Study Of Levetiracetam PH Sensitive Nasal Gel And Its Pharmacokinetics And Brain Targeting In Rats

Levetiracetam（LEV）has the characteristics of high pharmacological activity,few adverse reactions,and good patient tolerance.It is the only antiepileptic drug that can prevent the onset of epilepsy.The dosage forms marketed by LEV include tablets,oral solutions,injections,etc.The tablets and oral solutions absorb slowly and are prone to gastrointestinal side effects.The injections need to be assisted in medication,which is inconvenient for administration and poor patient compliance.In addition,levetiracetam has a high polarity and is difficult to penetrate the blood-brain barrier.After administration,the amount of the drug from the blood circulation into the brain is small,which affects its clinical efficacy.However,nasal administration can bypass the blood-brain barrier and quickly enter the central nervous system.It has the characteristics of fast absorption,high bioavailability and strong brain targeting.Therefore,this article intends to use LEV as a model drug to develop a new dosage form of the drug for nasal administration—pH-sensitive nasal gel.This article intends to study the pre-prescription preparations,in vitro transdermal experiments,pH-sensitive nasal gel prescription screening and preparation process research,in vitro quality evaluation of preparations,in vivo pharmacokinetics and bioavailability research,brain targeting research and The pH-sensitive nasal gel of LEV has been systematically and in-depth studied in terms of nasal mucosal cilia toxicity evaluation and other aspects.In the first chapter,firstly,an HPLC drug content determination method with strong specificity,good accuracy,high precision and sensitivity was established in the pre-prescription study of LEV pH-sensitive nasal gel.Then the effects of oil/water partition coefficient and ionic strength on the chemical stability of drug solution were studied.The results of the study on the chemical stability of the LEV solution show that when the medium is at pH 4.0 to 7.0,the LEV solution has almost no degradation,indicating that the LEV solution has good chemical stability and is unstable under strong alkaline and strong acid pH conditions.The chemical stability of the LEV solution is significantly reduced.The measurement result of the oil-water partition coefficient of LEV shows that the P value of LEV is about 0.24 between pH 2 and 10,indicating that the drug has low fat solubility and high polarity.The measurement result of ionic strength shows that ionic strength has almost no effect on the chemical stability of LEV solution.In the second chapter,in vitro transdermal experiments of LEV,the isolated sheep nasal mucosa was used as a model to compare the penetration enhancement effects of three absorption enhancers,DM-β-CD,SBE-β-CD and HP-β-CD,on LEV.And the influence of the concentration of penetration enhancer on the effect of penetration enhancement.The results show that 5.0%HP-β-CD has the best penetration enhancing effect,so the LEV pH-sensitive nasal gel chooses 5.0%HP-β-CD as the absorption and penetration enhancer.In the third chapter,research on prescription screening and preparation process of LEV pH-sensitive nasal gel,the effects of the hydroxypropyl methylcellulose（HPMC）and pH on the viscosity of blank gel formulations with carbomer 940 as the main matrix material were investigated.At the same time,the gelling ability of the blank gel was measured,and it was found that HPMC can significantly increase the viscosity of the CP940 gel formulation and the pH value has a certain effect on the viscosity.A comprehensive pre-prescription study of LEV solution determined that the optimal formulation of LEV pH-sensitive nasal gel is:5.0%LEV,0.5%CP940,0.8%HPMC,5.0%HP-β-CD,0.05%ethyl paraben and appropriate amount of distilled water.In the fourth chapter,the LEV pH-sensitive nasal gel was evaluated in vitro,and 3batches of LEV pH-sensitive nasal gel were prepared.The appearance,pH,viscosity,content of drugs and preservatives,and in vitro release of the same batch of preparations were observed and measured.It was found that the preparation was translucent and low-viscosity liquid with a pH of about 4.1 and a viscosity of 70m Pa·s.The contents of LEV and ethyl paraben were between 95%-105%of the labelled amount.In addition,in the in vitro release experiment of LEV nasal gel,it was found that the LEV solution release rate was very fast,with a cumulative release of 85%within 2h,while the drug’s pH-sensitive nasal gel released slowly,at the same time.The cumulative drug release is less than 60%,and the cumulative drug release in 8 hours is only 90.0%,indicating that the preparation has a significant sustained-release effect.In the fifth chapter,the pharmacokinetics and bioavailability of LEV pH-sensitive nasal gel were investigated.Firstly,the HPLC-UV detection method of LEV concentrat ion in rat plasma was established;Then,with intragastric administration as a reference,the plasma concentration of the rat LEV pH-sensitive nasal gel after nasal administrat ion was measured and the main pharmacokinetic parameters and relative bioavailability of the drug were calculated（Fr）etc.The results showed that the T_maxof LEV pH-se nsitive nasal gel was 0.075h,C_maxwas 5.22μg·m L^-1and AUC_0-∞was 10.43μg·h·m L^-1,T_maxof intragastric administration was 0.75h,C_maxis 10.79 and AUC_0-∞is 39.54μg·h·m L^-1,In addition,the F_rof LEV pH-sensitive nasal gel is as high as 275.05%.The abo ve results indicate that the absorption rate of the drug in rats is significantly accelerat ed after nasal administration,and the bioavailability is also significantly improved.In the sixth chapter,the brain targeting of LEV pH-sensitive nasal gel was studied.Firstly,an HPLC-UV detection method was established to determine the concentration of LEV in rat brain tissue;Then,taking the intragastric administration as a reference,the drug concentration in the brain tissue of the rat after nasal administration of the LEV pH-sensitive nasal gel was measured and the main pharmacokinetic parameters were calculated.The results showed that the T_maxof nasal administration was 0.625h,C_maxwas 10.60μg·g-1,AUC_0-∞was 24.57μg·h·g^-1,and the T_max,C_maxand AUC_0-∞of intragastric administration were 1.25h,19.75μg·g^-1and51.54μg·h·g^-1.The F_rof LEV pH-sensitive nasal gel was found to be 476.83%in rat brain tissue,indicating that it has obvious brain targeting.In the seventh chapter,in vitro and in vivo methods of toad upper jaw mucosal model were used to study the toxicity of LEV pH-sensitive nasal gel to nasal mucosal cilia.The ciliary toxicity of LEV solution,blank prescription and complete prescription to nasal mucosa were investigated respectively.The results showed that the effect of LEV solution on nasal mucosal cilia was greater than that of complete prescription,and the toxicity of blank prescription on nasal mucosal cilia was the least,but the toxicity was reversible...