H.N.SHIVAKUMAR*, SARASIJA SURESH & B.G.DESAI Department of Pharmaceutics, Al-Ameen College of Pharmacy, Hosur Road, Bangalore-560 027, India

JAN-FEB 2007Indian journal of pharmaceutical sciences 2007 69(1):73-79

Abstract

A pH-sensitive tablet in capsule system for colon targeting.

For chronotherapeutic delivery of theophylline is to target nocturnal peak symptoms of asthma.

The system comprising of Eudrigit S-100 coated mini tablets.

Dissolution studies showed 10% weight gain (30μm thickness) of acrylic coat imparts excellent gastro resistant property to tablets.

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Objective

To work out combination of tableting & acrylic pan coating to produce a pH-sensitive tablet of theophylline for colon targeting.

To modulate drug release of coated multiparticulates to specifically target the nocturnal peak symptoms of asthma.

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Chronobiology Of Nocturnal Asthma Asthma is chronic obstructive lung disease

characterized by airways inflammation & hyper-reactivity.(2)

Circadian Rhythm dependent. Chronotherapeutics refers to a clinical practice of

synchronizing drug delivery in a manner consistent with the body's circadian rhythm including disease states to produce maximum health benefit & minimum harm.(1)

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Colon specific targeting

Delivery of drugs using pH sensitive polymers such as Eudragit S(4) & Eudragit S100(5)

pH of colon varies from 6.4±0.6 to 7.5±0.4(6)

Multiparticulate system exhibit higher colonic residence time & more predictable gastric emptying

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Design of pH-sensitive mini tabletsTHEOPHYLLINE Short half life (7-9h)(3)

Good oral bioavailability (96%) Good colonic absorption When administered in evening was aimed to

achieve an elevated theophylline level overnight

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Design of pH-sensitive mini tablets

Core mini tablet compositionAnhydrous Theophylline (40%)Diluent Lactose (46%)Binder PVP K 30 (4%)Disintegrant SSG

(6%)Glidant & antiadherent Magnesium stearate (2%)Glidant & lubricant Talc (2%)

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Design of pH sensitive mini tablets Coating dispersion composition Eudragit S100 (6.0%) Triethyl citrate (0.6%) Purified talc (3.0%) Water (5.0%) Isopropyl alcohol (Q.S)

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Wet granulation method

SEIVING : 60mesh (250μ)DRY MIXING : Planetary mixer 50 rpm, 10minGRANULATION : 10 % PVP K30 150 rpm, 5min

16 mesh screen (1000μ)DRYING : 40 -45 °C for 1 Hr Thermostatic hot air oven

(2-3% moisture content)LUBRICATION COMPRESSION : 4 mm biconcave punches in

rotary tablet press (hardness

of 2 Kg)

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Acrylic film coating

Non aqueous film coating process

Preparation of coating solution Pilot type spray gun fitted with a 1 mm spray

nozzle. Pan rotation speed 20 rpm Spray rate 5-10g/min Atomization air pressure 4 Kg/cm2

Infra-red lamp 35 - 40 °C Four batches of coated tablets with 5%, 10%, 15%

& 20% weight gain

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Physical properties mean±SD

Weight (mg)Thickness (mm)Hardness (Kg)Friability (%)Disintegration time (min)Drug content (mg)

25.20±0.931.49±0.041.85±0.340.059±0.025.00±0.1710.00±0.13

Physical properties of the core mini tablets containing theophylline

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Physical properties of the acrylic film coated mini tablets containing theophylline

CODE WEIGHT (MG)

WEIGHT GAIN %

THICKNESS(mm)

D.T.(pH1.2)

D.T(pH7.5)

T1

T2

T3

T4

26.5627.8429.0730.51

5.4010.4815.3621.07

1.521.561.601.64

IntactIntactIntactintact

12.32.28.4231.5236.32

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Evaluation of coated mini tablets

Scanning electron microscopy (7)

Weigh variation Hardness Friability Disintegration Dissolution IR spectroscopy

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Results & discussion

Wet granulation method Lactose as filler; fast disintegration, good

friability & low weight variation with no signs of sticking, binding & capping.

SSG as disintegrant reduces disintegration time.

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Results & discussion

Eudragit S100 is a pH sensitive polymer having a threshold pH of 7.0 that assist in delivering drug to the colon exploiting the change in the physiological pH of GIT

Non-aqueous acrylic coating procedure Isopropyl alcohol was used as solvent High flash point (15°), low boiling point (82.3°),

low heat of evaporation (667J/g) low risk of toxicity.

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Results & discussion

Talc is added to polymer solution to reduce the porosity, lower the water permeability of the film so produced

Talc also reduces the stickiness of coating during the film forming process

Since eudragit was a brittle polymer , triethyl citrate was used to lower glass transition temperature & promote formation of a good elastic film.

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Results & discussion Polymer solution was diluted to 6.0% w/w of dry polymer

content to avoid aggregates during the pan coating process.

Higher temperatures lead to increase in sticking of film so tempt was maintained near to room tempt

An acrylic coat thickness of 30-50 μm provide excellent resistance to gastric fluid

Disintegration time in pH 7.5 was found to increase with increase in coat thickness or coat weights.

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Results & discussion Coated mini tablets showed limited drug

release in acidic pH Study revealed excellent gastro-resistant & entero-

soluble property. Slow dissolution phase in pH less than 7.0 showing

gastro resistant nature of Eudragit S100

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Results & discussion

Gastro-resistant property is more pronounced with increase in the acrylic film thickness.

A burst effect was observed that is attributed to the high entero soluble nature of Eudragit S100 at pH 7.5

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pH1.2 5.5 6.8 7.5

Time (Hr)

% drugrelease

T1

T2

T3

T4

1 2 3 4 5 6 7

100

0

50

Release profile of various batches of coated mini tablets

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CONCLUSION

The results collectively indicate that tablet compression & pan coating can be employed to successfully develop a colon specific drug delivery system using a pH sensitive polymer.

The pulsed release observed in most cases is highly desirable to target the nocturnal peak symptoms of asthma upon an evening administration of the multiunit system.

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3. Sweetman, S.C., In; Martindale, the Complete Drug Reference, 33rd Edn., Pharmaceutical Press, London, U.K., 2002, 777.

4. Ashford, M., Fell, J.T., Attwood, D. and Woodhead, P.J., Int. J. Pharm., 1993, 91, 241

 

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5.Krogars, K., Heinamak, J., Vesalahti, J., Marvola, M., Antikainen, O. and Yliruusi, J., Int. J. Pharm., 2000, 199, 187.6. Evans, D.F., Pye, G., Branley, R., Clarke, A.G., Dyson, T.J., and Hardcastle, J.D., Gastroenterol. , 1982, 83, 1062. 7. Qing-Ri, C, Han-Gon, C, Dong-Chool, K, and Beom-Jin, L, Int. J. Pharm., 2004, 274, 107.

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