Development of controlled release dosage forms of levodopa and benserazide and studies on dissolution tests and analysis of the commercial dosage forms of these drugs

I. SUMMARYThe formation reason of Parkinson disease is the lack ofdopamin in central nervous system in brain. Levodopa-benserazidecombination in dosage forms are widely used for semptomatic medicationof Parkinson?s disease.Floating dosage forms in stomach should be preferedbecause of the degradation of benserazide by oxydation and the increaseof oxydation rate of higher pH.Innovator firm Roche developped Madopar HBS capsuleswhich is a lipid matrix type dosage form. We tried to develop a controlledrelease dosage form of which release mechanism was osmotic pump withdrug and a polimer matris of which density is lower than that of water.Thus drug reservuar matris is covered by a rate limiting membrane withanother type of Evac (Elvax 350). A hole of which diameter is 0,6 mm andthe height is the 2/3 of matris height was opened at the upper side of themembrane covered matris.The F7 formulation of which matris consist of 14 % of Elvax210, 1 % of ascorbic acid, 85 % of the mixture of levodopa : benserazid (4: 1) was found to be most satisfactory of all the formulations we prepared.The relese kinetics of levodopa and benserazid in this dosage form wasobeyed to zero-order release kinetics.But the release rate of levodopa was found to be lower thanthat of calculated target profile.In the case of Madopar 125 mg x 2 capsules, the releaserate of benserazide was found to be higher than that of levodopa and therelease rate of levodopa was higher than that of calculated taget profileand that of F7.The release kinetics of levodopa and benserazid in F7 fitsthe matris kinetics. The most important problem in quantitative analysis ofbenserazide was the degredation by oxydation in the analyse mediumduring analysis. Following procedure were applied for the prevention ofoxydation during analysis:- Use of low pH analyse medium (simulated gastric juice,SGJ). Because the higher the pH the higher the rate of oxydation wastaken place.- Deairation of the analyse medium and dissolution medium- Prevention of katalysis effect of the light on the oxydationby working in dark and in red light.- Argon gas, an inert gas of which density is higher than thatof air was transfered to the analyse media and dissolution media forprevention of air contact to the media.- In the case of dissolution test of conventional tablets,Madopar 125 mg tablet and Madopar 250 mg tablet argon gas passedthrough the dissolution medium for one minute in every 30 minutes.- In the case of release tests of controlled releasepreparations Madopar HBS and F7 argon gas passed through thedissolution medium for one minute in every 10 minutes.- Release tests of designed floating dosage form in stomach,F7, 1,47 mg of ascorbic acid was added to the formulation and the samequantity of ascorbic acid (1,47 mg) was added to the dissolutionmedium(SGJ) in order to prevent oxydation of benserazide.- In the case of Madopar HBS commercial floating dosageform in stomach, 2,94 mg of ascorbic acid was added to dissolutionmedium(SGJ) for the same purpose.The effect of argon gas and ascorbic acid on the stability ofbenserazide was ivestigated release medium (SGJ) for 12 hours. In caseof argon gas transfer for 1 minutes in every 10 minutes, the result ofrelease can be acceptable but for a time longer than 4 hours the result ofrelease analysis can not be acceptable in this case 2,94 mg ascorbic acidmust be added to the medium. In the presence of ascorbic acid only 1 %of benserazide degredaded with in 12 hours. In case of levodopa, to benot degredaded in deaireted SGJ after passing for 1 minute for every 30minutes. Another purpose of our study was to develop on HPLC methodwith UV dedector instead of HPLC method with electrochemical dedector.HPLC coloumn was reverse phase C18, 5 µm, 4,6 x 250 mmand mobil phase was SGJ. The release tests of Madopar and F7 werecarried out by this HPLC method successfully.In the case of conventional dosage form Madopar 125 mgand Madopar 250 mg tablets, quantitative analyse of tablets and analysein dissolution tests were carried out by chemometric methods by usingcomputer aided spectrophotometer with UV Probe software. A training setof 40 solutions containing levodopa and benserazide in the concentrationrange of 0,0-80,0 µg/mL for levodopa and 0,0-250,0 µg/mL forbenserazide was prepared in SGJ. An independent set of 20 binarymixtures with various known concentrations was also prepared in SGJ asthe validation set. The sample of the solution were scanned in the range of250 nm-350 nm in the spectrophotometer and spectrum of the solutionsevery concentration were recorded to the computer by Matlab 7.0, PLStoolbox 3,5 and Excel software. Chemometric methods Classical LeastSquares(CLS), Partial Least Squares (PLS1, PLS2) and PartialComponent Regression (PCR) were applied for the quantitative analyseof the drugs and validation tests were performed. Validation test bystandart addition showed that tablets excipients were not were effective onthe analyse results. Dissolution profiles of Madopar 125 mg and Madopar250 mg were evaluated by this chemometric methods. Dissolution resultsshowed that 75 % of drugs dissolved within 30 minutes.