Preparation And Quality Evaluation Of Loxoprofen Sodium Cataplasm

BackgroundLoxoprofen Sodium is one of the styrene-acrylic acid non-steroidalanti-inflammatory drugs,It combined with cyclooxygenase to cover thecyclooxygenase activity center and block the enzyme-catalyzed arachid-onic acid intoprostaglandin （PG） in the metabolic processes to play anal-gesic and anti-inflammatory effect.It used for osteoarthritis, muscle paintrauma caused by swelling,pain and other musculoskeletal diseases. Atpresent, there are several kinds of oral administration dosage marketed suchas ordinary tablets, capsules, no transdermal drug delivery dosage.But It is easy to bring up gastrointestinal adverse reactions and itsbioavailability is reduced when oral administration, if it was used for a longtime,It could cause serious adverse effects. It also has the specialproperties of good lipophilic,low melting point,molecular weight.So It canbe prepared to be a transdermal form of dosage.ObjectiveCataplasm has the advantages of the drug volume,good moistureretention,rapid onset,easy to use,without irritation and hypersensitivity reaction,ect. It conduces to the drugs transdermal absorption and improvepatient compliance.Therefore, the Cataplasm of Loxoprofen Sodium wasformulated and studied in order to development of its clinical application.Method1.Investigation solubility,octanol/water partition coefficient ofLoxoprofen Sodium.2.High polymer material as the main matrix material, calender coatingmethod for thepreparation process, the single factor on the basisof percutaneous cumulative penetration amount and in vitro release of themain index, the reference index of adhesion and sensory orthogonaldesign, optimized cataplasm prescription and process.3.Establish in vitro transdermal determination methods and in vitrorelease experiments of Loxoprofen Sodium by HPLC.4.According to guidance principle of preparation quality standard inPharmacopoeia of the People’s Republic of China2010, the stability andquality including appearance,pH, viscosity and assaying,as well ascumulative permeated percentage were studied and Safety evaluation.5.Establish HPLC-MS/MS method to determine the contentof Loxoprofen Sodium in plasma,pharmacokinetics were investigated forpercutaneous permeation of Loxoprofen Sodium Cataplasm in rabbits.Result1.Loxoprofen Sodium has the maximum solubility in PH7.4PBS;the octanol/water partition coefficient is15.9272,with it logKo/w value at1.2021,This shows that loxoprofen has strong hydrophilic prompts mayneed to take appropriate and promote infiltration to enhance the percutane-ous absorption.2.The orthogonal method shows that the cataplasm systems iscomposed of NP700:6.5g, PVPK90:1g, CMC-Na:3g, glycerol:40g, Ganhydroxyl Aluminum:0.07g, tartaric acid:0.7g. The best promotepenetrants of Loxoprofen sodium cataplasm are azone and propylene glycolcomposite penetration enhancers.Use calender coating method to preparatecataplasm.3.The concentration of Loxoprofen Sodium in the receptorcompartment is determined by HPLC.The equation for the calibrationcurve is A=87.604×C-49.182， R=0.9995,with a good linearrelationship between its concentration of8～120μg/mL,recovery rate are99-101%,within-day and between-day are below1%.4.The cumulative release of Loxoprofen Sodium in vitro releaseexperiments is determined by HPLC.The equation for the calibration curveis A=85.743×C+1.161，N=6，R=0.9997,with a good linear relationshipbetween its concentration of1.5μg/mL～10.5μg/mL,recovery rate are99-101%,within-day and between-day are below2%.5.The content of Loxoprofen Sodium cataplasm is determined byHPLC.The equation for the calibration curve is A＝88.988C-7.97,R＝ 0.9999,with a good linear relationship between its concentration of20μg/ml～80μg/ml,Recovery rate are98-102%,within-day and between-dayare below1%.6.Loxoprofen Sodium in plasma was determined by HPLC-MS/MS.The equation for the calibration curve is Ai/As=0.2528Ci-0.0329，r=0.9994，with a good linear relationship between its concentration of10～400ng/mL,recovery rate were65.97%～77.80%,within-day and between-daywere below15%. Dose of Loxoprofen Sodium10g the AUC_0�'96were1135.96±63.54ng/ml*h,MRT_0-twere12.46±1.23h,C_maxwere95.61±9.89ng/ml,t_1/2zwere10.00±1.09,T_maxwere1.70±0.27h。7. The safety evaluation showed that loxoprofen sodium cataplasmirritation and allergic reaction prompted the loxoprofen sodium cataplasmagent with high security.8. The preliminary stability showed that the appearance,pH,viscosityand assaying,as well as cumulative permeated percentage ofLoxoprofen Sodium cataplasm remained constant.ConclusionOn the base of study of physical and chemical of Loxoprofen Sodium，selecting Loxoprofen Sodium as a hydrophilic model drug, we designedthe Loxoprofen Sodium Cataplasm.The Loxoprofen sodium cataplasm was prepared with water-solublepolymer material partially neutralized polyacrylate （NP700） as matrix, polyvinylpyrrolidone K90and carboxymethylcellulose sodium asviscosity-enhancing agents and gelatin as film forming material. Theformulation was optimized by orthogonal design. The product couldcompletely release in2h. The transdermal behavior through excised Bamaminiature pig skin fitted to zero-order kinetics equation. The cumulativetransdermal amount of cataplasm containing combined permeationenhancers was significantly higher than that of the blank group （containingno permeation enhancer） and other groups （containing a single permeationenhancer）. The results of preliminary stability study showed that theadhesion, content, in vitro release and transdermal property of the productstored in30℃,60%relative humidity environment for6months had nosignificant change.In vivo pharmacokinetics indicates that LoxoprofenSodium Cataplasm shows no skin irritation, the relative bioavailability ishigh.The results showed that loxoprofen sodium through transdermaldelivery can be guaranteed Its efficacy, and it is not bring upgastrointestinal adverse reactions and its bioavailability is reduced by oraladministration It provides new drug delivery formulations of anon-steroidal anti-inflammatory drugs in the treatment of musculoskeletaldiseases. which provide a good idea for study on transdermal hydrophilicdrug delivery system and product development.