DESIGN, FORMULATION AND IN VITRO EVALUATION OF SUSTAINED
RELEASE BILAYER TABLETS OF ACECLOFENAC AND ALLOPURINOL FOR GOUTY ARTHRITIS
M.Pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Mr. RAKESH ROUSHAN, B. Pharm
Under the Guidance of
Mrs. SUJATHA P. MUCHALAMBE, M.Pharm
Associate Professor
Department of Pharmaceutics
R. R. College of Pharmacy
# 40 Raja reddy Layout,Chikkabanavara (Post),
Hesarghatta main road, Bangalore – 560 090
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
ANNNEXURE II
1 / Name and address of candidate / Mr. Rakesh Roushan.s/o,
Rameshwar Prasad.
At-Patel nagar.
Post-Basudeo pur.
Dist-Munger.
State-Bihar.
Pin- 811202.
2 / Name of institution / R.R. college of pharmacy,
# 40 Rajareddy Layout, Hesarghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3 / Course of study and subject / M. Pharm
(Pharmaceutics)
4 / Date of admission /
15th January 2013
5 / Title of the project / "DESIGN, FORMULATION AND INVITRO EVALUATION OF SUSTAINED RELEASE BILAYER TABLETS OF ACECLOFENAC AND ALLOPURINOL FOR GOUTY ARTHRITIS"PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
6.06.1 / BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY:
ARTHRITIS:
It has been widely observed that patient suffering from arthritis have high concentration of uric acid in blood plasma. In arthritis there is deposition of uric acid crystals in joints which causes severe pain and restricts the movement of joint. Arthritis can make it very difficult for the individual to remain physically active, contributing to an increased risk of obesity, highcholesterolor vulnerability toheart disease. Individuals with arthritis are also at increased risk ofdepression, which may be related to fear of worsening symptoms. Rheumatoid arthritis is an auto immune disease which causes joint inflammation, synovial proliferation and destruction of particular cartilage. The NSAID’s are first choice of the drug used in the treatment of pain, inflammation and fever in the body1.
BILAYER TABLETS:
Oral route is the most commonly employed route of drug administration. Although different route of administration are used for delivery of drugs. The popularity of the oral route is attributed patient acceptance, ease of administration, accurate dosing, cost effective manufacturing and generally improved shelf life of the product. Even for sustained release system the oral route of administration has been investigated the most, because of flexibility in dosage forms design that the oral route offers2. The bilayer tablet is innovative drug delivery system. This is novel type of dosage form for oral administration which is composed of one fast release layer and one sustain release layer. Layered tablet concept is utilized to develop controlled and sustained release formulations. Such tablet is considered as biphasic delivery system that is designed to release the drug at two different rates and is usually composed of a fast release layer and sustain release layer. Conventional sustain release dosage form delay the release of drugs and do not provide the rapid onset of action after oral administration. Hence this layer tablet offer a pharmacokinetic advantage over conventional dosage forms as the drug is released quickly from the fast layer leading to the rapid raise in drug plasma concentration followed by continuation of drug release from the sustain-release layer. This release pattern is required for successful treatment in many therapies, Primarily when maximum relief needs to be achieved as soon as possible and is followed by a sustained released phase to avoid repeated drug administrated. The term Bilayer tablet refers to tablet containing subunits that may either the same or different. Bilayer tablets allow for designing and modulating dissolution and release characteristics and they are prepared with one layer of drug for immediate release. The second layer designed to release drug later3.
ADVANTAGES OF SUSTAINED RELEASE DRUG:
1.Improved patient compliance.
2.Reduction in frequency of drug administration.
3.Reduction in drug toxicity Decreases drug level fluctuation in blood.
4.Decreases drug accumulation with chronic therapy.
5.Stabilization of medical condition since drug level is uniform.
6.Economical to health care provide and patient.
ACECLOFENAC:
Aceclofenac is an orally administered potent analgesic and anti-inflammatory activities. and its phenyl acetic acid derivative, Due to its preferential COX-2 blockade it has better safety than conventional NSAIDs (mainly diclofenac) with respect to adverse effect on gastrointestinal and cardiovascular system. The mode of action of aceclofenac is largely based on inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase which is involved in the production of the prostaglandins. In patients with osteoarthritis of the knee, Aceclofenac decrease pain, reduces disease severity and improves the functional capacity of the knee. It reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis. The duration of morning stiffness and pain intensity are reduced by aceclofenac in patients4.
ALLOPURINOL:
Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid. Unlike uricosuric agents, which increase the urinary excretion of uric acid, allopurinol interferes with the catabolism of purines. Thus the concentrations of uric acid in the blood and urine is decreased. In addition, secondary to elevated concentrations of oxypurine, allopurinol indirectly inhibits purine biosynthesis by stimulating negative feedback. Oxypurinol, an allopurinol metabolite, also inhibits xanthine oxidase.It also facilitates the incorporation of hypoxanthine and xanthine into DNA and RNA, resulting in further reductions of serum uric acid concentration5.
Hence, by considering severe joint pain, increased concentration of uric acid in blood plasma and joint, shorter half life of NSAIDs and dosing frequency, the present study is aimed in the development and evaluation of bilayer sustain release tablets of aceclofenac and allopurinol for the treatment of gouty arthritis.
6.2
/ REVIEW OF LITERATURE:
· A research was done on metformin HCL SR 1000 mg and pioglitazone HCL15 mg in the form of bilayer sustains release matrix tablets by Satish Kumar, et al., They prepared the tablets by using sodium carboxy methyl cellulose (SCMC) and hydroxy propyl methyl cellulose (HPMC K4M and HPMC 15cps) as bio-adhesive polymers and cross carmellose sodium to act as an impermeable backing layer. They concluded that bilayer tablets of Pioglitazone HCL and Metformin HCL can be a good way to extend metabolism and to improve the bioavailability of Pioglitazone HCL and Metformin HCL6.
· Ashish Anand, et al., developed a bilayer sustained release tablet of Isosorbide- mononitrate which is an anti-anginal organic nitrate vasodilator. They prepared these tablets by wet granulation method. They used Hydrophilic and hydrophobic matrix materials such as hydroxy propyl methylcellulose, and polyox, which can release the drug up to 24 hrs in predetermined rate and used the PVP K-30 as binder. They finally reported influence of hydrophilic and hydrophobic polymer and granulation technique7.
· A researchwork was done by Nagaraju R and his co-workers on Salbutamol and theophylline which are available in conventional dosage forms, administered four times a day, leading to saw tooth kinetics and resulting in ineffective therapy. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong bronchodilation. They studied about various polymers, such as hydroxylpropylmethylcellulose K4M (HPMC- K4M), hydroxy propyl methylcellulose K100M (HPMC- K100M), xanthan gum, ethyl cellulose and hydroxy propyl methylcellulose phthalate (HPMC-P) and finally they found that HPMC-P and HPMC- K4M were best polymer in controlling the release of the drug
· Chitra K S, et al., developed aceclofenac sodium using super disintegrant, sodium starch glycolate for the fast release layer and water immiscible polymers such as Eudragit RL100 for the sustaining layer. They conducted FT-IR studies and concluded that there was no interaction between the drug and polymers. Finally it was reported that the drug released from F5 Formulation followed the zero order kinetics9.
· Bilayer tablets of propanolol hydrochloride were formed by Prasanthi N.L, et al., by using xanthan gum, locust bean gum and guar gum with different drug: gum ratios of 1:0.25, 1:0.5 and 1:1 by wet granulation method. They used sodium starch glycolate for immediate release layer. Sustained release layer was prepared by using gums in different drug to gum ratio. It was found the drug content of the formulations within 98.9‐101.7%. The release of propanolol hydrochloride was extended up to 12 hrs and was dependent upon the concentration of the gum. Finally they concluded that the release was better sustained with xanthan gum at the concentration of 1:110.
· Rajeev Shankar M and co-authers reported on the invention related to a bilayer tablet comprising: a slow releasing layer comprising niacin and a release retarding agent; and an immediate release layer comprising HMG-CoA reductase inhibitor11.
· Maheswara Reddy A, et al., patented on the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of hydrochlorthiazide from a dissolving matrix to treat hypertension12.
· Nagori SA, et al., conducted immidiate release of paracetamol and slower release of diclofenac sodium from bilayer tablets. They adopted a factorial design by using the polyethylene glycol (PEG), microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The invitrodrug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bilayer tablets. They finally reported that bilayer tablets showed immediate release of paracetamol and modified release of diclofenac13.
· Sustained release matrix tablets of flutamide were developed by Jaber, et al., These were prepared by direct compression method using different polymers. They taken cellulose ethers (HPMC and Na CMC), natural gums (guar and xanthan gums), compressible Eudragits (RSPO and RLPO) and their combinations in different ratios to examine their influence on tablet properties and drug release profile. A suitable sustained release dosage form should release its content within 8-10 hrs. In this series, formulation containing 25% of HPMC, released about 70% of flutamidein 8 hrs and this could be considered as a sustained release formulation. This formulation could release more than 90% of its content within 10 hrs. They concluded that the rate and amount of drug release is inversely proportional to the HPMC percentage in formulations14.
· Namath ulla, et al., formulated and evaluated sustained release matrix tablets of lornoxicam. Lornoxicam has a shorter half life. Due to its acidic nature, its release from sustained release delivery system is limited to the lower gastro intestinal tract, consequently leads to a delayed onset of analgesic action. So they developedlornaxicam sustained release matrix tablets to provide complete drug release that starts in stomach and maintains its analgesic effect15.
· Arunachalam A, et al., on Metoprolol Succinate and Telmisartan which are available in conventional dosage forms, administered in a day, leading to saw tooth kinetics and resulting in ineffective therapy. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong cardiovascular system. They studied about various polymers, such as hydroxy propyl methylcellulose K4M (HPMC- K4M), hydroxy propyl methylcellulose K100M (HPMC- K100M), MCC pH102, Lactose DCL 11, Bronopol and they found that the HPMC- K4M was best in controlling the release. They carried out invitro dissolution studies for all the bi-layered tablets. The tablets were prepared by Direct Compression method16.
· Shiyani B, et al., on bilayer tablet of Metoclopramide Hydrochloride and Ibuprofen for the effective treatment of migraine. They formulated MTH and IB for immediate and sustained release layer respectively. They used various disintegrants like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum for immediate release of MTH. They prepared treated form of gellan gum and agar; and compared their disintegrant efficiency with other disintegrants. They used hydrophilic matrix (hydroxypropylmethylcellulose (HPMC K4M) to form sustained release layer of ibuprofen. They studied the effect of concentration of hydrophilic matrix (HPMC K4M), binder (polyvinylpyrollidone ( PVP K30) and buffer (sodium bicarbonate) on the release rate of ibuprofen. The dissolution study of sustained release layer showed that an increasing amount of HPMC or PVP K30 results in reduced ibuprofen release17.
· Chinam NP, et al., researched on sustained release bilayer tablets of propranolol hydrochloride. They developed a bilayer tablet of propranolol hydrochloride using superdisintegrant sodium starch glycolate for the fast release layer and water immiscible They used polymers such as ethylcellulose, Eudragit RLPO and Eudragit RSPO for the sustaining layer and finally they concluded that there was no significant difference in the cumulative amount of drug release after 15 min, but significant difference in the amount of drug released after 12 h from optimized formulations was observed18.
· Afser C S, et al., formulated and evaluated sustained release tablets of aceclofenac by wet granulation method. They used hydrophilic polymer like Hydroxy propyl methyl cellulose K ‐100 in the formulation. The drug excipient mixtures were subjected to preformulation studies. They also performed physicochemical studies, in vitro drug release, kinetic studies and stability studies and FTIR studies. The physicochemical properties of tablets were found within the limits. The drug release from optimized formulations was extended for a period of 24 hrs19.
· Rajendran N.N, et al., formulated and evaluated sustained release bilayer tablets of metformin HCL and pioglitazone HCL present. They conducted the study to establish bilayer tablets containing Metformin HCL as sustained release and Pioglitazone HCL as immediate release layer.Sustained layer were prepared by wet granulation method using different viscosity grade of HPMC (HPMC K4M & HPMC K100M) as polymers and immediate release layer were prepared by direct compression method using superdisintegrants such as sodium starch glycolate and crosscarmellose sodium. In vitro releasestudies were carried out by USP type‐2 paddle apparatus. Finally it was reported that combinations of polymers namely HPMC K100M and HPMC K4M in sustained layer can control the release of drug20.
· Jain Jitendra, et al., formulated and evaluated indomethacin bilayer sustained release tablets to develop a bilayer floating tablet for Indomethacin using direct compression technology. Bilayer tablets were punched using HPMC K4M,Avicel pH-112, magnesium stearate and aerosil in fast release layer and optimized floating layer as sustained release layer. Tablets were evaluated for physico-Chemical properties such as hardness, friability, thickness, weight variation and drug content uniformity. Invitro dissolution studies were carried out in a USP type II Paddle type apparatus21.