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Objective: between nisoldipine (m-Nisoldipine, m-Nis) is the first synthesis of Hebei Medical University, the national drug belonging to dihydropyridine calcium antagonists, as nisoldipine of isomers. Main pharmacological effects that inhibit calcium ions into excitable cells, selectively induced peripheral vascular and coronary vascular dilation, myocardial contractility and cardiac conduction system had no effect. Primarily for the treatment of coronary heart disease, angina, hypertension and chronic congestive heart failure and cardiogenic shock. Pharmacological experiments showed that: between nisoldipine enhanced light stability, and has a long-lasting, quick, powerful features. According to the former prescription drug research shows that it is stable under acidic conditions to afford a gastric floating sustained release tablets, in order to increase drug absorption, stable plasma concentration, reduce the toxic side effects and improved bioavailability for clinical research and provide a promising application of slow-release formulations. Methods: In a large number of documents and on the basis of preliminary experiments, in different proportions of stearic acid and porogen blockers polyethylene glycol -6000 (PEG-6000) and a dispersion having a solid nisoldipine (m -Nis-SD), and the use of differential scanning calorimetry (DSC), to form a solid dispersion authentication. Determine the use of hydroxypropyl methylcellulose (HPMC) is a hydrophilic gel matrix, adding Bleaching agent octadecanol (C18H38O), blowing agent sodium bicarbonate (NaHCO3) and (m-Nis-SD) in order to prepare different conditions intragastric floating sustained release tablet, the tablet floating performance while considering for affecting drug release rate single factor, determine the impact of the stomach Floating drug release formulations of the main factors for the process factors (tablet hardness, dry and wet, adhesives), and the several formulation factors. Select the appropriate preparation to HPMC, polyethylene glycol-6000, stearyl alcohol, sodium bicarbonate four factors and three levels of orthogonal design, evaluation and release tablet floating performance, through poor analysis to determine the optimal prescription form. Between nisoldipine intragastric floating sustained release tablets release determination method, according to the 2005 edition of \ammonium HCL solution (9 → 1000) for the release of medium speed 100r · min-1, temperature (37 ± 0.5) ℃, respectively, in 2,4,6,8,10,12 h sampling 5ml, filtered, then added isothermal volume of blank media, the filtrate obtained, according to the spectrophotometric absorbance was measured at 237nm wavelength A values, calculated according to the standard curve equation drug concentrations obtained between nisoldipine intragastric floating sustained release tablets cumulative release percentage Homemade investigated with France nisoldipine between ordinary tablets dissolution. To optimize the preparation of batches of prescription stomach floating sustained release tablet, to determine the content and release test, inspection preparation process stability and Higuchi release rate data were used to model equations and a zero-order equations were fitted. Will be made between nisoldipine intragastric floating sustained release tablet (m-Nis-HBS) for high temperature, high humidity, and bright light, stability under investigation, and placed under seal natural one month after preparation, respectively, two month, three months and six months of its floating properties and in vitro determination of the cumulative release percentage investigate its stability. Floating Performance Investigation: at (37 ± 0.5) ℃ artificial gastric juice, using the paddle speed 100r · min-1, simulated gastric motility, visits between homemade nisoldipine intragastric floating sustained release tablet morphological changes, drift from the drift time and hold time, and with France nisoldipine visits between conventional tablet floating performance for comparison. In vivo drug release characteristics of Beagle dogs as experimental animals, six divided into two groups (n = 3) of m-Nis-HBS and control common immediate-release tablets pharmacokinetics process at different time points after administration The Beagle dog femoral vein blood samples were taken after pretreatment, the use of simple, rapid and sensitive HPLC determination of plasma concentrations of nisoldipine middle. Results are 3p97 pharmacokinetic program processing, analog concentration - time curve, and the pharmacokinetic parameters were calculated. To Tmax, Cmax and AUC as an index comprehensive evaluation m-Nis-HBS and m-Nis conventional tablets relative bioavailability. Both m-Nis-HBS at different times in vitro release percentage Fr its corresponding time in vivo absorption fraction Fa regression, find the regression line equation and correlation coefficient, m-Nis-HBS investigated in vitro release and absorption in vivo correlation. Results: DSC, proved a nisoldipine as amorphous in a carrier to form a solid dispersion. Preparation of single factor determining process: with 75% ethanol as a binder by wet granulation tabletting Preparation of m-Nis-HBS tablets, the principal factors determining the amount of the prescribed levels. By L9 (34) orthogonal experimental design has been optimized formulation was A2B2C1D1, HPMC35mg, stearic acid - polyethylene glycol-6000 - between nisoldipine (15:10:5) SD30mg, lactose 15mg, octadecanol 10mg, NaHCO310mg , according to the size of the poor shows that the performance of various factors on drug release and floating properties of degree C gt; A gt; B gt; D. Tablets obtained rounded smooth surface, good appearance, hardness 4 ~ 5kg. Prescription swellable HPMC form a gel barrier, prevent internal tablet core further hydration, controlled drug release; stearate and PEG-6000 as a carrier made of a solid dispersion, can a uniform dispersion nisoldipine, adjust medication released. Octadecanol as co bleaching agent, NaHCO3 as a foam, can significantly improve the tablet floating performance. According to optimize the prescription tablet batches were prepared, the same six sampling time points with homogeneity, three batches of tablets reproducible drug release, illustrates the preparation process stability. This product will be zero order release profile were used equation, Higuchi model, an equation was fitted regression equations were: Explanation release characteristics more consistent with Higuchi model, m-Nis-HBS release tablets has obvious characteristics. Release data were fitted to Peppas equation, the release mechanism for drug diffusion and skeleton dissolution synergy. High temperature, high humidity, glare factors experimental results show that: m-Nis-HBS piece light instability in the production and storage process should be strictly protected from light; temperature and humidity is more stable, although the content is decreased, but the decline values ??were less than 5% RH75% 10d tablet weight of less than 5% moisture, in accordance with pharmacopoeia. Order prescription volume 80%, 100%, 120% of the room nisoldipine and corresponding accessories for the recovery experiment, recoveries were: (99.85 ± 0.23)%, (100.1 ± 0.41)%, (99.91 ± 0.24)% (n = 3). Assay results for the three batches of tablets: (102.6 ± 0.25)%, (101.1 ± 0.56)%, (99.60 ± 0.62)% (n = 3), and content uniformity qualified. Floating PERFORMANCE OF RESULTS: at (37 ± 0.5) ℃ artificial gastric juice, stirring paddle speed 100r · min-1 case, homemade m-Nis-HBS were within 3min and sustainable floating drift from more than 12h. The m-Nis that all conventional tablets disintegrated within 3min sinking. According to Beagle dogs m-Nis-HBS tablets and immediate-release tablets were normal in vivo pharmacokinetic study process to calculate the pharmacokinetic parameters. m-Nis-HBS and m-Nis conventional tablets pharmacokinetic parameters were as follows: 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 both in vivo kinetics of the process are in line with a one-compartment model. The parameters by paired t-test showed that: elimination rate constant Ke is no significant difference (P gt; 0.05); elimination half-life T1 / 2 (Ke), absorption half-life T1 / 2 (Ka), peak concentration Cmax, Tmax time to peak , drug - AUC area under the curve were significantly different (P lt; 0.05), described m-Nis-HBS in Beagle dogs has obvious characteristics of sustained-release formulations. To Tmax, Cmax and AUC as an index comprehensive evaluation m-Nis-HBS and m-Nis conventional tablets relative bioavailability. To m-Nis-HBS at different times in vitro release percentage Fr Fa their scores for the absorption regression, linear equation: Fa = 0.8777Fr-7.486, r = 0.9928, indicates m-Nis-HBS in vivo absorption and in vitro release significant correlation in vitro drug release can be absorbed into the body when the curve forecasting. Conclusion: between nisoldipine intragastric floating sustained release tablets in vitro release test, indicating that the m-Nis-HBS sustainable floating in artificial gastric juice more than 12h and the drug release followed Higuchi model. Beagle dogs pharmacokinetic studies have shown that the process of their in vivo release also has obvious characteristics between nisoldipine for clinical research and applications provide a promising sustained release dosage forms.
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