INTRODUCTION:

Oral route is the most frequently used route of drug administration and is the most convenient and economic. 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 being tablets and capsules. Tablets are solid unit dosage form containing a medicament or mixture of medicaments and excipient. Drinking water plays an important role in the swallowing of oral dosage forms.¹

Dysphagia, or difficulty in swallowing, is common among all age groups. According to a study dysphagia is common in about 35% of the general population, as well as an additional 30–40% of elderly institutionalized patients and 18–22% of all persons in long-term care facilities. Common complaints about the difficulty in swallowing tablets in the order of frequency of complaints are size, surface, form, and taste of tablets. Geriatric and pediatric patients and traveling patients who may not have ready access to water are most in need of easy swallowing dosage forms.

Another study shows that an estimated 50% of the population suffers from this problem. These studies show an urgent need for a new dosage form that can improve patient compliance.3 Solid dosage forms that can be dissolved or suspended with water in the mouth for easy swallowing are highly desirable for the pediatricand geriatric population, as well as other patients who prefer the convenience of readily administered dosage forms.²

Diabetes Mellitus commonly referred to as “diabetes”, is a group of metabolic diseases characterized by defects at multiple organ sites. These defects include insulin secretion, insulin action or both. These cases rise due to defects in function or loss of the pancreatic beta-cell and due to decreased insulin motivated glucose uptake in skeletal muscle.¹⁰

Type 1 diabetes mellitus is also known as insulin dependent diabetes mellitus (IDDM). This occurs as a result of cellular-mediated autoimmune destruction of the beta cells of the pancreas. Generally this demolition of the beta cells leads to absolute insulin deficiency. As the beta cells destruction is quite rapid in infants and children therefore prevalence of type 1 diabetes is greater in children and young as compared to others. It also developed in many type 2 diabetic patients with severe insulin resistance.¹⁰

Type 2 Diabetes Mellitus is also known as the non-insulin dependent diabetes mellitus (NIDDM) and occurs as a result of progressive insulin secretory defect along with insulin resistance. Its different forms are characterized by a variable degree of insulin resistance and beta cells dysfunction. Type 2 DM is the most common form of diabetes. About 90 to 95% of people with diabetes are suffering from type 2 DM . This form of diabetes is related with family history, age, ethnicity, previous history of gestational diabetes and physical inactivity.¹⁰

During the last decade, fast disintegrating tablet (FDT) technologies that make tablets disintegrate in the mouth without chewing and additional water intake have drawn a great deal of attention. The FDT is also known as fast melting, fast dispersing, rapid dissolve, rapid melt, and/or quick disintegrating tablet. All FDTs approved by the Food and Drug Administration (FDA) are classified as orally disintegrating tablets.³ Recently, the European Pharmacopeia adopted the term orodispersible tablet for a tablet that disperses or disintegrates in less than 3 minutes in the mouth before swallowing. Such a tablet disintegrates into smaller granules or melts in the mouth from a hard solid to a gel-like structure, allowing easy swallowing by patients.⁴Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolves or disperses in saliva. The faster the drug into solution , quicker the absorption and onset of clinical effect. In this, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form. The amount of drug that is subject to first pass metabolism is reduced as compared to standard The disintegration time for good FDTs varies from several seconds to about a minute.⁵ The basic approach used in development of FDT is the use of superdisintegrants like cross linked carboxy methyl cellulose (croscarmellose), Sodium starch glycolate (Primogel, Explotab), Polyvinylpyrrolidone (polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in saliva.⁶

MATERIALS AND METHODS:

All the materials including superdisintegrants were obtained from Central Drug House (CDH).

Preparation of tablets

All the ingredients were weighed and passed through #60 mesh separately. Then the ingredients were mixed and compressed in to tablet using 8mm flat-faced punches on 16 station rotary tablet machine (Lincoln Pharmaceuticals Ltd, Ahmadabad.) The blend was compressed into tablets by direct compression technique. Actual values of ingredients taken for the preparation of tablets are shown in Table 1.^7,8

Evaluation of tablet blend

1. Angle of repose

Weighed quantity of the drug was passed through a funnel kept at a height 2 cm from the base. The powder is passed till it forms a heap and touches the tip of the funnel. The radius was measured and angle of repose was calculated by using the formula.⁹

tan (θ) = h / r θ = tan-1 (h / r)

θ is the angle of repose.

h is the height in cms

r is the radius in cms.

2. Bulk density

Weighed quantity of drug was transferred into 100 ml measuring cylinder without tapping during transfer. The volume occupied by drug was measured. Bulk density was measured by using formula.¹¹

Bulk density=weight of powder/bulk volume

3. Tapped density

Weighed quantity of drug was taken into a 100ml graduated cylinder. Volume occupied by the drug was noted down. Then mechanically tap the cylinder containing the sample for 500 times initially and measure the tapped volume (V1) to the nearest graduated units, repeat the tapping an additional 750 times and measure the tapped volume (V2) to the nearest graduated units. If the difference between the two volumes is less than 2% then final the volume (V2).Calculate the tapped bulk density in g/ml by the following formula.

Tapped density= weight of powder/tapped volume

4. Carr’s index (or) % compressibility

It indicates powder flow properties. It is expressed in percentage.¹¹

Carr’s index = TD - BD/TD *100

Where, TD is the tapped density of the powder

BD is the bulk density of the powder

5. Hausner ratio

Hausner ratio is an indirect index of ease of powder flow. It is calculate by the following formula.⁹

Hausner ratio = Tapped Density/Bulk Density

Lower hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25).

Evaluation parameters of fast dissolving tablet

1. Weight variation test

Weight variation test was done by weighing 20 tablets individually, calculating the average weight and comparing the individual tablet weight to the average weight.¹¹

2. Thickness

Thickness was determined by using vernire caliper.¹¹

Table 1: Actual values of ingredients taken for fast dissolving tablet

Ingredients	F1	F2	F3	F4	F5	F6	F7
Pioglitazone	15	15	15	15	15	15	15
Croscarmellose sodium	12	14	16		-	-	8
Crospovidone	--	--	--	12	14	16	8
MCC	111	109	107	111	109	107	107
Pregelatinised starch	3	3	3	3	3	3	3
Mag. Stearate	2	2	2	2	2	2	2
Mannitol	4	4	4	4	4	4	4
Menthol	1	1	1	1	1	1	1
Talc	2	2	2	2		2	2
Total weight	150	150	150	150	150	150	150

Table 2: Physical characteristics of prepared blend of Pioglitazone

Parameters	F1	F2	F3	F4	F5	F6	F7
Bulk density(g/ml)	0.42	0.40	0.38	0.42	0.44	0.43	0.47
Tapped density (g/ml)	0.52	0.50	0.47	0.50	0.52	0.51	0.57
Angle of repose(°c)	32.14	32.10	32.11	32.15	32.10	32.16	32.17
Carr’s index (%)	17.18	20	19.14	16	15.38	15.60	17.50
Hausner ratio	1.21	1.25	1.23	1.19	1.18	1.18	1.21

Table 3: Evaluation properties of Pioglitazone compressed tablets

Parameters	F1	F2	F3	F4	F5	F6	F7
Hardness (kg/cm²)	3.8	3.9	3.9	4.1	4.0	3.9	4.0
Friability (%)	0.82	0.78	0.79	0.83	0.81	0.82	0.80
Wetting time (sec)	35	33	32	30	32	31	29
Thickness (mm)	3.2	3.3	3.5	3.1	3.2	3.2	3.3
Disintegration time (sec)	33	30	32	25	24	26	23

Table 4: In vitro dissolution profile % Drug release in 900ml 0.1N HCl USP type 2

Time(min)	% Drug release in 900ml 0.1N HCl in USP type 2(paddle)
	F1	F2	F3	F4	F5	F6	F7
0	0	0	0	0	0	0	0
1	43.25	45.35	42.71	48.73	45.21	47.32	48.32
5	55.27	56.52	58.23	59.62	55.32	57.65	59.61
10	63.56	62.37	64.25	68.45	66.73	65.33	67.52
15	72.92	73.32	72.34	77.32	74.35	75.56	76.25
20	83.21	82.71	84.62	85.27	86.12	85.36	87.61
25	89.72	90.21	91.25	93.35	92.32	91.35	93.21
30	97.52	97.23	96.35	98.25	98.21	97.25	98.97

Table 5: Characterization of innovator product

Parameter	Result
Wt. of tablet(mg)	300
Hardness(kg/cm²)	5.2
Thickness(mm)	3.64
Friability(%)	0.400

Table 6: Comparison of dissolution profiles of Optimized formulation F7 with marketed tablet

Time(min)	% Drug release in 900ml 0.1N HCl in USP type 2(paddle)
Time(min)	Innovator	F7
0	0	0
1	12.32	48.32
5	28.36	59.61
10	43.24	67.52
15	67.50	76.25
20	79.61	85.61
25	90.68	93.21
30	96.87	8.97

Table 7: Stability studies of optimized formula Comparison profile of stability batch, initial and 1 month

Parameter	Condition
Parameter	Initial	1 Month
Hardness	3.4-3.5	3.4-3.5
Friability	0.82	0.83
Disintegration time	23	24
Wetting time	26	26

Table 8: Dissolution profile of stability batch, initial and 1 month

Time (min)	% Drug release
Time (min)	Initial	1 months
0	0	0
1	48.32	47.21
5	59.61	58.52
10	67.52	67.35
15	76.25	75.31
20	85.61	85.63
25	93.21	92.98
30	98.97	98.20

Fig 1: In vitro release study

Fig 2:In vitro dissolution comparison betweenthe innovator and the optimized formulation

Fig 3: Stability study comparison of F7 and innovator

3. Hardness

The tablet hardness, which is the force required to break a tablet in a diametric compression force. The hardness tester used in the study was Monsanto hardness tester, which applies force to the tablet diametrically with the help of an inbuilt spring.¹⁰

4. Friability

The friability of a sample of 20 tablets was measured using Roche friabilator (Electrolab, Mumbai, India). Twenty tablets were weighed, rotated at 25 rpm for 4 minutes. Tablets were reweighed after removal of fines (dedusted) and the percentage of weight loss was calculated. Friability below 1% was considered acceptable.¹¹

5. In vitro disintegration time

The disintegration time of the tablet was measured in water (37±2°C) according to disintegration test apparatus with disk. The time in seconds taken for the complete disintegration of the tablet with no palpable mass in the apparatus was measured in seconds. Three tablets from each batch(formulation) were tested for the disintegration time calculations.^10,11

6. Wetting time

A piece of tissue paper folded twice was placed in a small petridish (ID= 6.5 cm) containing 6 ml of simulated saliva pH 6.8, a tablet was put on the paper, and the time for complete wetting was measured.¹¹

7. In vitro dissolution profile

The in-vitro drug release studies of pioglitazone from the tablets were carried out using USP dissolution test apparatus type-II (Paddle type) in 900 ml of dissolution medium (0.1N HCl) at 37±0.5°C temperature and rotated at 75 rpm. In this test, single tablet from each formulation was used for the studies. At specified time intervals, 5 ml samples were collected and immediately replaced with an equal volume of fresh medium. Samples were suitably diluted and analyzed by using UV spectrophotometer at 237nm.¹¹

Optimization of formula

From the above formulations the optimized formula from is F7 in which both superdisintegrants i.e crospovidone and croscarmellose sod. are used; tablets was selected, depending upon the several factors such as less disintegrant concentration, less disintegration time and fast dissolution rate.

Stability studies

The stability studies of formulated tablets were carried out at 40ºC and 75% RH using a stability chamber for one month. The effects of temperature and time on the physical characteristics of the tablet were evaluated for assessing the stability of the prepared formulations. The different parameters that were studied are disintegration time, hardness, friability, drug content and dissolution rate.⁹

RESULTS AND DISCUSSION;

The Aim of the present study was to formulate and evaluate oral dispersible tablet of pioglitazone hydrochloride. Before the development of oral dispersible tablet various preformulation test were carried out to determine Bulk density, Tapped density, Compressibility index, Hausner’s ratio.

Preformulation study of drug shows that the Drug is off-white to white in color, bitter in taste and odorless. The Drug has bulk density 0.36g/ml, tapped density 0.42g/ml, Compressibility index was good, Hausner’s ratio was also good and angle of repose was good.

The present investigation was undertaken to formulate and evaluate fast dissolving tablets of pioglitazone by direct compression method using Croscarmellose sodium and crospovidone as superdisintegrants. Superdisintegrants are generally used for developing FDTs or for improvement of solubility for drugs. These superdisintegrants accelerate disintegration of tablets by virtue of their ability to absorb a large amount of water when exposed to aqueous environment. The absorption of water results in breaking of tablets and therefore faster disintegration is reported to have an effect on dissolution characteristics as well. A prepared fast dissolving tablet gets dispersed in the mouth quickly and released the drug as early as compared to its formulated conventional tablets. The amount of Superdisintegrants was optimized in the formulation of FDTs. The total 7 formulation (F1-F7) prepared using different concentration of Croscarmellose sodium and crospovidone to study its effect on disintegration time. From the dissolution studies, it was confirmed that the more than 98% drug release for optimized formulation was within 30 minutes.

CONCLUSION:

Tablets containing Croscarmellose sodium along with crospovidone formulation F-7 shown fastest disintegration. Characteristics of tablets are further tabulated. The study shows that the dissolution rate of pioglitazone can be enhanced to a great extent by direct compression technique with the addition of mixture of superdisintegrants. The tablets disintegrated rapidly in oral cavity and had acceptable hardness and friability. In vitro drug release from the tablets shows significantly improved drug dissolution.

ACKNOWLEDGEMENT:

I am grateful to the management of Maharishi Arvind Institute of Pharmacy for providing excellent facility to carry out this work.

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9. Chang, R, Guo, X, Burnside, B. A, Couch, R. Fast-dissolving tablets. Indian Journal of Pharmaceutical Education and Research. 24(6); 2003: 52-58.

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11. Leon lachman, The Theory and Practice of Industrial Pharmacy, 3^rd ed. 1987.

Received on 06.04.2012 Modified on 01.05.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 817-821