Development Of Compound Of Captopril Pulsed Sustained-Release Capsule

Captopril (Captopril,.CAP) is the first generation of angiotensin converting enzyme inhibitors.and the first treatment choice of high blood pressure and congestive heart failure.Anti-hypertensie mainly by inhibiting the angiotensin I invertase which around and organization, inhibit the inactive of AT I into shrinkage vascular activity ATâ…¡, inable the function of shrinkage vascular; At the same time slow the hydrolysis, of hock peptide (easy exciting respiratory) ,leading to vasodilation and the blood olume reduction,exert its step-down the blood pressure and protective effect.on the cardiovascular.Hydrochlorothiazide (Hydrochlorothiazide,HCTZ) is the thiazide diuretics. Generally speaking its buck mechanism in the early time is through the platoon sodium diuresis cause body making Na⁺ and water in negative balance, make extracellular fluid and blood olume reduction, while for a long time,mechanism is platoon sodium, making Na⁺which inside the cell reduce while the exchange between Na⁺ and Ca 2+ reduce too, and Ca²⁺which in intracellular the hemal wall smooth muscle expansion, Meanwhile endovascular Ca²⁺ decrease in vascular smooth muscle contraction material such as norepinephrine etc, abate the effect.Of shrinkage vascular.The above two drugs coupled can develop good synergy, hydrochlorothiazide can restrain the compensatory sex fight step-down ACEI, captopril antagonism mechanism can be caused by diuresis medicine the hypokalemia, high uric acid and secondary sympathetic renin-angiotensin-aldosterone system (RASS) excited, make the adverse reactions don't happen, could remarkably reduce the peripheral ascular resistance, increase urinary sodium excretion, good curative effect, the two drugs coupled high safety.With the development of time biology and hour pharmacology,show that many outbreak are presenting Circadian variation.This put forward new requirements to drug preparation research i.e. drug release should be able to comply with disease,Disease onset of rhythmic, through on-demand dosing to achieve the best effection. While hypertension is a typical day and night Rhythmic cardioascular disease, its the highest frequency attackion hours are in the morning, so need to undertake Hour treatment. Therefore, the experiments choose CAP and HCTZ for model and developed the compound Captopril and hydrochlorothiazide pulsed sustained-release capsule (namely CAP - HCTZ), this preparation was made up of hydrochlorothiazide sustained-release pellets and Captopril pulsed sustained-release pellets, suitable for night before sleeping pills interval "time lag" the morning after release drugs.We choose HPLC to established a method that can analysis the two drugs once in vitro and in vivo. Using liquid-liquid extraction treatment deal with the plasma samples, , the results indicate that the method is simple and feasible, sensitive and accurate, and can satisfy body analysis request.With the mini Glatt fluidized-bed coating to Prepare cappulse pellets and HCTZ sustained-release pellets, Sustained-release pellets structure from inside to outside is : microcrystalline cellulose blank pill cores, medicated layer, slow-releasing layer, by single-factor test to determine the release of the influence on three factors, by orthogonal design optimization prescription, selects the best prescription for weight slow-release layer gain for10% , pore agent lactose dosage for 1.5% (polymer 1.5%), post-treatment time for 12h; Pulse pellets structure by in to outside for: sucrose blank pill cores, medicated layer, swelling layer, controlled-release layer, According factor investigation results cognizance slow-release layer weight gain,controlled-release layer weight gain and controlled release layer death-cause in hole agent directly influence the lag time and when to release, through CCD to choose the best prescription optimization prescription process for swelling layer, increase weight 16.20% controlled-release layer 22.84%, send pore weight gain 5.52% agent, finally will gain reasonable garment membrane gained weight with the component reaches release requirements of two kinds of pellets by administration dosage fill in capsule, release conditions mainly inspects the dissloution medium pH value and turn basket speed etc, the results showed that the release conditions of this impulse micro pill in vitro release little impact. This product in vitro release effect ideal, and simple process maturity, easy to realize industrialization production. This paper also adopt various mathematical model in compound CAP-HCTZ pulse slow-release micro pill in vitro release characteristics by fitting and comparing, optimum fitting model level equation.Preliminary stability study shows that, the compound capsule on humidity has certain sensitivity, easy absorption of moisture, therefore packaging and storage need moistureproof. Accelerated testing and long-term stability test results show that the preparation is good, the colour and lustre of pellets, relevant material, content and release degrees indices such as no change.Carrying out the pharmacokinetics study of compound CAP - HCTZ pulsed sustained-release pellets on rats,and use DAS2.0 software calculated the pharmacokinetic parameters, the results show that the compound preparations in rats in vivo accord with single room model absorption process, and compound level compared with ordinary preparations ,compound preparations pellets has an obvious slow-releasing performance and lag time 4.75h , and improve the bioavailability, through in vivo-vitro correlation, compound preparations have good correlation, We can use drug delivering parameter in vitro prediction in vivo drug dynamic rule, the future enterprise industrialized production control sustained-release micro pill preparations of significance.To sum up, the compound Captopril pulsed sustained-release capsules can be taken before sleeping in the evening, after about 5h around reach peak, effectively avoid blood pressure sharply caused the occurrence of such as cerebral apoplexy, realized the timing drug delivering effect, accord with hour pharmacology theory; The preparation also reduced the number of drug, by ordinary sheets of every 3-4 times every day improve the patient compliance, reached the topic design requirements.