Preparation And Pharmacokinetics In Rats Of S(+)-ibuprofen/montmorillonite Sustained-release Dry Suspension

Dexibuprofen,(S)-(+)2-(4-isobutylphenyl)propionic acid,is one of non-steroidal anti-inflammatory drugs(NSAID)in clinic.It is bordly used to cure some chronic dull pain such as rheumatism or type rheumatism disease and joint muscle pain,headache pain,month menstrual cramp.Its was normally adiministed in shorter intervals,and that may result in bigger the fluctuation of plasma concentration,some adverse drug reactions,and less compliance.The purpose of the present study was to prepare S(+)-IBU/MMT sustained release composites by using montmorillonite(MMT)which would reduce dosing frequency and be more convenient for patients.Objective:To prepare S(+)-IBU/MMT sustained release composites by using MMT as drug delivery carrier.To evaluate the sustained release properties and release mechanisms of S(+)-IBU/MMT sustained release composites.To optimize the process of acid treatment MMT by central composite design response surface methodology.Acid-MMT and S(+)-IBU were formed composites which could improve drug loading capacity and the mount release property of S(+)-IBU.The release behaviors and its mechanisma of S(+)-IBU/Acid-MMT composites were studied in different media of different p H.To study the pharmacokinetics of S(+)-IBU/Acid-MMT sustained release dry suspension in rats.Methods:1.Pre-formulation studies UV is used to determine the maximum adsorption wave length of S(+)-IBU.Media of different p H according to Chinese Pharmacopoeia(edition 2015)were prepared,UV method was used for determination of S(+)-IBU stability and equilibrium solubility in different media.2.Preparation and release of S(+)-IBU/MMT sustained release dry suspension The S(+)-IBU/MMT composites was prepared by solution intercalation methods,and were characterized by power XRD and FTIR.In vitro release properties and its mechanisms of the S(+)-IBU were assessed by the drug release equation,such as zero order kinetics equation,first order kinetics equation,Higuchi equation and peppas equation.3.Preparation and release of S(+)-IBU/Acid-MMT sustained release dry suspension The most suitable modified MMT for screening of sulfuric acid,phosphoric acid,hydrochloric acid by N2 adsorption isotherm experiment and pore size distribution.To optimize Acid-MMT increase drug loading capacity by central composite design-response surface method based on single facter experiments,and were characterized by powder XRD and SEM.In vitro release properties and its mechanisms of the S(+)-IBU were assessed by the drug release equation fitting release curve.4.Study the pharmacokinetics of S(+)-IBU/Acid-MMT sustained release dry suspension in rats SD rats were given S(+)-IBU/Acid-MMT or commecial supplying S(+)-IBU suspension with a single oral dose of 60 mg/kg,respectively.The concentrations of S(+)-IBU in plasma were determined by HPLC.DAS2.0 software was used to calculate the pharmacokinetics parameters and relative bioavailability.Results:1.Pre-formulation studies The maximum adsorption wave length of S(+)-IBU is at 264 nm by ultraviolet scanning pattern.Its physical and chemical properties results show that solubility is4.28mg/ml,0.22mg/ml,0.084mg/ml in p H6.8 phosphate buffer,p H4.5 acetate buffer and0.1mol/L HCl,respectively.2.Preparation and release S(+)-IBU/MMT sustained release dry suspension Based on the XRD data,the interlayer space of S(+)-IBU/MMT has increased from1.25 nm to 1.31 nm,which suggested that S(+)-IBU had been intercalated into the interlayer of MMT.According to the FTIR,S(+)IBU/MMT composites showed characteristic absorption peak of MMT and S(+)-IBU,and some new absorption peaks,such as in 2390cm-1,also the strength of 3623cm-1、3425 cm-1、1030 cm-1 were decreased.The results shows that S(+)-IBU and MMT have formed stable sustained release system.In vitro release ability of S(+)-IBU from the S(+)-IBU/MMT composites was affected by p H of the release media.The in vitro cumulative release amount of the S(+)-IBU from S(+)-IBU/MMT composites were respectively 88%(p H6.8),36%(p H4.5)and 18%(p H1.0).3.Preparation and release of S(+)-IBU/Acid-MMT sustained release dry suspension With the sulfuric acid increasing to 25%,the lamellar of MMT had been delaminated.It has a large water inbibition at room temperature and small particles after modified by phosphoric acid.Comprehensive analysis,hydrochloric acid is the most suitable in this study.Prescription finalized by central composite design is 11% of Hcl,5.5h of reaction time and 55℃,The BET surface area and pore volume of S(+)-IBU/Acid-MMT is 318m2/g and 0.498 cm2/g,respectively.In vitro release ability of S(+)-IBU from the S(+)-IBU/Acid-MMT complexes was affectd by p H of the release media.The cumulative release amount of the S(+)-IBU from S(+)-IBU/Acid-MMT composites were respectively92%(p H6.8),33%(p H1.0).4.Study the pharmacokinetics of S(+)-IBU/Acid-MMT sustained release dry suspension in rats The main pharmacokinetics parameters of commecial supplying S(+)-IBU suspension and S(+)-IBU/Acid-MMT sustained release composites,in rats were as follows respectively: t1/2 were 0.5 and(5.58 ± 0.55)h,Cmax were(86.05 ± 5.96)and(123.5 ± 41.74)μg/ml,tmax were 0.5 h and(2 ± 0.20)h,AUC0-24 were(439.88 ± 84.41)and(644.49 ± 73.26)μg/ml·h.The relative bioavailability of self-prepared S(+)-IBU/Acid-MMT sustained release composites to reference formulation is(154.11 ± 27.41)%.There was significant difference in parameters between the two formulations(P < 0.05).Conclusion:1.S(+)-IBU have proper stability in various media.2.S(+)-IBU is combined with MMT by intercalating,physical adsorption and chemical adsorption.The release of S(+)-IBU/MMT composites has p H dependence.The drug release behavior followed first-order kinetic equation.The Peppas equation(n=0.41)shows the process of drug release was diffusion mechanism.3.S(+)-IBU BET surface area and pore volume of hydrochloric acid modified MMT were both bigger than MMT.The release of S(+)-IBU/Acid-MMT composites was p H dependent.The drug release behavior was consistent with Higuchi equation.The Peppas equation(n=0.86)shows the process of drug release which was diffusion and frame erosion mechanism.4.S(+)-IBU/Acid-MMT sustained release dry suspension of Cmax is smaller than that of S(+)-IBU suspension;but its t1/2,tmax and AUC0-24 is larger than those of S(+)-IBU suspension correspondingly.In conclusion,S(+)-IBU/Acid-MMT sustained release dry suspension has achieved to sustained release effect.