Studies On L-Dopa Floating And Pulsatile Capsule

Time-controlled pulsatile release system, which is called intelligent drug delivery system too, is capable of releasing drug after pre-determined time to address clinically therapeutic requirements. It is used to treat rhythm diseases.Parkinson's disease(PD), which is called agitans paralysis too, is the most common neurodegenerative movement disorder beside Alzheimer disease in the meddle and old-aged. The motor dysfunction caused by PD has a great impact on the life quality of patients and bring heavy burden to society and family life. Levodopa (L-dopa) is the most active drug during the treatment of PD and PD syndrome. However, the PD patients always have serious morning stiffness with the progress of disease during using traditional L-dopa preparation. The existing therapeutic regimens are not fit for chronopharmacology due to failure of consideration of temporal rhythm of morning stiffness. The compliance of patients is bad because of the high dose and more adverse effects of these administrations. Therefore, it is necessary to develop a delivery system fitted for temporal rhythm of PD.The study develop the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. The L-dopa releases next morning after 7 hours and leads to effect quickly after the PD patients taking this capsule before sleep. This capsule is used to improve morning stiffness, raise bioavailability and reduce dose of L-dopa. It is important for treating PD and PD syndrome.PartⅠThe principle of the L-dopa floating and pulsatile capsule and the work of preformulation1. This study develops the L-dopa floating and pulsatile capsule connecting to erosion time-controlled pulsatile capsule technique, stomach floating technique and hydrostatic pressure principle on the basis of chronophysiology, chronopharmacology and chronotherapeutics. This capsule is composed of impermeable capsule body, erodible plugs, fast-released L-dopa tablets, effervesce filling granules and soluble gelatin cap.2. The ultraviolet absorption maximum of L-Dopa was 280nm in 0.1mol·L-1 hydrochloric acid solution, PBS (pH6.8) and ultrapure water. Establishing the assaying methods in 0.1mol·L-1 hydrochloric acid solution, PBS(pH6.8), ultrapure water by ultraviolet spectrophotometry. The calibration curves were liner ranging from 1 to 60μg·ml-1. The regression equations were: A=0.0166+0.0140C (r=0.99992), A=0.0017 +0.0158C (r=0.99965), A=0.0007+0.0136C (r=0.99990).PartⅡThe preparation of L-dopa floating and pulsatile capsule1. This study used the optimized formulation to prepare EC capsule with ethylcellulose and solvent of dichlormethane/dehydrated alcohol/acetic ether. The EC capsule was well forming, regular, transparent, clean, no abnormal flavour, well hardness and tenacity.2. L-Dopa is used as a model drug and lactose as bulking agent. The optimized formulation was selected by single factor experiment with evaluation index of disintegration time, angle of repose, hardness and friability. The fast-released L-dopa tablets were prepared by direct compression after mixing in self-made blender with optimized formulation which composed of drug(50% L-dopa), bulking agent(25.75% lactose), binding agent(20% MCC), disintegrating agent(3% cCMC-Na), lubricant/ glidant (0.25% magnesium stearate / 1% Silicon dioxide). The fast-released tablets were consistent with the requirement of CP on appearance, hardness, friability, disintegration time, weight variation.3. The effervesce filling granules were prepared by nonaqueous granulating method with citric acid, lactose, NaHCO3 and binding agent(10%PVP ethyl alcohol solution). The tests of dissolubility and appearance were consistent with the requirement of CP.4. The erodible plugs were prepared by direct compression with HPMC-E50 and lactose. The effect of HPMC dosage on the lag time of the floating and pulsatile capsule was investigated. The result indicates that the lag time was lengthened with the increase of HPMC dosage. Formula 4 and5 were selected to enter next experiment.PartⅢStudy on release of L-dopa floating and pulsatile capsule in vitro1. The lag time of erodible plugs of formula 4 and 5 at different paddle speed (50 and 100r/min) were studied by dissolution method. The release medium was 900ml simulated gastric fluid and the temperature was 37℃±0.5℃. The lag time of formula 4 at 50 and 100r/min were (389±20) min and (252±18) min. The lag time of formula 5 was (438±18) min and (281±15) min. The result indicates that the lag time of L-dopa floating and pulsatile capsule was shortened with increase of paddle speed.2. The effect of viscosity of the release medium on lag time was investigated by dissolution method. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M or not. The temperature was 37℃±0.5℃and the paddle speed was 50r/min. The result shows that the lag time of formula 4 and 5 in simulated gastric fluid and simulated gastric fluid with 1%HPMC-K4M was (389±20),(428±16),(437±18) and (491±24) min. This indicates that the lag time of L-dopa floating and pulsatile capsule was lengthened with increase of viscosity. The lag time in simulated gastric fluid with 1%HPMC-K4M approaches to time in vivo.3. The improved release method of L-dopa floating and pulsatile capsule was established by dissolution apparatus. The release medium was 900mL simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃.4. The effects of effervesce filling granules and lactose filling granules on the lag time were investigated by release testing. The result indicates effervesce filling granules can elevate the release rate of fast-released L-dopa tablets significantly.5. The erosion behavior of erodible plugs in L-dopa floating and pulsatile capsule was investigated using dissolution apparatus. The release medium was 900ml simulated gastric fluid with 1%HPMC-K4M. The paddle speed was 50r/min and the temperature was 37℃±0.5℃. The mathematical model by erosion remaining percentage was established as Peppas equations(0.45