| Nifedipine, a calcium channel blocking agent, is frequently used for the treatment of angina pectoris and hypertension. Conventional preparations, which would increase heart rate reflectly and activate the sympathetic nervous system due to its short half-life(2-3h), are not convenient clinically. Using mucoadhesive microspheres sustained technique can prolong the time detained in gastrointestinal tract and control the drug release, well in compliance with mild adverse effects owing to its less variation of blood concentration and longer maintenance time.To synthesize and characterize the poly-(pyromellitic acid-dodecanediol)ester. Liquid condensation polymerization method was used to synthesize the polyester, and its technology was optimized by single factor investigation method; its construction was corroborated by FT-IR and 1H-NMR.The optimized technology were as follow:the ratio between solvent and monomer was 2 to 1, molar ratio between PMDA and DCD was 1 to 1, catalyst was SnCl2, and reaction time was 10 h. The result of FI-IR revealed that a polymer of poly(pyromellitic acid-dodecanediol)ester was achieved. Mn was 10760 Da, and it was easily soluble in methanol, ethanol and tetrahydrofuran; Intrinsic viscosity was 18.27mL·g-1; Acid value was 257.76 mg·g-1;Glass temperature was 57.9℃,and melting point was 288℃.The HPLC method was applied to determine the balanced solubility of nifedipine, and ultraviolet spectrophotometry was employed to determine the content and drug release of nifedipine in microspheres. Sink conditions of release determination are considered to be fulfilled by dissolving Nifedipine(20mg) in 0.5% SDS 500 mL. Methodology studies indicated that the method was of high specificity and accuracy and can meet the requirement in this study.The microspheres were prepared using Eudragit(?) RS100 and self-synthesized polyester as microsphere matrix, nefidipine as model drug. The emulsion-solvent volatilixation method was adopted to prepare NF-Polyester-MS. The optimum formulation and technique were obtained through single factor studies and orthogonal experiments. The final determined formulation and technique were as follows:ERS 0.9g, polyester 0.6g and nifedipine 0.3g were dissolved in acetone(9 mL) and magnesium stearate was added as a powder. The homogeneous final dispersion was cooled to 10℃and poured slowly with stirring (600 rpm) into 72 mL of liquid paraffin with 1.0% Span-80, which was previously also cooled to 10℃. The obtained emulsion was stirred at 40℃for 40 min. The suspension of microspheres in liquid paraffin was filtered, microspheres were washed by n-hexane and dried in vacuum at 35℃overnight.The microspheres prepared using the optimum formulation had a D50 of 216.1±2.77μm in particle size. The average yield, average drug loading and Entrapment efficiency were 90.24±1.08%,14.95±0.24%,87.72±1.10%, respectively.The appearance and powder technology of the microspheres were studied to evaluate its quality. The in vitro and in vivo bioadhesiveness were studied compared with NF-CS-MS and NF-ERS-MS, and the release profile as well as release mechanism in vitro were also studied. Quality research showed the microspheres had a spherical shape, narrow particle span, good sphericity and fluidity. The experiments of Ranga Rao&Buri method, the everted sac technique and the microspheres retarding at rats GI showed that the mucoadhesiveness of NF-Polyrster-MS and NF-CS-MS was much higher than that NF-ERS-MS, which indicated the mucoadhesiveness of polyester was correspondent with chitosan. The result of release rate indicated that the microspheres had a good reproducibility of intra-batch and inter-batch; The 8h cumulative release can reach 80.0%. The release profile in vitro conformed to the Higuchi model, and the main mechanism of drug release was diffusion.The plasma concentrations of nifedipine in rats were determined using an HPLC method. The pharmacokinetic parameters of nifedipine were calculated using non-compartmental model by measuring the plasma concentrations in rats after oral administering self-made NF-Polyester-MS(test preparation,T) and commercial nifedipine tablets(reference preparation,R). AUC0-t, Cmax, tmax of T and R were 1306.7±123.24,1030.36±106.2, 159.95±12.51 ng·mL-1,243.09±15.91 ng·mL-1,5.6 h and 3.0 h, respectively. Relative bioavailability was 126.82%. Compared with commercial tablets, the Cmax was significantly lower and tmax delayed, MRT prolonged, which indicated NF-Polyester-MS can achieve the objective of prolonging the time detained in gastrointestinal tract, extending the drug release rate and elevating the bioavailability. |
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