Formulation and Characterization of Taste Masked Rapid Disintegrating Tablets of Trimetazidine HCl

 

Barokar A.A.*, Wagh R.D., Baviskar D.T. and Shaikh T.J.

A.R.A. College of Pharmacy, Nagaon, Dist: Dhule (Maharashtra).

*Corresponding Author E-mail: amitbarokar07@rediffmail.com

ABSTRACT:

Trimetazidine HCl is used in angina pectoris and in ischaemia of neurosensoral tissue as in manieres disease. It will be much advantageous to present such drug in Rapid Disintegrating dosage form, as their administration is easier for the patient of angina attack. Bitter taste of the drug pose a main problem in patient compliance. Hence Eudragit EPO polymer was used for complexation with drug for overcoming taste problem. The Lyophilization method was used to form the drug polymer complex in a tablet. 1:3 ratio of the drug to polymer was effectively masked the bitter taste of drug. PVP were used in different ratios. 0.25% PVP forms the optimized tablet. FTIR studies were done to study the drug polymer interaction. Rapid Disintegrating Tablet was formulated in the blister packs using Freeze Drying Method. The tablets were evaluated for different evaluation parameters. The tablet batch TEP3 having 1:3 ratio of Drug: Eudragit EPO were selected as the optimized batches. The marketed formulation showed much longer disintegration time (205±0.04) as compared to the presented formulations. Also the dissolution of marketed tablet is more (t₉₀ around 13 min) as compared to the prepared tablet (t₉₀ for TEP3 and TEG3 around 2.5 min).Thus prepared tablet is superior to marketed formulation in term of disintegration time and dissolution behavior.

 

KEYWORDS: Trimetazidine Hcl, Taste masking, Eudragit EPO, Polyvinylpyrrolidone, Rapid disintegrating tablets.

 

INTRODUCTION:

Convenience of administration and patient compliance are gaining significant importance in the design of dosage forms. Recently, more stress is laid down on the development of an organoleptically elegant and patientfriendly drug delivery system for pediatric and geriatric patients.^1-2 More than 50% of the pharmaceutical products are orally administered for several reasons, and undesirable taste is one of the important formulation problems encountered with such oral products. Taste of a pharmaceutical product is an important parameter for governing compliance. Thus, taste masking of oral pharmaceuticals has become an important tool to improve patient compliance and the quality of treatment, especially in pediatrics. Therefore, formulation of taste-masked products is a challenge to the pharmacists.^3-4

 

Trimetazidine HCl is used in angina pectoris and in ischaemia of neurosensoral tissue as in manieres disease.⁵ It has clinical application in coronary insufficiency, angina pectoris, myocardial infarction and other old, right with severe cardiac dysfunction, and can be used with digitalis.

 

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. It will be much advantageous to present such drug in Rapid Disintegrating dosage form, as their administration is easier for the patient of angina attack. Therefore, considering above factors, an attempt has been made to mask the taste of Trimetazidine HCl and to formulate rapid disintegrating tablet with pleasant taste and better mouth feel.

 

MATERIALS AND METHODS:

Trimetazidine HCl was procured as a gift sample from IPCA labs Ltd, Ratlam, India; Aminoalkylmethacrylate Copolymer was obtained as a gift sample from Degussa India Pvt. Ltd., Mumbai, India under trade name of Eudragit EPO. Polyvinylpyrrolidone was purchased from Loba Cheme. Pvt. Ltd. All other chemicals used in the study were of analytical grade.

 

 

Drug-Polymer interaction study:

Pure Drug, polymer Eudragit EPO, physical mixture of Drug+Eudragit EPO and Drug+Eudragit EPO+PVP were analyzed for interaction by Fourier Transform Infrared Spectroscopy (FTIR) using KBr disk method.

 

Formulations of freeze dried Rapid disintegrating tablets:

A 0.25, 0.5, and 1% w/v solution of PVP in acidified water pH 1.2 was prepared. Equal weights of Glycine (0.886% w/v) and Mannitol (0.886% w/v) were added to the PVP solution while stirring until completely dissolved. An accurately weighed amount of Trimetazidine Hcl and Eudragit EPO in different ratios was then dispersed in the aqueous solution of PVP, Glycine, and Mannitol.

 

0.2 ml of the resulting suspension was poured into each of the pockets of a tablet blister pack to result in a Trimetazidine HCl dose of 20 mg in each tablet. The tablet blister packs, each containing 10 tablets, were then transferred to a freezer at −22°C and kept in the freezer for 24 h. The frozen tablets were placed in a lyophilizer for 24 h using a Freeze Dryer (LARK, Penguin Classic Plus, Chennai.) with a condenser temperature of −45°C and a pressure of 7 × 10−2 mbar.⁶ The Lyophilized Rapid Disintegrating Tablets were kept in a desiccators over calcium chloride (0% relative humidity) at room temperature until further use. Six blister packs containing a total of 60 tablets were produced in each run. The formula of the tablets is as shown in table 1.

Table 1: Formulation design.

Sr. No.	Batch	Drug: Eudragit EPO	PVP (%w/v)	GLYCINE (%w/v)
1	TEP1	1:1	0.25%	0.8%
2	TEP2	1:2	0.25%	0.8%
3	TEP3	1:3	0.25%	0.8%
4	TEP4	1:4	0.25%	0.8%
5	TEV1	1:1	0.5%	0.8%
6	TEV2	1:2	0.5%	0.8%
7	TEV3	1:3	0.5%	0.8%
8	TEV4	1:4	0.5%	0.8%
9	TEL1	1:1	1%	0.8%
10	TEL2	1:2	1%	0.8%
11	TEL3	1:3	1%	0.8%
12	TEL4	1:4	1%	0.8%

 

Evaluation of Tablets:

Rapid disintegrating tablets were evaluated for following parameters.

 

Drug Content, Hardness, Friability Weight variation and Weight variation:⁷

Ten tablets were taken and triturated in a glass mortar. The powdered tablet equivalent to 20 mg of drug was dissolved in a 500ml of simulated gastric fluid and the drug content was determined spectrophotometrically at 269.4 nm. Hardness was measured using Monsanto hardness tester. Friability was evaluated as the weight loss of tablets equivalent to 625 mg, tumbled in a friabilator for 4 min at 25 rpm. The tablets then were dedusted, and the loss in weight caused by fracture or abrasion was recorded as percentage friability. For weight variation, 20 tablets were weighed individually. Average weight was calculated and individual tablet weights were compared to the average.

 

Wetting time and Water absorption ratio: ^8-10

A piece of tissue paper folded twice was kept in a culture dish (i.d. 5.5 cm) containing about 6ml of purified water. A tablet having small amount of amaranth powder on the upper surface was placed on the tissue paper. Time required to develop red color on the upper surface of the tablet was recorded as a wetting time.

The same procedure was repeated for determining water absorption ratio without using amaranth. The wetted tablet was then weighed and water absorption ratio, R, was determined according to following equation:

               R= {(W_a-W_b)/ W_b}* 100--------------eq.no.1.

Where,

W_b = weight of tablet before study

W_a = weight of tablet after study.

 

Taste evaluation of lyophilized tablets:

In-vitro taste evaluation of lyophilized tablets: ⁹

Any substance, which is soluble in saliva will interact with taste buds, and can impart its taste. Therefore dissolution study of lyophilized tablets was conducted in simulated salivary fluid pH 6.2 for approximate estimation of release in human saliva before doing actual volunteer study.

 

Lyophilized tablet containing 20 mg of Trimetazidine HCL was taken in a 25ml volumetric flask. To this, 10ml of simulated salivary fluid (SSF) was added and was shaken for 60 seconds on mechanical shaker. The amount of drug released was analyzed spectrophotometrically at 269.8 nm.

 

Disintegration Time:

In Vitro Disintegration Study:

For rapid disintegrating tablets, drug formulation is intended to disperse rapidly (less than 1 min) in oral cavity, so that dose is easy to swallow. Hence the assessment of the disintegration profile of rapidly disintegrating tablet (RDT) is very important in the evaluation and the development of new formulation of this type.

 

In Vivo Disintegration Time: ⁸

This study was performed with six healthy volunteers, from whom informed consent was first obtained. After the mouth was rinsed with purified water, one tablet was held in the mouth and the time required for complete disintegration of tablet was recorded. The same disintegrated material was held in the mouth for up to 60 sec. then spat out. Mouth was again rinsed with water without swallowing the disintegrated materials and compaired with marked tablets.

 

Dissolution study of tablets:

In vitro dissolution studies for lyophilized rapid disintegrating tablets of different batches and marketed tablet were carried out in 500 ml simulated gastric fluid without enzymes (SGF) pH 1.2 using USP type II (paddle) apparatus at 50 rpm and 37± 0.5°C temperature.

 

RESULTS AND DISCUSSION:

Trimetazidine HCl is used in angina pectoris and in ischaemia of neurosensoral tissue as in manieres disease. It has clinical application in coronary insufficiency, angina pectoris, myocardial infarction and other old, right with severe cardiac dysfunction, and can be used with digitalis. Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties.

Table 2: Evaluation of Tablets.

Sr. No.	Parameters Formulation	Drug content (%)	Hardness (kg/cm2)	Friability (%)	Wetting time (sec)	Water absorption ratio (%)
1	TEP1	99.3±0.02	0.71±0.037	0.11±0.034	11±0.031	170.27±0.04
2	TEP2	99.3±0.067	0.67±0.040	0.12±0.042	13.2±0.044	166.46±0.003
3	TEP3	99.99±0.006	0.73±0.020	0.12±0.064	12.4±0.031	165.74±0.03
4	TEP4	100.69±0.076	0.77±0.06	0.14±0.053	14.21±0.053	166.17±0.1
5	TEV1	99.3±0.056	0.74±0.004	0.11±0.042	15.32±0.062	167.06±0.005
6	TEV2	101.38±0.066	0.75±0.005	0.13±0.023	17.3±0.058	157.32±0.04
7	TEV3	98.61±0.036	0.70±0.006	0.12±0.045	16.23±0.027	160.62±0.12
8	TEV4	100.69±0.1	0.78±0.007	0.1±0.036	18.4±0.002	154.11±0.007
9	TEL1	99.99±0.4	0.61±0.009	0.12±0.045	17±0.01	163.06±0.033
10	TEL2	98.6±0.012	0.85±0.006	0.11±0.024	17.9±0.2	156.76±0.014
11	TEL3	100.69±0.004	0.82±0.004	0.21±0.031	18±0.5	158.51±0.005
12	TEL4	98.61±0.005	0.78±0.002	0.2±0.067	18.2±0.002	162.26±0.003

* Average of three determinations

 

Figure 1: FTIR Spectrum of (A) Trimetazidine HCl, (B) Eudragit EPO, (C) Trimetazidine HCl + Eudragit EPO, (D) Trimetazidine HCl + Eudragit EPO + PVP

 

Drug-polymer Interaction Study:

FTIR spectrum of the physical mixture of the drug and Eudragit EPO shows no significant shifts or reduction of intensity of FTIR bands of Trimetazidine HCl. The figure 1 shows Principal peaks of Trimetazidine HCl found at wavenumbers 1730, 1802, 1098, 1200, 770, 1295 cm^-1 which matches with reference peaks.¹¹ In case of Eudragit EPO, The figure 1 shows the characteristic bands of the ester groups at 1,150 - 1,190, 1,240 and 1,270 cm-1, as well as the C = O ester vibration at 1,730 cm-1. In addition, CHX vibrations can be discerned at 1,385, 1,450 - 1,490 and 2,950 cm-1. The absorptions at 2,770 and 2,820 cm-1 can be assigned to the dimethylamino groups. Also the combination of Drug, Eudragit EPO, PVP shows no change in the peaks.

Formulation of Rapid Disintegrating Tablet:

It is well known fact that polyvinylpyrrolidone and gelatin are the main constituents in the preparation of lyophilized Rapid Disintegrating Tablet.¹² Hence PVP were used in different ratios. Glycin was also used in all 24 batches in the concentration range of 0.8% w/v as it prevents shrinkage of the tablet during manufacturing.

 

Evaluation of lyophilized tablets:

All Rapid Disintegrating Tablets from batches TEP1 to TEG4 were evaluated for tablet properties like friability, weight variation, drug content. Tablets passed all the tests. Friability, Weight variation and Content uniformity of all formulations were within acceptable limits as shown in Table 2.

 

Table 3: Comparative Study of Disintegration Time with Different Methods:

Sr. no.	Batch	In vitro disintegration time(sec.)	In vivo disintegration time(sec.)
0	0	0	0
1	TEP1	14.5±1.02	14.8±1.11
2	TEP2	16±0.1	17±0.91
3	TEP3	12.73±1.88	12.75±0.22
4	TEP4	15.6±1.03	16.1±1.16
5	TEV1	17±0.92	18±1.34
6	TEV2	18.92±1	19.01±0.95
7	TEV3	17.32±1.45	18±1.12
8	TEV4	16.42±1.22	18.4±1.07
9	TEL1	13.14±0.76	15±0.78
10	TEL2	18.4±0.077	19.2±1.35
11	TEL3	20.24±1.34	21.02±1.41
12	TEL4	22.13±1.29	22.24±2.04
13	M	205±0.04	190±0.06

M-Marketed Tablet

 

Table 4: Cumulative % Drug Released from Lyophilized Rapid Disintegrating Tablet at Different Time Interval.

Sr. No.	Time (sec)	Cumulative % Drug released
		TEP1	TEP2	TEP3	TEP4
1	0	0	0	0	0
2	30	22.91±2.11	22.91±1.09	45.8±2.23	14.5±2.43
3	60	25.09±0.95	29.27±2.17	58.5±3.11	25±1.33
4	90	33.49±1.43	50.2±2.31	71.1±2.56	14.6±1.92
5	120	44±2.31	75.35±3.04	77.5±1.88	48.1±0.76
6	150	58.7±2.11	85.94±1.64	92.3±2.67	73.2±1.11
7 7	180	71.34±2.18	90.28±2.38	100.8±3.53	85.9±2.45
8	210	88.18±0.98	92.55±1.92	101.0±1.9	79.8±1.29
9	240	92.53±1.22	99±1.73	101.2±2.44	73.7±1.19
10	270	96.89±1.26	101.28±1.08	99.4±0.98	92.6±3.12
11	300	99.17±1.79	93.13±2.17	99.5±3.01	82.4±2.33

* Average of three determinations

 

 

In-vitro taste evaluation:

in-vitro taste evaluation study of the lyophilised Rapid Disintegrating Tablet was done in the simulated salivary fluid for approximate estimation of drug release in human saliva before doing actual volunteer study.¹³ This study shows that batch TEP3 having 1:3 (drug:Eudragit EPO) ratio and 0.25% PVP shows 3.6±0.02% of the drug release from the tablet in simulated salivary fluid. The amount released was less than the amount that can induce bitterness. The low amount of drug was released in Simulated Salivary Fluid because Eudragit EPO is insoluble above pH 5. Sensory evaluation of optimized tablet proves better palatability.

 

Wetting and Disintegration time of tablets:

There was not much difference in the wetting time of tablets containing PVP are hydrophilic and form open-network type matrix on lyophilization which get wet rapidly in the presence of aqueous medium. Wetting time for TEP3 was lowest 12.4±0.031 sec.

 

From the results, it can be observed that tablets containing 0.25% PVP and ratio 1:3 (Drug: Eudragit EPO) disintegrate quickly. The probable reason behind this might be, as the concentration of PVP increases the tablet after lyophilisation got contracted giving rise to more compact mass, as PVP is also binder hence it is difficult to permeate the disintegrating fluid through the compact mass. The batch TEP3 having minimum disintegration time was selected as the optimised batch amongst all 12 batches containing PVP. The batch TEP3 with disintegration time (12.73±1.88sec) was much less, (p<0.02) as compared to the marketed tablet (205±0.04sec) as shown in Table 3.

 

Hence, the tablet having the sufficient hardness and the minimum disintegrating time the batch TEP3 were selected as the optimised batches amongst all the 12 batches. These dosage forms include of an open matrix network of water-soluble or water dispersible carrier material, which is impregnated with a unit dose of the pharmaceutical active agent.^14-15

 

Dissolution studies:

Dissolution studies of the optimized tablet of batch TEP3 reveled rapid release of drug (t₉₀ for both batch TEP3 is 150 sec.) as compared to marketed tablet wherein t₉₀ around 780 sec. (p<0.03) as shown in Table 4.

 

 

Conclusion:

From present study it can be concluded that bitter taste of Trimetazidine HCl can be successfully with Eudragit EPO using lyophilization method. Well palatable and patient compliant Rapid Disintegrating Tablet can successfully prepared using lyophilization method. The prepared optimized tablet showed rapid disintegration as well as rapid dissolution as compared to marketed tablet. Thus, the Rapid Disintegrating Tablet of bitter drug having better taste and pleasant mouth feel can be successfully formulated.

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Received on 26.03.2011       Modified on 03.04.2011

Accepted on 08.04.2011      © RJPT All right reserved