INTRODUCTION:

The oral route of administration still continues to be the most preferred and popular route about 80% of the total dosage forms are administered due to its manifold advantages including ease of administration, pain avoidance, versatility and most importantly patient compliance¹. The concept of mouth dissolving drug delivery system emerged from the desire to provide patient with more conventional means of taking their medication. Recent advances in Novel Drug Delivery System (NDDS) aim at enhancing safety and efficacy of drug molecule by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is Fast Mouth Dissolving Tablet. Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms. Dysphagia is a common problem encountered in all age groups as far as solid dosage forms are concerned. To solve the problem of dysphagia and improve patient compliance, orodispersible tablets have emerged as an alternative to conventional oral dosage forms. These are the tablets, which will rapidly disintegrate in the mouth without the need for water. Hence these are very useful in the conditions where water is not available and in case of motion sickness (kinetosis), sudden episodes of coughing during common cold, allergic conditions and bronchitis. Oral route of drug administration has wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance. The most popular solid dosage forms are tablets and capsules, one important drawback of these dosage forms for some patients, is the difficulty to swallow. For these reasons, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Orodispersible tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people^2-4.

Orodispersible tablets are also called as mouth dissolving tablets, melt-in-mouth tablets, fast dissolving tablets, rapimelts, porous tablets, quick dissolving etc. Orodispersible tablets are those when put on tongue, disintegrate instantaneously, releasing the drug, which dissolves or disperses in the saliva. The faster the drug goes into solution, quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than that observed from conventional tablet dosage form. The advantages of mouth dissolving dosage forms are increasingly being recognized in both, industry and academics. Their growing importance was underlined recently when European Pharmacopoeia adopted the term “Orodispersible tablet” as a tablet that to be placed in the mouth where it disperses rapidly before swallowing^5-7.

The objective was to formulate taste masked trimetazidine dihydrochloride fast dissolving tablets to formulate stable, effective, and optimum dosage form using different super disintegrants and diluents, ease of administration and better patient compliance and to perform the stability studies for the optimized formulation.

MATERIALS AND METHODS

Materials:

Trimetazidine dihydrochloride was obtained from Serida Pharma, Bangalore, India as gift sample. All other solvents, reagents and chemicals used were of either Pharmacopoeial or analytical grade

Methods:

Isolation of Mucilage:

Mucilage was isolated by soaking seeds of plantago ovata in water (20-30 times) for at least 48 hrs, boiled for 2 hrs subsequently mucilage was released into the water completely. With the help of the muslin cloth the mucilage was squeezed out and separated from seeds. The mucilage collected and precipitated using 3 times of 95% ethanol. Collected mucilage was dried in the oven at 50-55°.Dried mucilage was scraped and powdered using pestle and mortar. Powder was sieved using mesh no.608

Preparation of Trimetazidine Dihydrochloride Fast Dissolving Tablet

Trimetazidine Hydrochloride tablets each containing 40 mg of Trimetazidine Hydrochloride were prepared by direct compression as per the formulae given in the tables below. The study was intended to explore the disintegrant property of the Plantago Ovata mucilage powder to optimize the concentration of these disintegrants and to compare the disintegration efficiency of these with established super disintegrants and to select the best possible diluent – disintegrant combination to formulate rapidly disintegrating tablets from among various diluents and disintegrants used. The various superdisintegrants used were cross carmallose sodium, sodium starch glycolate and plantago ovata powder. The various diluents used were Lactose, Mannitol/Pearlitol, Microcrystalline cellulose/Avicel. The tablets were formulated employing direct compression method using flat-faced punches. The drug, diluent, superdisintegrant, sweetener and flavor were passed through sieve number 40. All the above ingredients were properly mixed together (in a poly-bag). 1% of magnesium stearate and 1% talc were then passed through mesh number 80, mixed, and blended with the initial mixture in a poly-bag before compression of the blend (table 1-3).

Table 1: Composition of Trimetazidine dihydrochloride FDTs containing lactose as diluent*

Ingredients	L1	L2	L3	L4	L5	L6	L7	L8	L9	L10	L11	L12
Trimetazidine Hydrochloride	20	20	20	20	20	20	20	20	20	20	20	20
POM^*	1	2	3	4	-	-	-	-	-	-	-	-
Cross carmellose sodium	-	-	-	-	1	2	3	4	-	-	-	-
Sodium starch glycolate	-	-	-	-	-	-	-	-	1	2	3	4
Aspartame	4	4	4	4	4	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2	2	2	2	2	2
Magnesium Stearate	2	2	2	2	2	2	2	2	2	2	2	2
Orange Flavor	1	1	1	1	1	1	1	1	1	1	1	1
Lactose	170	169	168	167	170	169	168	167	170	169	168	167

Table 2: Composition of Trimetazidine dihydrochloride FDTs containing Avicel as diluent*

Ingredients	A1	A2	A3	A4	A5	A6	A7	A8	A9	A10	A11	A12
Trimetazidine Hydrochloride	20	20	20	20	20	20	20	20	20	20	20	20
POM*	1	2	3	4	-	-	-	-	-	-	-	-
Cross carmellose sodium	-	-	-	-	1	2	3	4	-	-	-	-
Sodium starch glycolate	-	-	-	-	-	-	-	-	1	2	3	4
Aspartame	4	4	4	4	4	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2	2	2	2	2	2
Magnesium Stearate	2	2	2	2	2	2	2	2	2	2	2	2
Orange Flavor	1	1	1	1	1	1	1	1	1	1	1	1
Avicel	170	169	168	167	170	169	168	167	170	169	168	167

Table 3: Composition of Trimetazidine dihydrochloride FDTs containing mannitol as diluent*

Ingredients	M1	M2	M3	M4	M5	M6	M7	M8	M9	M10	M11	M12
Trimetazidine Hydrochloride	20	20	20	20	20	20	20	20	20	20	20	20
POM^*	1	2	3	4	-	-	-	-	-	-	-	-
Cross carmellose sodium	-	-	-	-	1	2	3	4	-	-	-	-
Sodium starch glycolate	-	-	-	-	-	-	-	-	1	2	3	4
Aspartame	4	4	4	4	4	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2	2	2	2	2	2
Magnesium Stearate	2	2	2	2	2	2	2	2	2	2	2	2
Orange Flavor	1	1	1	1	1	1	1	1	1	1	1	1
Mannitol	170	169	168	167	170	169	168	167	170	169	168	167

POM* -Plantago Ovata mucilage

Evaluation of fast dissolving tablet^8-9

Pre-Compressional Studies

(i) Bulk Density (D_b):

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve # 20) into a measuring cylinder and the initial volume was noted. This initial volume is called the Bulk volume. From this, the bulk density is calculated according to the formula mentioned below. It is expressed in gm/ml and is given by

(ii) Tapped Density (D_t):

It is the ratio of total mass of powder to the tapped volume of powder. The tapped volume was measured by tapping the powder to constant volume (in a bulk density apparatus). It is expressed in gm/ml and is given by

Where, M is the mass of powder, V_tis the tapped volume of the powder.

(iii) Angle of Repose (θ):

The frictional forces in a loose powder can be measured by the angle of repose, θ. It is indicative of the flow properties of the powder.

It is defined as the maximum angle possible between the surface of a pile of powder and the horizontal plane.

tan θ = h / r,θ = tan^-1 (h / r)

Where, θ is the angle of repose, h is the height in cms, r is the radius in cms. The powder mixture was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Care was taken to see that the powder particles slip and roll over each other through the sides of the funnel.

(iv) Carr’s Index (I):

It indicates powder flow properties. It is expressed in percentage and is given by

Where, D_t is the tapped density of the powder, D_b is the bulk density of the powder.

Post compressional studies¹⁰

(i) Hardness:

The hardness of the tablet was determined using a Monsanto hardness tester. It is expressed in Kg/cm².

(ii) Friability (F):

The friability of the tablet was determined using Roche Friabilator. It is expressed in percentage (%). 20 tablets were initially weighed (W_initial) and transferred into the friabilator. The friabilator was operated at 25 rpm for 4 mins. The tablets were weighed again (W_final). The % friability was then calculated by

(iii) Weight Variation: (IP-1996)

20 tablets were selected randomly from the lot and weighed individually to check for weight variation.

(iv) Thickness:

The thickness of the tablets was measured using Vernier Caliper. It is expressed in mm

(v) Disintegration Time (in vitro)

The In vitro disintegration time was determined using disintegration test apparatus. A tablet was placed in each of the six tubes of the apparatus and one disc was added to each tube. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

(i) Disintegration time in oral cavity

The disintegration time in the oral cavity of human volunteers was measured by placing the tablet on the tongue until no lumps remained. It is expressed in seconds¹¹.

(ii) Wetting Time and water absorption ratio

Wetting time is closely related to the inner structure of tablets and to the hydrophilicity of the excipients. A piece of tissue paper folded twice was placed in a small Petri plate (internal diameter = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper, and the time for complete wetting of the tablet was measured in seconds. The method was slightly modified by maintaining water at 37^oC. Water absorption ratio( R), was determined using following equation,

R = Wb - Wa/Wa * 100

Where, Wa is the weight of tablet before water absorption and Wb is weight of tablet after water absorption^12-13.

Stability studies of the tablet formulations (According to ICH guidelines):

Definition: Stability can be defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

ICH specifies the length of study and storage conditions:

Long term study – 25^o C ± 2^o C / 60% RH ± 5% RH for 12 months

Accelerated study - 40^o C ± 2^o C / 75 % RH ± 5% RH for 6 months.

It was decided that the stability studies would be carried out on only a few formulations. The formulations for stability studies were selected based on the disintegration time in oral cavity, wetting time and mouth feel of the formulation. The selected formulations were packed in glass vials (tightly sealed) and kept at 40±2^oC /75 ± 5% RH and 25 ± 2^oC / 60 ± 5% RH as per ICH specifications. The stability studies were conducted for a period of three months.

RESULT AND DISCUSSION:

The present study was carried out and to explore the disintegrating properties of plantago ovate mucilage by formulating orally disintegrating tablets of trimetazidine dihydrochloride by direct compression method Disintegrant property of above disintegrant was evaluated by comparing their formulation with the formulation of various super disintegrants. And to select the best possible diluent disintegrants combination to formulate rapidly disintegrating tablets amongst various diluents and disintegrants used.

Preformulation Studies of Drug and Excipients:

Description / Appearance:

White and crystalline powder. It was found to be as per the specification mentioned in pharmacopoeia.

Identification Test:

Trimetazidine dihydrochloride is an official drug in Indian Pharmacopoeia and the identification tests given in I.P. 1996 were conducted. The drug has given positive results for the identification tests.

Loss on Drying:

The value of LOD was found to be 0.2%, which was found to comply with the specification of Pharmacopoeia (NMT 0.5%).

Solubility Profile:

Practically insoluble in water, soluble in dimethyl formamide, slightly soluble in alcohol and methanol.

Drug- excipient compatibility studies:

Drug – excipient compatibility studies were carried out. From, the DSC Thermograms and IR spectra’s, it was found that there was no compatibility related problems between the drug and the excipients used in the formulation. The prominent peaks for particular functional groups for Trimetazidine Hydrochloride are shown in the spectra’s of both drug alone and in drug with excipients. Thus all the excipients used in the formulation were compatible with the drug. From The DSC studies, it was found that the melting point of Trimetazidine Hydrochloride was 228°C. The melting point of drug was not changed significantly in presence of excipients and ranged from 228±2°C. Hence the DSC Thermograms clearly gives an indication of compatibility of drug and excipients used for the formulation (figure 1-4).

Figure 3: FTIR spectra of pure Trimetazidine dihydrochloride

Figure.4: FTIR spectra of trimetazidine dihydrochloride +all excipients

Table 4: Pre compression parameters for Trimetazidine dihydrochloride FDTs containing lactose as diluent

Parameters	L1	L 2	L3	L4	L5	L6	L 7	L8	L9	L10	L11	L12
Bulk density (g/cc)	0.47	0.54	0.55	0.59	0.46	0.54	0.57	0.6	0.49	0.51	0.6	0.63
Tapped density (g/cc)	0.54	0.68	0.72	0.74	0.57	0.67	0.74	0.8	0.57	0.65	0.78	0.81
Bulkiness (cc/g)	2.12	1.85	1.81	1.69	2.17	1.85	1.66	1.66	2.04	1.96	1.66	1.58
Carr’s Index (%)	12.96	20.58	23.61	20.27	19.40	19.40	22.97	25	14.03	21.53	23.07	22.22
Hausner ratio	1.15	1.25	1.30	1.25	1.23	1.24	1.29	1.33	1.16	1.27	1.3	1.28
Angle of repose (°)	25	26	28	29	26	26.8	27	28.7	25	25.9	26.8	29

Table 5: Pre compression parameters for Trimetazidine dihydrochloride FDTs containing Avicel as diluent

Parameters	A1	A 2	A3	A4	A5	A6	A 7	A8	A9	A10	A11	A12
Bulk density (g/cc)	0.49	0.52	0.57	0.6	0.46	0.52	0.56	0.59	0.47	0.49	0.56	0.59
Tapped density (g/cc)	0.58	0.65	0.69	0.72	0.57	0.63	0.69	0.72	0.55	0.59	0.68	0.76
Bulkiness (cc/g)	2.04	1.92	1.75	1.67	2.17	1.92	1.78	1.69	2.12	2.04	1.78	1.69
Carr’s Index (%)	15.51	20	17.39	16.67	19.29	17.46	18.84	18.05	14.54	16.94	17.64	22.36
Hausner ratio	1.18	1.25	1.21	1.2	1.23	1.21	1.23	1.22	1.17	1.20	1.21	1.28
Angle of repose ( °)	25	25.6	27.2	28	24	24.9	26	27.2	25	25.8	27	28.2

Table 6: Pre compression parameters for Trimetazidine dihydrochloride FDTs containing Mannitol as diluent

Parameters	M1	M2	M3	M4	M5	M6	M7	M8	M9	M10	M11	M12
Bulk density (g/cc)	0.47	0.52	0.55	0.57	0.47	0.49	0.55	0.6	0.46	0.49	0.51	0.58
Tapped density (g/cc)	0.56	0.66	0.63	0.74	0.56	0.58	0.62	0.69	0.55	0.57	0.62	0.71
Bulkiness (cc/g)	2.12	1.92	1.82	1.75	2.12	2.04	1.18	1.67	2.17	2.04	1.96	1.72
Carr’s Index (%)	16.07	21.21	12.69	22.97	16.07	15.51	11.29	13.04	16.36	14.03	17.74	18.3
Hausner ratio	1.19	1.26	1.14	1.29	1.19	1.18	1.12	1.15	1.19	1.16	1.21	1.22
Angle of repose ( °)	26	28	28.3	29	26.4	28.3	29	31	24.7	26.2	28.3	30.3

Table 7: Post compression parameters for Trimetazidine dihydrochloride FDTs containing Avicel as diluent

Parameters	A1	A 2	A3	A4	A5	A6	A 7	A8	A9	A10	A11	A12
Hardness (kg/cm²)	3	3.2	3.1	3.7	2.9	3.1	3.5	3.6	2.8	3.2	3.2	3.4
Friability (%)	0.30	0.35	0.38	0.40	0.31	0.36	0.40	0.42	0.38	0.38	0.42	0.45
Thickness (mm)	4.5±0.01				4.5±0.03				4.5±0.03
Weight variation	200±4
Content uniformity	99±0.5

Table 8: Post compression parameters for Trimetazidine dihydrochloride FDTs containing Mannitol as diluent

Parameters	M1	M2	M3	M4	M5	M6	M7	M8	M9	M10	M11	M12
Hardness (kg/cm²)	2.8	3.3	3.5	3.5	2.7	3.1	3.5	3.7	2.9	3.2	3.4	3.6
Friability (%)	0.3	0.35	0.43	0.46	0.38	0.38	0.41	0.44	0.34	0.37	0.4	0.42
Thickness (mm)	4.4±0.03				4.4±0.02				4.5±0.01
Weight variation	200±4
Content uniformity	99±0.5

Table 9: Post compression parameters for Trimetazidine dihydrochloride FDTs containing lactose as diluent

Parameters	L1	L 2	L3	L4	L5	L6	L 7	L8	L9	L10	L11	L12
Hardness (kg/cm²)	2.9	3.1	3.2	3.6	2.8	3.2	3.4	3.5	2.7	3	3.1	3.3
Friability (%)	0.35	0.39	0.41	0.43	0.37	0.37	0.41	0.42	0.36	0.38	0.42	0.42
Thickness (mm)	4.5 ±0.01				4.4±0.02				4.5±0.01
Weight variation (mg)	200±4
Content uniformity	99±0.5

Stability Studies:

The optimized formulations were evaluated for the effect of aging on hardness, disintegration time and on in vitro release of drug. The storage conditions were room temperature (3 month), 25±2°C/60± 5%RH for (2 weeks) and 40±2°C/75± 5%RH (9 weeks). After storage for three month at room temperature, there was no noticeable effect of aging on hardness and on in vitro release of the tablets. But after storage at 25±2°C/60± 5%RH for (2 weeks), there was a reduction in the hardness of tablets containing superdisintegrants and formulations containing Mucilage. But the ability of all the superdisintegrants and formulations containing Mucilage to promote dissolution tended to decrease slightly. However, after storage at 40±2°C/75± 5%RH for (3 Months) hardness was increased considerably for all tablet formulations including control tablets. It was interesting to note that irrespective of hardness variation, dissolution profiles were decreased, indicating that the decrease in dissolution rate was due to a change in effectiveness of superdisintegrants and Mucilage powder at elevated conditions. Mechanisms of case hardening may also be a reason for decrease in dissolution rate. The initial decrease in hardness may be due to the water sorption property of super disintegrants, which was proved by control tablets by showing no change in hardness values. After that, increase may be due to the loss of, water of hydration during storage for prolonged period of time.

CONCLUSION:

The present work was carried out to study the disintegrating property of Plantago ovata mucilage by formulating orally disintegrating tablets of trimetazidine dihydrochloride by direct compression methods. Disintegrating property was evaluated by comparing their formulations with the formulation of various superdisintegrants and to select the optimum concentration of disintegrants and to select the best diluents disintegrants combination to produce shortest disintegration time.

It can be concluded from the study that orally disintegrating tablets of trimetazidine dihydrochloride can be formulated by direct compression method using Plantago ovata mucilage as disintegrants. To know the safety level of extracted mucilage acute and sub acute toxicity studies are carried out. In both studies no manifestations of toxic syndrome were observed. Mucilage at 1% produce shortest disintegration time and wetting time. From this study we can conclude that mucilage can be used as disintegrants in the formulation of fast/dispersible tablets, since the primary ingredients are inexpensive, devoid of toxicity, bio compatible , biodegradable and easy to manufacture, they can used in place of currently marketed super disintegrants. Direct compression method was found to e the best approach in the formulation of fast dissolving tablets.

All the formulation prepared in this study disintegrated in the oral cavity within the limits and all excipients used were suitable to formulate rapidly disintegrating tablets of trimetazidine dihydrochloride. All formulations were evaluated for physical characteristic, in vitro dissolution and stability. The tabulating properties found within the limits. Among the various diluents used, Avicel gave the best disintegration time. Thus the objectives of formulating orally disintegrating tablets of trimetazidine dihydrochloride have been achieved with success.

ACKNOWLEDGEMENTS:

The authors are thankful to the Management and Principal of Karavali college of Pharmacy, Mangalore for providing all the facilities to conduct the research work and the authors are also thankful to Serida Pharma, in Bangalore, for generous gift sample of trimetazidine dihydrochloride.

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Received on 16.03.2016 Modified on 05.04.2016

Res. J. Pharm. Dosage Form. and Tech. 2016; 8(2):95-104.

DOI: 10.5958/0975-4377.2016.00013.6