F7	F8	F9
1	0	0	0	0	0	0	0	0	0	0
2	30	15.48	16.20	15.40	14.32	17.23	15.67	16.34	15.39	18.12
3	60	22.40	21.12	23.47	25.71	24.89	22.11	23.78	21.56	23.90
4	90	39.20	38.87	37.56	39.40	36.34	39.41	39.23	36.34	38.12
5	120	59.50	58.13	57.21	55.28	59.30	57.69	58.12	57.89	56.33
6	150	67.30	68.43	66.31	68.13	69.20	67.39	66.49	68.88	65.90
7	180	71.32	72.13	72.33	71.80	74.33	70.67	71.20	71.77	72.11
8	210	78.14	77.89	76.39	75.90	79.44	77.34	76.55	77.45	75.76
9	240	84.20	85.11	84.23	85.67	88.78	86.57	85.40	84.60	85.38
10	270	92.14	93.18	91.49	92.56	93.50	91.77	92.96	90.22	92.34
11	300	97.11	96.87	97.23	95.66	98.78	95.43	96.71	97.30	96.11

 

Figure 2: UV spectrum of Amlodipine besylate.

 

Figure 3 : % Drug release of Amlodipine formulation F1 -F9

Fig. A	Fig. B
Fig. C	Fig. D

Figure 4: Fig. A- Film of HPMC and colour, Fig. B and C- Film containing Amlodipine Besylate, Fig. D- Packaging of films.

 

 

 

ACKNOWLEDGEMENT:

The author wish to give the thanks to Principal of  Loknete Dr. J. D. Pawar college of pharmacy,  Manur (Kalwan) for their support and availability of  all the material which was required to carry out this project.

 

CONCLUSION:

All the prepared films was evaluated for different parameters and the formulations were shows satisfactory results. The formulation 'F5' shows comparatively good results for all evaluation parameters. Hence we conclude that the formulation 'F5' is optimized formulation.

 

REFERENCES:

1.       Bhura Nikunj et al, A review on fast dissolving films, International Journal of Pharmaceutical Research and Bioscience, 1(3);2012: 66-89.

2.       Patil Swapnil et al, Fast dissolving oral films: An innovative drug delivery system, International Journal of Research and Reviews in Pharmacy and Applied Science, 2(3): 482-496.

3.       Thakur Nishi et al, Overview, A Novel Approach of Fast Dissolving Films and Their Patients, Advances in Biological Research, 7(2); 2013: 50-58.

4.       Nagar Mona et al, Formulation and evaluation of mouth dissolving films of antipsychotic drug Aripiprazole, Scholars Research Library, 4(4); 2012: 1221-1227.

5.       Nagarju R et al, Design and evaluation of fast dissolving films containing Nizatidine, Indian Journal of Pharmaceutical Education and Research,46(4); 2012: 318-322.

6.       K. Vijaya Sri. et al, Montelukast sodium oral thin films: Formulation and in-vitro evaluation, Asian Journal of Pharmaceutical and Clinical Research, 5(4); 2012: 266-270.

7.       Mital Panchal et al, Formulation and Evaluation of Mouth Dissolving Films of Ropinirole Hydrochloride by using Pullulan polymers, International Journal of Pharmaceutical Research and Allied Sciences, 1(3); 2012: 60-72.

8.       Chauhan Nitesh et al, Formulation and Evaluation of Fast Dissolving Oral Films of Dicyclomine as potential route of Buccal Delivery, International Journal of Drug Development and Research, 4(2); 2012: 408-417.

 

 

 

 

Received on 12.06.2014                Modified on 16.06.2014

Accepted on 18.06.2014                © RJPT All right reserved