FORMULATION RELEASE STUDY OF SOME IMPORTANT DRUGS FROM SUPPOSITORY

FORMULATION RELEASE STUDY OF SOME IMPORTANT DRUGS FROM SUPPOSITORY Mohammed Younus Ali*, Sadat Ali JJT University, Churu-Bisau Road, Jhunjhunu Rajasthan ABSTRACT: The purpose of this study was to formulate and study the release of drugs namely atenolol a antihypertensive and aceclofenac a non steroidalanti inflammatory drug from suppositories prepared using hydrogenated vegetable oil as a hydrophobic polymer and in combination with beeswax as hardening agent, propylene glycol as plasticizer and propyl paraben as preservative. Suppositories were prepared using fusion method the prepared suppositories were studied for various parameters viz., physical appearance, assay and dissolution studies. The dissolution studies suggest that suppositories of atenolol prepared using hydrogenated vegetable oil along with 7.5% beeswax has released upto 99% of atenolol in 150 minutes and followed zero order kinetics ( r=0.9902) and release mechanism was found to be diffusion controlled which is evident by Higuchi s equation (r=0.9598), where as the suppositories of aceclofenac prepared utilizing hydrogenated vegetable oil along with 7.5% of beeswax has released 99.18% of aceclofenac with 240 minutes sustain release that might due to effect of hydrophobic hydrogenate vegetable oil and followed zero order kinetics (r=0.9927) and the release was by diffusion mechanism according to Higuchi s equation (r=0.9783). FT-IR studies showed that there was no drug excipient interaction. Key Words: Atenolol, Aceclofenac, Zero order, Diffusion Introduction: Oral administration is the route of choice in the daily practice of pharmacotherapy. However, oral route becomes impractical in certain cases such as nausea, vomiting or convulsion. In such conditions the rectal route may provide a practical alternative. The human rectum represents a body cavity in which drug is can be easily introduced and retained well. Rectal route is also good for drugs that irritates gastro intestinal mucosa [1], avoiding first pass effect in the liver and in Ideal suppository would be easy to administer and with good patient compliance and remain at the administered site [2] avoiding first pass effect in the liver and in gastro intestinal tract. Conventional suppositories are semisolid dosage form [3] The rectal route is much preferred in pediatric and geriatric patient with difficulties in swallowing solid oral dosage form [4].In pursuit to the above findings the suppositories are proven to be a convenient dosage form in the treatment of chronic health disorders Corresponding Author* Mohammed Younus Ali 33 P a g e

such as rheumatism and cardiovascular diseases specially among the aged patients. In the present work suppositories of atenolol and aceclofenac are prepared. Atenolol [5] is an antihypertensive drug used in the management of hypertension, angina pectoris and emergency treatment of cardiac arrhythmias, but its oral bioavailability is only 50% because of its poor absorption from gastrointestinal tract, on the other hand the drug has a few gastro intestinal side effects such as nausea, vomiting and diarrhea. Aceclofenac [6] (ACL) is a new generation NSAID widely used in the long term therapy of various rheumatic disorders and is associated with gastro-intestinal disorders such as gastric irritation and ulceration which can be prevented by administering through rectum in the form of solid suppositories. In the present study, rectal suppositories of Atenolol and Aceclofenac were developed by using hydrophobic polymeric bases like hydrogenated vegetable oil using propylene glycol as plasticizer and beeswax as hardening agent. Fat like bases are used for water-soluble drugs and a hydrophilic base for a drug, insoluble in water [7]. Material and Methods Aceclofenac and Atenolol was a gift sample from Glenmark Pharmaceutical Nasik, Hydrogenated vegetable oil was procured, and all the other materials was procured from SD Fine chemicals and was of analytical grade. Preparation of Suppositories: Before preparing the suppositories it is essential to calculate the displacement value for fatty base. The displacement values were found to be 1.23gm and 1.58 gm for atenolol and aceclofenac respectively. The pre calibrated suppository moulds were used for the preparation of suppositories. The suppositories were prepared employing fusion (Pour Moulding ) method [8].hydrogenated vegetable oil was melted in a beaker the drug either atenolol or aceclofenac was dispersed in the melted base with continuous stirring until homogeneous dispersion is obtained, add the propylene glycol and propyl paraben with stirring. The mass was fed in to the precalibrated mould under cooled conditions and kept until the suppository hardens and then removed from the mould, wrapped in a aluminium foil and stored at refrigeration. The composition of suppositories are given in table-1 Evaluation of Suppositories: The physical appearance of the suppositories was examined by cutting the suppository longitudinally and examining by naked eyes for any defects. The uniformity of weight was determined as per I.P specification [9]. The drug content assay was carried out using methanol for both atenolol and aceclofeanac at 276 and 222.4 nm respectively using spectrophotometer In vitro Dissolution Studies: In vitro Dissolution studies of were carried out in USP XIII tablet dissolution test apparatus I (Electrolab TDT 06N) Employing a basket at 50 rpm using 900 ml of buffer [Ph. 7.4] at 37±0.5ºC as dissolution medium. One suppository was used in each test. At predetermined time intervals 5ml of the sample were withdrawn by means of a syringe fitted 34 P a g e

with a prefilter. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium maintained at 37±0.5ºC. The samples were analyzed for drug release by measuring the absorbance using UV-visible spectrophotometer after suitable dissolutions. All the studies were conducted in triplicate. Rectal suppositories of Atenolol and Aceclofenac were formulated by fusion method using hydrogenated vegetable oil ( AT 0 - AT 3 and AC 1 - AC 5 ), as base, beeswax for increasing the melting point of hydrogenated vegetable oil and propylene glycol as plasticizer. The prepared suppositories were evaluated for appearance, drug content uniformity, in vitro dissolution and drug excipient interaction. All the suppositories were free from pits, fissures and cracks. The longitudinal section of the suppositories was opaque and uniform in appearance, indicating complete and even distribution of drug in the base. The drug content was found to be in the range of 95.52% to 99.5%, which is within the acceptable limits. The low standard deviation values indicate drug content was uniform in the suppositories prepared. The suppositories prepared with hydrogenated vegetable oils alone were soft with low melting below 37 o C, to increase the hardness beeswax was added in the formulation. In vitro dissolution studies on the formulated hydrogenated vegetable oil- beeswax suppositories (( AT 0 - AT 3 and AC 1 - AC 5 ), were carried out in ph 7.4 phosphate buffer and the various dissolution parameters, viz., percent drug dissolved, t 50% and t 70% are shown in table-2and dissolution profile are depicted in Figures1 and 2. This data shows that hydrogenated vegetable oilbeeswax suppositories of atenolol have released up to 99.20% ( AT 2 containing 7.5% bees wax) of the drug in 150 min whereas that of Aceclofenac hydrogenated vegetable oil-beeswax suppositories have released up to 99.18% (AC 4, which contains 7.5% w/w bees wax) of the drug in 4 hours. In case of suppositories prepared with hydrogenated vegetable oilbeeswax suppository base, the release rate decreases as the concentration of the beeswax increases; this might be due to the increase in melting time. Drug Release Kinetics: The in vitro drug release data was subjected to goodness of fit test by linear regression analysis, according to firstorder kinetic equations, zero order, Higuchi and Peppas models to determine the mechanism of drug release. The regression coefficient r values for Higuchi s equation range from 0.9427 to 0.9894 indicating that the drug release is by diffusion mechanism, and those of n values of Peppas equation range from 0.5536to 1.51. As per the n values of Peppa s equation the prepared suppositories have shown non-fickian (AT 1, ATVS 2, AT 3 n>0.45), and super case-ii transport (AT 0 n>1.0) release mechanism. The super case-ii transport release mechanism may attribute to burst effect displayed by these formulations. All the formulations except AT 3 have shown zero order drug release kinetics. Similarly for Aceclofenac suppositories the data was subjected to goodness of fit, The 35 P a g e

regression coefficient r values for Higuchi s equation range from 0.9547 to 0.9789 indicating that the drug release is by diffusion mechanism, and those of n values of Peppas equation range from 0.4128to 1.465. As per the n values of Peppas equation, the prepared suppositories have shown Fickian (AC 4 n<0.45), non-fickian (AC 3, AC 5 0.89>n>0.45) and super case-ii (AC 1 and AC 2, n>1.0) release mechanism. The super case-ii release mechanism may be attributed to burst- effect displayed by these formulations, this, in turn, might be because of high concentration of beeswax ( 8.75 to 10 % w/w). The formulation AC 3 containing 7.5% w/w beeswax in hydrogenated vegetable oil has displayed zero-order release rate (r = 0.9927), and it has released 99.18 % ACL within 4 hours. All the formulations have shown zeroorder drug release kinetics. FT-IR: FT-IR was done to evaluate interactions between the drug and polymer and was found that there was no drug-excipient interaction. Conclusion: it can be stated that fatty bases retard the release of water insoluble drug (Aceclofenac) and enhances the release the water soluble drug (Atenolol) from the prepared suppositories. Reference: 1. Taha EI, Zaghloul AA, Samyb AM, Al-Saidan S, Kassem AA and Khan MA. Bioavailability assessment of salbutamol sulfate suppositories in human volunteers. Int. J. Pharm 2004; 279: 3-7 2. Young J P, Chul SY, Hak MK, Jong DR, Yu KO, Chong KK and Han GC. Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. Int. J. Pharm 2003; 263: 105 111. 3. Larry JC and Herbert AL. Suppositories. In: LachmanL,Liberman HA and Kanig JC. (eds.) The Theory and Practice of Industrial Pharmacy. 3 rd ed. Varghese Publishing House, Mumbai, 1987, pp 564-587. 4. Lawrence HB. Remington. The Science and Practice of Pharmacy.19 th ed. Mack Publishing House, New York, 1995, pp 1577. 5. Sweetman SC. Martindale. The Complete Drug Reference.34 th ed. Pharmaceutical Press.London, 2005, pp 865. 6. Sweetman SC. Martindale, 2005, The Complete Drug Reference. 34 th ed. Pharmaceutical Press. London, 2005, pp. 11 7. Hermann TW. Recent research on bioavailability of drugs from suppositories.int. J. Pharm. 1995; 123: 1-11. 8. Carter SJ. Cooper and Gun s Dispensing for Pharmaceutical Students.12 th ed. CBS Publishers, New Delhi. 2008, pp 232-52. 9. Indian Pharmacopoeia. 4 th ed. Controller of Publications, Ministry of Health and Family Welfare, Govt of India, New Delhi, 1996, pp 572. 36 P a g e

Table-1 Composition of Suppositories (10) Formulation Code S.N Ingredients AT 0 AT 1 AT 2 AT 3 AC 1 AC 2 AC 3 AC 4 AC 5 1 Hydrogenated 9.5 9.11 8.87 8.63 7.86 7.97 8.08 8.2 8.30 Vegetable oil (gm) 2 Beeswax(gm) - 0.48 0.72 0.96 0.870 0.76 0.654 0.54 0.44 3 Propylene 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Glycol (gm) 4 Propyl 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Paraben(gm) 5 Distill Water 1 1 1 1 1 1 1 1 1 6 Aceclofenac 3.00 3.00 3.00 3.00 3.00 7 Atenolol 0.5 0.5 0.5 0.5 Table-2 Atenolol and Aceclofenac Release Data from suppositories Formulation Code Time (mins) Cummulative % amount drug release t 50% (mins) t 70% (mins) Zero order r Higuchi s Equation r Peppa s Equation n AT 0(CONTROL) 240 99.04±0.56 99.00 118.50 0.9594 0.9621 1.510 AT 1 150 98.19±0.97 76.50 100.50 0.9821 0.9560 0.7657 AT 2 150 99.20±1.00 78.00 106.50 0.9902 0.9894 0.6664 AT 3 120 98.34±0.51 27.01 39.10 0.8870 0.9427 0.5536 AC 1 270 98.9±1.40 120.2 166.50 0.9716 0.9561 1.376 AC 2 210 98.01±1.01 81.01 120.01 0.9508 0.9547 1.465 AC 3 240 99.18±0.98 82.05 146.01 0.9927 0.9783 0.4617 AC 4 210 99.20±0.24 72.09 136.45 0.9951 0.9741 0.4128 AC 5 180 98.37±1.08 80.50 116.49 0.9933 0.9789 0.5519 37 P a g e

Cummulative Percent Drug Release Cummulative percent drug release 120 100 80 60 40 20 0 0 50 100 150 200 250 300 Time (mins) AT0 AT1 AT2 AT3 AC1 AC2 AC3 AC4 AC5 Figure-1 Cumulative percent Drug release versus time (ZERO ORDER) Plots 120 100 80 60 40 20 0 0 5 10 15 20 Square root of time AT0 AT1 AT2 AT3 AC1 AC2 AC3 AC4 AC5 Figure-2 Cumulative percent Drug Released V/s Square root of Time (HIGUCHI'S) PLOT 38 P a g e