Study On Nimodipine Self-microemulsifying Fast-disintegrating Sublingual Tablets

OBJECTIVE: Dihydropyridine(dihydropyridine,DHP)calcium bbcker is one of tfa e most important drugs in the treatment of cardiovascular and cerebrovascular dis ease s at present However The disadvantage of the prevalence of these drugs are po or solubility,slow dissolution rate, and strong first-pass eflect,which seriously affect the imrovement of the bioava3ability,and limits its clinical application.Nimodipine (NM) is t he typical dihydropyridine drug,and is used more clinical. Nimodipine is the drug of c hoice in cerebrovascular diseases,which is for hypertension,ischemic c erebrovascular disease,vasospasm after subarachnoid hemorrhage,stroke,migraine,a nd have a good effect in acute cerebral infarctioaangina pectoris,myocardial infarct ion,sudden deafoes s.I njections, tab lets and capsules listed in the existing dosage for ms.However,these for m illations generally had poor compliance,drug dissolution dif ficultSolid self emulsifying drug deliver y system(S-SEDDS),mixed by drugs,an oi1phase,a non-ionic surfactant,co-surfactant,with a suitable solid material, is prepare d a s a solid preparation. S-SEDDS have dual advantages of both SEDDS and solid prepa ration.lt is as follow s:Fristly,it improve the insoluble drug solubility,dissoluti on rate and bioavailability,and reduce gastrointestinal irritation;Secondry, it increases stability, extended storage time,convenience patient compliance and so oaOral muc osal delive ry system is that the drug is prepared into a suitable dosage form and ad ministered t hrough the sublingual. It can be divided into the the sublingual mucosal drug delivery fo rmulations;the bucc al mucosa administered formulations;oral topic al formulations. T he sublingually prep aration is the most studied,which has some a dvanrages,it is as follows: Fristly, sublingual mucosa is rich in bbod vessels, good permeability.the d rug is rapidly absorbed a nd the onset of rapid; Secondly, it is part icularly suitable for th e elderly, children and patients with dysphagia, and easy to us e, good compliance; Thirdly, drugs can prevent enzymatic destruction of the gastroi ntestinal tract and hep atic first pass effect, which increases the bioavailability. Fourt hry,Sublingual admini stration can reduce die toxic side effects of the drugs on the g astrointestinal tract and five r.The article select nimodipine, on behalf of dihydropyr id ine, as a model drug. Nimo dipine self-microemulsifying drug d elivery(NM-SME DDS) is prepared with self-mi croemubifying excipients including Captex200P, Cr emophorEL,Labrasol.an d Nimodipine solid self-microemulsifying Fast-disinteg rating Sublingual Tablets are pre pared by sreened solid carrier of adsorpti on of NM-SMEDDS,the quality of a nd phar macokinetics of which are on the research and discussion. The formulation combine the advantages of solid self-microemulsif ying drug deliver y system? and or al mucos al drug delivery systems.METHODS: Firstly, Various excipients on the solubility of the drug are measure d by solubility tests, and pick strong ability to dissolve accessories for further experi ments;Compatibility and emulsifying condition is investigated by compatibility test afier mixing of the oil phase and surface active agent (SA),and men best oil phase an d SA are screened combination of dispersed drug-containing microemulsion stability; Pseu do-ternary phase diagrams screen cosurfactant (CoSA),which makes effective self-microemulsifying area as a screening indicator,and can also be determined the e xtremum range of th e oil phase and the SA/CoSA in the same time;Best SMEDD S prescri ption is optimized by a two-factor, five-level central composite design-r esponse surf ace methodology, which makes the oil phase and the SA/CoSA as in dependent varia bles;Nknodipine saturation solubility in SMEDDS is determined an d drug loading was determined by observing the emulsion stability after disperse d.The Optimal formula tion was prepared.And the dissolution,self-microemulsifying efficiency influencing fa ctors,preliminary stability were determined.Secondly, The type of adsorbents were scr eened with the maximum saturation and taste as inde x,a nd the quality of adsor bents were determined by inve stigating influence of adsorbe nts to NM-SMEDDS powder f low and dissolution,an d preparation methods and se veral major factors affect ing the pres cription are sreened by single factor, The pres cription was optimized by Orthog onal test,the quality and stability of which was ev aluated. Finally, The pharmac okine tics of the two formukti ons are studied, The ra bbits are fed conventional tablets and NM-S MEDDS Fast-di sintegrating Sublingu al Tablets by the single-dose rando mize d cross over trial in the paper.Ear vein bloo d was collected before administration and after ad ministration0.17、0.33、0.5、1.0、1.5、2.0、3.0、4.0、6.0、8.0、12.0h,and the content of nimodipine is determined after separation and purification. The results are fitting anal ys is of the pha rmacokineticu sing DAS2.1.1software.RESULTS:The solubility test results show that Nimodpine have better solubility in Ethyl oleate,Catex200P, Cremophor EL,Cremo phor RH40, Tween80,Labrasol,T ranscutol P;The compatibility test results show that the Captex200P and EL is superi or to other components, and the drug-containing microemulsion stability is relatively hig h after dispersed; The results of the pseudo-ternary phase diag rams showed that the e ffective self-microemulsifying area formed by Captex200P+E L and Labrasol is gre ater than Transcutol P,and microemulsnn after dispersed is more clear, bright; The p ropoition of the best prescription for30:4723by central composi te design-re sponse surface methodology; Ninodipine saturation solubility in SMED DS is137.38mg/g,13.738%(w/w) of highest drug bading, The vitro dispersion test result sho w that dm gs separate out when drug bading is greater than9%,Therefore, th is attic le eve ntually determine the drug loading of9%,90mg/g. In th e dissolution tes t,The perce nt of ac cumulated dissolution of NM-SMEDDS was appr oximately98.69%,which was appr oximately4.76times and3.75times as much as th at of bulk dr ugs and mar keted table ts in1hour. In the examine impact factor of the efficiency o f self-microemulsifying t est,The influence of the dispersion medium and the di lutbn to the self-e mulsificatbn efficiency is not obvious, but the stirring speed, tern perature, drug influe nce. Self-mic roemulsifying time as the stirring speed and the t emperature increa sed gradually dec reases. When the adding a mount of the drug is more than12%, the em ulsion become s unstable, resulting in much drug precipitatb n.and the appearance of the solution be conies turbid. The prescription indicators ar e investigated in the initial stability test,in cluding the appearance, self-microemulsif ying time, particle size, drug content There was no obvbus influence under the con ditions of high temperature (60°C),bw ternp erature(4℃) and strong light(4500±500)Lx in10days, but the conte nt of NM decree sed from99.20%to79.54%in the condition of strong light(4500±500) lx m10days.In the research of Fast-dismtegra ting Sublingual Tablets, The presc ription choices Ae rosil-300of superior suction p erformance as the carrier for adsorpt ion and the better t he powder flowability and dissolution of NM-SMEDDS after Mi xing Aerosil-300an d NM-SMEDDS in0.7:1proportioa Th e single factor results fo und that the disinteg ration performance of t he tablet prepared by direct powder tablet ting is better.Prepara tbn process is simpl e,which favor indu strial production,In exci pients screening tests, The PVPP, MCC, Aspartame significa ntly affect prescription disintegra tion time and taste, The optim al prescription by orth ogonal design was68.6%of NM-SMEDDS p owder,12.4%of manntol,8%of M CC,8%of PVPP,3%of Aspartame. NM-SMEDDS Fast-disi ntegrating Sublmgua1Tablets ate prepared by the best prescription and prediction p rocess. The quality in dicators, including the ap pearance, particle diameter after em ulsification, content, con tent uniformity, disinteg ration time, wetting time, dissoluti on and taste are in line with the quality requiremen ts of the sublingual tab lets, and meet the experimental targets. In me stability test, N M-SMEDDS Fast-disi ntegra ting Sublingual Tablets are unst able in the condition of strong light (4000±5001x) a nd high humidity (room temperatu re, RH9.25%),it is ea sy to cause tablets content decr eased (the content of NM decrea sed from99.60%to88.55%in10da ys) and t he surf ace roughness. In vivo pharmacoki netic trial, the pha rmacokinetic data of th e two for mutations is non-compartment mod el fitted by DAS2.1.1. The results sho w that com pared pharmacokinetic characteristics of sublingual tablets group and co nvention al tablets group in rabbits, The speed of drug absorption in sublingual table ts group was more onetime faster than conventional tablets, Tmax of sublingual tab lets was(0.92±0.20)h. Cmax in the plasma was (108.67±18.38) μ g/L in subling ual tablet s group, w hich significantly improved co mpared with conve ntional table ts group(P<0.001),an dthe AUC (0-t) of sublingual tab lets group was1.63times t ban that of conventional t ablets group,which showed significant differen ces(P<0.001).CONCLUSION: This article find the new formul ation has certain advantages an d feasibility through the evaluation of the quality of me NM-SMEDDS Fast-disin te grating Sublingual T ablets and in vivo pharmacokinetic stud ies. It mainly reflecte d th at the prescription pr eparation and the method of proces s of screening, the opti mization is simple and easy to control,which is conducive to indust rial productio n;I n vitro quality evaluation resu Its show that NM-SMEDDS Fast-disintegrating Su blingual Ta blets have better taste, shorter disintegration and wetting ti me, better st ability and Hig her dissolution rate. The pharmacokinetic studies results show the dru g is absorb ed rapidly in subliigual ta blets compared conventional tablets,t he maxi mum plasma co ncentration was reache d in soon,it had larger peak plasma concentr ation and bioa vailability in vivo.In short, the advantages of S-SMEDDS and Oral mucosal deliver y system we re used in Dihydropyridine calcium blocker in article,which solved the de fects of th ese drugs from the dissolution performance and first pass effect This article studies i n vitro and in vivo show that the application of the new formulation achieved the des ired re suits and objectives,and had certain science and feasibility.However,some iss ues rema in to further in-depth research and discussion, such as new solid carrier rese arch, in viv o correlation study.