ADITYA BANGALORE INSTITUTE OF PHARMACY EDUCATION AND RESEARCH BANGALORE
PROTOCOL FOR M.PHARM DISSERTATION WORK
2012-13
1. / Name of the Candidate / Srinivasa rao.chintapalli
2. / Name of the Department / Pharmaceutics
3. / Registration Number
4. / Date of Submission of Protocol
5. / Name of the Guide & Designation
6. / Title of the Dissertation Topic / FORMULATION & EVALUATION OF DIVALPROEX SODIUM E.R. TABLETS.
7 / Brief resume of the intended work
7.1 Need for the study
Divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).
The efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania.
The safety and effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex sodium extended-release tablets for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient.
Divalproex sodium extended-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate).
Divalproex sodium, USP occurs as a white crystalline powder with a characteristic odor.
Divalproex sodium extended-release 250 mg and 500 mg tablets are for oral administration. Divalproex sodium extended-release tablets contain divalproex sodium in a once-a-day extended-release formulation equivalent to 250 mg or 500 mg of valproic acid.
7.2 Review of literature
Controlled release technology is relatively a new field and as a consequence research in this field has been extremely fertile and has produced many discoveries. New and more sophisticated sustained release drug delivery systems are constantly being developed and tested. Successful fabrication of sustained release products is usually difficult and involves consideration of the physicochemical properties of the drug, pharmacokinetic behavior of the drug, and route of administration, diseased state to be treated and most importantly placement of the drug in a dosage form that will provide the desired temporal and spatial delivery pattern for the drug.
There are literally dozens of names associated with sustained release products such as continuous release, controlled release, delayed release, delayed action, depot, extended action, gradual release, long acting, long lasting, long‐term release, prolonged release, repository retard, slow acting, slow release, time coat, sustained release, sustained action, timed disintegration, timed release ctc..
Spatial placement relates to the targeting of the drug to a specific organ or tissue while temporal delivery refers to controlling the rate of the drug delivery to the target tissue. An appropriately designed drug delivery system can be a major step towards solving these two problems. This technique for the drug administration is termed as ‘sustained release’ or ‘controlled release3. Drugs with dosage not exceeding 125mg – 325mg are more suited as extended release products in order to limit the size of the delivery system.
In the case of soluble matrix the matrix swells or dissolves. These matrices then undergo surface erosion with little or no bulk erosion. The surface area of the matrix decreases with time, with a concomitant decrease in drug release. The diffusion depends on the solubility of the drug in the polymer. The drug release mechanism across the membrane involves diffusion of water through the membrane to the inside of the core, dissolution of the drug and then diffusion of the drug into the surrounding fluid.
In reservoir dissolution control system the drug particles are coated or encapsulated by one of the several micro encapsulation techniques with slowly dissolving materials like cellulose derivatives, poly ethylene glycols, waxes etc., the resulting reservoirs may be filled as such in hard gelatin capsules or compressed into tablet. Oral osmotic pump, popularly called as OROS works with the principle of osmotic pressure to release the drug at a constant rate. The rate of release of drug in these products is determined by the
constant inflow of water across a semi permeable membrane into a reservoir, which contains an osmotic agent. The hydrophilic gel forming matrix tablets are extensively used for oral extended release dosage forms due to their simplicity, cost effectiveness and reduction of the risk of systemic toxicity due to dose dumping .Epilepsy is a common chronic neurological disorder that is characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain.
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of Gamma‐Amino Butyric Acid (GABA). The absolute bioavailability of Divalproate ER tablets administered a single dose after a meal was approximately 90% relative to intravenous infusion. Formulation of Divalproex sodium ER tablets expected to reduce Divalproex sodium ER is used by patient for treatment of chronic epilepsy. So reduces the frequent administration of dose (twice in a day), avoids first pass metabolism, improved patient compliance, maintain therapeutic action by administration of a single dose in a day.
7.3 Objectives of the study
· To carry out pre-formulation studies of a drug & compatibility studies of drug & excipients by FT-IR & DSC studies.
· To carry out Evaluation of granules.
· To carry out Drug release kinetics.
· To carry out in vitro dissolution studies.
· To carry out the dissolution profiles of formulated tablets with the marketed products.
· To carry out stability studies on an optimized formulation as per ICH guidelines.
8. / Materials and Methods
Drugs:
Divalproex Sodium
Materials
Polymers: H.P.M.C. K 100M, H.P.M.C. K4M, Maltose 90SH4000 SR, POVIDONE K30, AVICEL PH-102, STARCH, LACTOSE, AEROSIL.
Glidants: Magnesium stearate, talc,
Solvents: Isopropyl Alcohol,Methylenechloride.
METHOD:
· Direct compression method
Sifting
Drymixing
Lubrication
Compression
Film coating
Evaluation of Divalproex Sodium E.R Tablets:
Hardness
Friability
Thickness
Weight variation
Buoyancy properties
Drug content
In vitro drug release
Short term stability studies.
9. / Proposed Plan of Work
Jun – July 2012
· Review of literature
Aug - Sep 2012
· Procurement of drug and other excipients
· Preformulation and compatibility studies
Oct - Nov 2012
· To formulate and evaluate swellable floating matrix tablets and hollow microspheres
Dec – Jan 2013
· To characterize prepared formulations by FT-IR, SEM, DSC and XRD studies
· To carry out in vitro drug release studies
Feb – Apr 2013
· Short term stability studies
10. / References
1. Lee VH, Robinson JR. Sustained and controlled release drug delivery system.
New York: Marcel Dekker; 1978. p. 71 ]121.
2. Ballard BE. Prolonged action pharmaceuticals. Pennsylvania:
Mack publishing company; 1980.
3. Donald LW. Bioploymeric controlled release system. USA:
CRS Press Inc; Vol I, 1984.
4. Jain NK. Controlled and novel drug delivery. 1sted. New delhi:
CBS publishers; 2002. p.1 ]26.
5. Aulton ME, Wells TI. Pharmaceutics: The Science of Dosage
Form Design. 2nd ed; 2002.
6. Biju. Dual coated erodible microcapsules for modified release of
diclofenac sodium. Eur. J. Pharm. Biopharm 2004; May;58(1): 61 ]67.
7. Kuksal A. Formulation and in vitro, in vivo evaluation of extended release
Matrix tablets of zidovudine: influence of combination of hydrophilic
And hydrophobic matrix formers.AAPS PharmSci Tech 2006; 7(1).
8. Gao PR, Meury H. Swelling of hydroxypropylmethylcellulose
matrix tablet. Part ]II.
9. Commission on Epidemiology and Prognosis, International League
Against Epilepsy "Guidelines for epidemiologic studieson epilepsy.
Commission on Epidemiology and Prognosis, International League
against Epilepsy". Epilepsia 1993; 34 (4):592.596.
10. James MA, Sung Wankim. Advances in drug delivery systems.
Controlled release series. New York: Elsevier, 1980.
11. Branmankar M, Sunil BJ. Biopharmaceutics and Pharmacokinetics.
Vallabai Publication: New Delhi: 1985, 326.
12. Chien YW. Rate controlled drug delivery systems. 2nd ed.
New York: Marcel Dekker; 2005.
13. Gomez AD. Role of water ]uptake on tablet disintegration:design of
improved method for penetration measurements.Acta Helv 1986; 61(1): 22 ]9.
14. Higuchi T. Mechanism of sustained action medication.Theoretical analysis of
Rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci 1963;
(52): 1145 ]9
15. Guidelines for the design and evaluation of prolonged
releasedosage forms.Ministry of Health and Welfare: Japan; March 11,
11. / Signature of the Candidate
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Classification: Confidential