| Objectives: m-Nisoldipine(m-Nis), a new isomer of nisoldipine(nis), is one of dihydropyridines calcium antagonists(DHP-CaA), being first developed by Department of Organic Chemistry, Hebei Medical University. Its main pharmacological action lies in suppresses the calcium ion to enter may the excitatory cells, selectively causes the circumference blood vessel and the crown arteries blood vessel's expansion, does not have the influence to the cardiac muscle shrinkage force and the heart conduction system. Mainly uses in treating coronary disease, the angina pectoris, hypertension and the chronic congested heart failure and the heart source shock. Pharmacology experiment showed: m-Nis was more stable than nis to light and it was ultralente, prompt and powerful. According to m-Nis's pre-preparation research, it is stable in acid medium. In order to increase m-Nis's in vivo absorption, steady the drug concentration in blood, reduce its adverse effects, and enhance its bioavailability, the intragastric floating sustained-release tablet was prepared with HPMC hydrophilic matrix. It will provide a potential sustained-release dosege form for m-Nis's clinical research and application. Methods: On the basis of scientific materials and the pre-preparation investigation, we select HPMC as the hydrophilic matrix, add PEG-6000 as the porogeneous compound, stearic acid and stearylalcohol as the retarder, and NaHCO3 as the gas-generating agent in the formulation. Considering the release properties and floating ability of the tablet, We carried through monofactorial investigations. After choosing suitable preparation technics, we use L9(34) orthogonal design to select the optimum formulation in terms of the floating capabilities and in vitro accumulative release percentage.Paddle agitation was used in the experiment of in vitro release test. The release test is carried out in simulated gastric fluid HCL(9→1000) with rotation rate 100r·min-1 at temperature (37±0.5)℃. Samples were withdrawn periodically at 2, 4, 6, 8, 10, 12h from the release medium, replensihed with the same volume of fresh medium each time, and then analyzed and determined for their drug contents at 237nm by ultraviolet spectrophotometer. The conventional m-Nis tablet was studied by the same means. Three batches of m-Nis-HBS were prepared and studied through release experiment to investigate the stability of formulation and technics. The release data were analyzed with three models: Higuchi equation, zero order kinetics, and first order kinetics. We studied the stability of m-Nis-HBS under following circumstances: high humidities, high temperature, strong light and natural store condition. To elucidate the mechanism of drug release we used Peppas equation to analyze the release data. Its floating properties was invertigated in (37±0.5)℃0.1molL-1HCL under 100r·min-1 paddle agitation.In vivo study: The intragastric residence experiment was carried in Beagle dogs. The release properties in vivo were investigated as following: 6 Beagle dogs were divided into two groups. One was given m-Nis-HBS, and the other group was given the conventional tablet. Plasma samples were obtained at different time after the administration. The plasma concentration of m-Nis was determined by High performance Liquid Chromatograph(HPLC) with Ultraviolet detector.Results: Through the L9(34) orthogonal design, the optimum formulation was founded: A2B2C1D1, that is: HPMC(A) 35mg stearic acid-PEG-6000(B)-m-Nis(15:10:5)SD 30mg stearyl alcohol(C) 10mg NaHCO3(D) 10mg Lactose 15mgThe factors influence the tablet's release and floating properties as following turn: C>A>B>D. Three batches HBS tablets were prepared according to the optimum formulation. The release data were analyzed with three models: Higuchi equation, zero and first order kinetics, the regression equations: Q=7.6486t+9.16, r=0.9909 Q=37.857t1/2-33.952, r=0.9966 lnQ=0.1456t+3.0022, r=0.9536 The results showed that m-Nis-HBS conformed to Higuchi equation better than the other two models. The drug release mechanism was non-Fick's diffusion, that was concurrence of the matrix's dissolution and the drug's diffusion. The HBS tablet was sensitive to high humidity, high temperature and strong light. The recoveries of equivalent 80%, 100%, 120% of the optimum formula were (99.85±0.23)%, (100.1±0.41)%, (99.91±0.24)% respectively. The contents of three batches of m-Nis-HBS tablet were (102.6±0.25)%, (101.1±0.56)%, (99.60±0.62)% (n=3). The content uniformity of the three batches optimum formula were within the stated range(n=10). Buoyancy test: the HBS tablet can set on floating within three minutes and maintain floating for more than twelve hours in each condition above. While the conventional tablet dissolved in less than three minutes and subsidised.The result of the pharmacokinetics in Beagle dogs shows that m-Nis-HBS and the conventional tablet both conformed to one compartment model. Pharmacokinetics parameters of m-Nis-HBS and m-Nis conventional tablet were respectively as following: T1/2Ka(h):1.509±0.1001,0.7684±0.1658 T1/2Ke(h):7.794±1.800,3.447±1.185 Tmax(h):5.854±0.5077,2.213±0.3225 Cmax(ng·ml-1):79.40±10.60,116.7±20.35 AUC(ng·ml-1)·h:1315±296.0,867.8±146.7 MRT(h):12.86±1.896,5.640±1.309 The result of t-test showed significant difference between the parameters T1/2(Ka), Tmax, Cmax, AUC and MRT of the two groups(P<0.05). The relative bioavailability of m-Nis-HBS and m-Nis conventional tablet is 156.2%. The vitro release percentage and the vivo absorption percentage showed significant correlation, the regression equation was: Fa=0.8777Fr-7.486, r=0.9928.Conclusions: Through the release experiment in vitro and pharmacokinetics study in Beagle dogs, we know that the m-Nis-HBS tablet showed obvious sustained-release properties in both vitro and vivo, it will provide a potentially promising preparation for the clinical research and applications of m-Nisoldipine. |
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