Preparation Of Phenytoin Drug Resin Sustained-release Suspension And Its In Vitro And In Vivo Studies

Phenytoinum Natricum?PN?is a broad-spectrum antiepileptic drug,which has become the treatment of choice for grand mal seizure,with few side-effects,it is widely used in clinical practice.The domestic formulations are tablet and injection.The American Pharmacopoeia also contains the dosage form of Phenytoin sustained-release capsule.In the oral administration,PN is mainly absorbed through the small intestine.There is a remarkable difference in drug absorption between individuals.The range of effective blood concentration of PN is from 10 to 20 mg·L-1.It is easy to produce toxic reactions when the concentration is more than 20 mg·L-1.The half-life in vivo of PN is relatively longer,it is 3⁷ hours.Patients need to gradually increase the dose of medication to the steady plasma concentration,and then use the maintenance dose.In addition,Patients need to adjust the medication dose according to the condition when the epileptic seizures is frequent.Therefore,it is necessary to prepare a new pharmaceutical agent of PN which has a certain sustained release effect and is easy to distribute the dose.In order to solve the above problems,this dissertation takes PN as the model drug and uses the anion exchange resin as the drug carrier.Enclosing the preparing conditions and the drug release in vitro and in vivo of the sustained-release suspension,systematical research is carried out,which can be divided into the following five parts:Part ? Preparation of PN-resin complexesThe method for determination of PN in vitro based on the PN sustained-release capsules in the United States pharmacopoeia.A full wavelength scan of PN and the various sample solution was conduced in this part.The wavelength of _maximum absorption of the PN was at 258 nm.And the analysis method of PN in different solutions in vitro was established.The influence factors of the preparation of drug-resin on bath method and column method were studied.Bath method was adopted through a comparative analysis and the optimum drug-loading process was established.The adsorption kinetic and thermodynamic results of PN resin showed that the ion exchange reaction between PN and anionic resin conformed to the first order reaction model.The process was an endothermic process and the reaction was spontaneous to the right.Part ? The bonding mechanism of PN-resin and the in vitro releaseThe study showed that the combination of PN and resin was a kind of chemical combination by SEM,XRD and DSC.On the basis of the United States Pharmacopoeia and related literature.The release conditions were as follows: 37.0?±0.5?;50 rpm;900 m L 0.15 mol·L-1 Na Cl solution as dissolution medium.And the effects of the experimental conditions on the release behavior were investigated.The in vitro release of PN resin was modeled with mathematical methods.The results showed that it conformed to the process of particle diffusion.Part ? Research on PN-resin coating technology and prescriptionIn order to avoid the burst release of the drug caused by the swelling of the resin,the PN-resin was impregnated treatment,and then was prepared as the sustained-release microcapsules by emulsion-evaporation method.According to the result of the single factor investigation and orthogonal design,the coating conditions were as the follows:the coating material was RL100;the amount of coating materials was 10% weight of PN resin.The plasticizer was PEG 400 with 10% of the coating material.Finally,incubated at 35? for 4.5 h,the PN-microcapsules were prepared with a significant sustained release effect.The analysis of the data showed that the release of PN-microcapsules conformed to the first order eliminate equation and drug diffusion mainly belonged to membrane control.Part ? Preparation of PN sustained-release suspensionIn this chapter,the ratio of subsided volume?F?and redispersibility?RI?were taken as index to investigate suspending ability of excipients.The optimal prescription of the suspension was screened with good physical stability and chemical stability.The in vitro release behavior of PN resin microcapsules and suspensions was analyzed.The results showed that the suspension medium did not affect the drug release.In addition,the stability test of the final prescription showed that the sustained-release suspensions had a good stability.Part ? Study on in vivo pharmacokinetics of PN sustained-release suspensionIn this chapter,SD rats were used as model animal and the in vivo analysis method of PN was established.With self-made suspension being the test preparation and PN tablets being the reference preparation,the concentration of PN in blood plasma was measured by HPLC method and the non-compartment model was used to obtain the pharmacokinetic parameters of two preparations and evaluate the relative bioavailability.Pharmacokinetics showed that the C_max of PN tablets and self-made suspension were 24.97 ?g·m L-1and 16.22 ?g·m L-1.The time peak of drug concentrations(T_max)were 4 h and 6 h.The T_max of self-made suspension had a certain delay and the C_max was reduced,which indicated that PN suspensions could effectively reduce the fluctuation range of blood concentration and the risk of medication.The AUC0-24 of PN tablets and sustained suspension were 181.165?g·h·m L-1and 172.176 ?g·h·m L-1.The relative bioavailability of sustained-release suspension was 91.46% compared with the PN tablets.