INTRODUCTION:

Oral administration is considered as one of the most convenient and widely accepted routes of delivery for most therapeutic agents because of its advantages like ease of administration, compactness and flexibility in manufacture. However, Pediatric, geriatric, bedridden, nauseous patients express difficulty in swallowing tablets, which leads to poor compliance and ineffective therapy. Traditionally, oral dosage forms refer to tablets, capsules taken orally, swallowed and transiting the gastro intestinal tract (GIT) for post buccal absorption. However, some undesirable properties of the GIT limit the feasibility of administering certain drugs. The relatively poor absorption, first pass metabolism and subsequent elimination limit the ability of reaching therapeutic levels by this route. To overcome these problems, fast dissolving tablets are developed. These dosage forms dissolve or disintegrate in the oral cavity within a minute without the need of water or chewing^(1,2).This pre - gastric absorption results in improved bioavailability. These tablets enhance the safety and efficacy of drug molecules, these tablets provide convenience of administration and accurate dosing is possible. Moreover, this dosage form combines the advantages of both liquid and tablet formulations. Most commonly used methods to prepare fast dissolving tablets are freeze drying/ lyophilisation, molding, spray drying, sublimation, direct compression methods.

Direct compression is the simple and most effective tablet manufacturing technique with low manufacturing cost and high mechanical integrity of tablets compared to other techniques. Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class^(3,4). The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5] benzodiazepine. It is a selective monoaminergic antagonist used to treat schizophrenia and bipolar disorder^(5,6). The present investigation deals with the development of Olanzapine fast dissolving tablets by direct compression technique and the evaluation of the same.

MATERIALS AND METHODS:

Olanzapine (obtained as gift sample from Ortin Laboratories Ltd, Hyderabad), cornstarch, Mannitol, L-HPC II, Aspartame, Sodium saccharine and Magnesium stearate used were of Pharmacoepial grade .

Preparation of Olanzapine tablets⁽⁷⁾:

Tablets containing 10 mg of Olanzapine were prepared by Roll compaction process and the various formulae used in the study are shown in the table 1.The Drug, Cornstarch, Mannitol, Croscarmellose sodium, L-HPC II was sifted through #30 ASTM fitted in a vibratory sifter. Unloaded the mixture for 10 and blended for 20 minutes in an octagonal blender to ensure uniform mixing. Lubricated the resulting mixture with #40 ASTM sifted magnesium stearate and continued the blending for 5 minutes. Bulk density, Tap density and particle size distribution were determined for the blend (pre - compacted blend). Roll compacted the blend using Roll compactor after optimizing the roll pressure and roller rpm. The compacts were sifted through oscillating granulator fitted with #30 ASTM sieve. Bulk density, Tap density and particle size distribution were determined for the blend ( compacted blend) .Unloaded the blend and to that #30 sifted extra-granular materials were incorporated. Colloidal silicon dioxide, and magnesium stearate sifted through #40 ASTM were added. Bulk density, Tap density and particle size distribution were determined for the blend ( final blend). The final blend was compressed into tablets in sixteen-station single rotary cadmach compression machine using 5.5mm FFB punches.

Evaluation of tablets:

Tablets are evaluated for weight variation, hardness, friability, thickness and disintegration time. In weight variation test, twenty tablets were selected at random and average weight was determined using an electronic balance. Tablets were weighed individually and compared with average weight. Roche friabilator and Monsanto hardness tester were used to test the friability and hardness respectively. Thickness of the tablet was determined by thickness tester (Erweka, Mumbai). Disintegration time was determined by using disintegration test apparatus (Electrolab,Mumbai).The results were shown in Table 2.

Fig1: Effect of Croscarmellose sodium level on the release of Oleanzapine

F-1: 4% Croscarmellose sodium F-2: 8% Croscarmellose sodium

F-3: 10%Croscarmellose sodium

Dissolution study of Olanzapine tablets⁽⁸⁾:

In-vitro release of Olanzapine from tablets was monitored by employing 900 ml of 0.1N Hcl at 37±0.5⁰cand 50 rpm using Labindia Disso 2000, an eight stage dissolution rate testing apparatus with paddle. Aliquots of dissolution medium were withdrawn at specific intervals of time and were replenished immediately with the same volume of fresh medium. The withdrawn samples are analyzed for drug content by measuring the absorbance at 270 nm. The cumulative percent of Olanzapine released was calculated and plotted against time.

Stability studies:

The stability studies of selected formulations were carried out by storing the drug at 40⁰c/75 % RH and 25⁰c /60 % RH. The required quantity of tablets in 40⁰c /75 %RH were analyzed at the end of 3^rd and 6^th month for its physical appearance, assay, water content, disintegration time and dissolution.

RESULTS AND DISCUSSION:

Olanzapine orally disintegrating tablet was formulated by Roll compaction process and the disintegrant and binder concentrations were optimized by various trails. Disintegrants are essential components of solid dosage forms. Appropriate selection and suitable concentration of disintegrant play an indispensable role in the development of a fast dissolving tablet. From the drug-excipient compatibility study, Croscarmellose sodium was selected as the disintegrant and its concentration was optimized by taking three different trials employing various concentrations. The details of the formula utilized were furnished in Table1. The trials were carried out to study the effect of variations in disintegrant concentration on formulated tablet characteristics and the results were plotted. (Fig1).

Binders like cellulose derivatives are essential to improve the cohesiveness among the powder particles. It is mandatory to optimize its concentration, as both low and high concentration may affect the cohesiveness of the powder particles and hardness of the tablets. Based on the drug excipient compatibility study, L-HPC II was selected as the binder and its optimization was carried out by taking three different trails and the results were plotted (Fig2).

Fig2: Effect of L-Hpc II level on the release of Oleanzapine

F-4: 2% L-HpcII ; F-5: 4%L-Hpc II: F-6: 6% L-HpcII

Table1 : Formulations of Orodispersible tablets of Olanzapine:

Formulation ingredients	F-1	F-2	F-3	F-4	F-5	F-6
Intra-granular addition
Olanzapine	7.69	7.69	7.69	7.69	7.69	7.69
Cornstarch	15.38	7.69	31.62	15.38	7.69	31.62
Mannitol	33.62	39.31	13.38	34.62	38.31	14.38
Croscarmellose sodium	2	3	4	2	3	2
L-Hpc II	3	3	3	2	4	6
Magnesium stearate	0.25	0.25	0.25	0.25	0.25	0.25
Extra-granular addition
Mannitol	28.40	28.40	28.40	29.3	27.3	25.3
Croscarmellose sodium	2	3	4	2	3	2
L-Hpc-II	3	3	3	2	4	6
Aspartame	0.58	0.58	0.58	0.58	0.58	0.58
Sodium saccharin	0.38	0.38	0.38	0.38	0.38	0.38
Talc	1.00	1.00	1.00	1.00	1.00	1.00
Colloidal silicon-di-oxide	0.38	0.38	0.38	0.38	0.38	0.38
Lubrication
Colloidal silicon-di-oxide	0.62	0.62	0.62	0.62	0.62	0.62
Magnesium stearate	1.69	1.69	1.69	1.69	1.69	1.69
Tablet fill weight in % w/w	100	100	100	100	100	100

Table2 : Evaluation of fast-dissolving tablets of Olanzapine:

Formulation parameters	F-1	F-2	F-3	F-4	F-5	F-6
Hardness(kg/cm2)	3.4	3.5	3.7	3.4	3.3	4.0
Thickness(mm)	2.30	2.52	2.70	2.43	2.48	2.64
Disintegration time(sec)	34	23	35	26	22	26
Friability(%)	0.014	0.011	0.013	0.021	0.012	0.029
Drug release (5 min)	97.1	97.5	95.6	94.3	99.2	89.4

Table3 : Stability study data of the tablet formulation (F-5) :

S. No.	Condition	Initial	1st month	2nd month	3rd month
1	Assay (% w/w)	100.2	99.8	99.4	99.3
2.	Water by KF (% w/w)	0.058	0.061	0.065	0.065
3.	Dissolution (15 min)	99.2	98.7	98.1	97.4
4.	Disintegration time (sec)	22	24	25	26
5.	Related substances (w/w)	0.081	0.091	0.094	0.093

The optimization procedures aided in the stabilization of the formula and in the formulation of the Olanzapine as orally disintegrating tablet. Of the various formulations F-5 showed lowest disintegration time (22 sec) and maximum percent drug release. The dissolution profile of the prepared Olanzapine was compared with that of the reference product, which was found to be comparable with the reference product (Fig 3).

Fig3: Comparative dissolution profile of F-5 and Marketed formulation

The stability of the product F-5 was determined by conducting Accelerated stability testing in 40⁰c/75%RH conditions for 3 months as per ICH guidelines in PVC/PVDC blisters. Finally after the duration, the product was analyzed for physical appearance, related substance, water by KF and dissolution. Related substances (impurities) were found to be within the specification limits as per ICH guidelines. No significant changes in the analyzed characteristics were observed during the period of study. No significant variation in in-vitro dissolution study was observed. By the stability studies the formulated Olanzapine ODT was proved to be stable throughout the period of the storage. Formulated Olanzapine ODT by Roll compaction process is found to be stable through out the shelf life and comparable with reference product. The Stability study data of the tablet formulation F-5 was shown in Table 3.

CONCLUSION:

A stable, effective and pleasant tasting fast dissolve tablet, which had a balance over disintegration time and mechanical strength, was formulated using croscarmellose sodium (6%) as a superdisintegrant and 8% L-Hpc II as a binder.

ACKNOWLEDGEMENT:

The authors are very much thankful to the Principal and Management of KVSR Siddhartha College of pharmaceutical sciences, Vijayawada-10, for their support and constant encouragement.

REFERENCES:

1. Allen, L.V.,Wang, B., Davis J.D., “Rapidly dissolving tablet”, US Patent #US 5807576,1998.

2. Pabley , W.S., Jager, N.E., Thompson S.J., “Rapidly Disintegrating Tablets”, US Patent #US 529261, 1994.

3. US Food and Drug Administration, CDER Data Standards Manual, 2003, www.fda.gov/cder/dsm/DRG/drg00201.htm

4. Lalla, J.K.Sharma, A.H.,Indian drugs,1994,31(11), 503-508.

5. Bever K.A., Perry P.J., “Olanzapine: a serotonin-dopamine-receptor antagonist for anti-psychotic therapy”, 1998 May 15,559100,1003-1016.

6. Bartko G., “New formulations of Olanzapine in the treatment of acute agitation”, Neuropsychopharmacol Hung.2006 Dec, 8(4), 171-178.

7. Allen, L.V., Wang,B., ”Method for making a rapidly dissolving tablet”, US Patent# US5635210,1997.

8. Chue F., Jones B., Talor C.C., Dickson r., “Dissolution profile, Tolerability and acceptability of the orally disintegrating Olanzapine Tablet in patients with Schizophrenia”. Canadian journal of psychiatry,2002,47(8),771-774.

Received on 27.11.2009 Modified on 29.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 543-546