| Objective Citalopram Hydrobromide?CTH?is a new generation of selective 5-HT reuptake inhibitor.It has the characteristics of small dosage,high pharmacological activity,few side effects,and good tolerance.It can be used in many clinical applications.Treatment of various types of depression.At present,CTH has been marketed in the form of tablets,oral solutions and capsules.The above-mentioned preparations are generally slowly absorbed and easily cause gastrointestinal side effects;in addition,the drug is highly polar and does not easily penetrate the blood-brain barrier.After oral administration,the amount of drug that enters the brain from the blood circulation is small,thereby affecting its clinical efficacy.Nasal administration has the characteristics of fast absorption effect,high bioavailability,bypassing the blood-brain barrier,and direct delivery to the brain.Therefore,this article intends to use CTH as a model drug to develop a new nasal dosage form of the drug,a nasal in situ gel,in order to achieve rapid absorption and onset,high bioavailability,convenient use,and brain-targeted administration.This article intends to conduct research from pre-preparation research,in vitro transdermal experimental research,prescription screening of nasal in situ gels,preparation process research,preparation in vitro quality evaluation,in vivo pharmacokinetics and bioavailability research,brain targeting research,and systematic and in-depth study of nasal mucosa ciliary toxicity evaluation on CTH nasal in situ gels.Method In the first chapter of the pre-preparation study of CTH nasal in-situ gels,a method for determining HPLC drug content with strong specificity,good accuracy,high precision,and high sensitivity was first established,and then the oil-water partition coefficient of the drug?P?,The chemical stability of the solution and the effects of different solvents on the solubility of CTH in three aspects.The results of the oil-water partition coefficient study found that when the p H of the buffer solution was?5.0,the P value of CTH was much less than 1.When the p H of the buffer solution was>5.0,the P value gradually increased with the increase of p H;the chemical stability of the drug solution The results show that the chemical stability of the CTH solution is better when the p H value is?8;when the p H value is greater than 8,the chemical stability of the CTH solution begins to decrease,and decreases with the increase of the p H value of the medium.The solubility study found that the order of the solubility of CTH in different solvents is:30%ethanol>water>cyclodextrin derivatives>polyethylene glycol>propylene glycol>Tween 80.In the second chapter of the in vitro transdermal experimental study of CTH,using isolated sheep nasal mucosa as a model,the dermal penetration enhancers of DM-?-CD,SBE-?-CD and HP-?-CD on CTH were studied and compared.Permeation promoting effect and the effect of the concentration of promoting agent on the effect of permeation promoting effect.The research results show that all three?-CD water-soluble derivatives have obvious promoting effect on CTH.Among them,DM-?-CD has the best promoting effect;and when the concentration of DM-?-CD is 3.0%,the best effect is to promote penetration.Therefore,3.0%DM-?-CD was selected as the absorption enhancer of CTH nasal in situ gel.In the third chapter,the study of prescription screening and preparation process of CTH nasal in-situ gels,the effect of the addition of carbopol 940?CP940?on the viscosity of poloxamer 407?F127?blank gel was first investigated.It was found that CP940 can significantly increase the viscosity of F127 gel prescription.Then,using the star point design-response surface method experimental design,taking the mass concentration?w/v,%?of F127 and CP940 as the investigation factors,and using gelation temperature and gelation time as observation indicators,blank blank in situ gels were selected.The best prescription composition is:20.27%F127,0.17%CP940.Secondly,the effect of the addition of CTH on the gelation temperature of the blank in situ gel was investigated using a single factor experiment,and it was found that the addition of the drug can increase the gelation temperature of the blank in situ gel.Finally,based on the results of CTH oil-water partition coefficient and solution chemical stability studies,and CTH in vitro transdermal experiments,the rational prescription composition of CTH nasal in-situ gel was determined as:8.0%CTH,20.27%F127,0.17%CP940,3.0%DM-?-CD,0.05%paraben ethyl ester and appropriate amount of water,the p H of the preparation is about 5.0.In the fourth chapter of the in vitro quality evaluation of CTH nasal in-situ gels,the appearance,p H,gelation temperature,gelation time,viscosity,drug and preservative content,in vitro corrosion rate,and in vitro release of the preparation were studied separately.It was found that the appearance of the preparation was clear and transparent,the p H value was about 5.0,the gelation temperature and gelation time were 32°C and 40 s,the viscosity was150 m Pa·s,and the contents of CTH and ethyl paraben were 99.0%?101.0%.In addition,the in vitro erosion rate of CTH nasal gel in situ at 9min was 92.0%,and the drug release rate was 90.07%,and there was a significant linear correlation between the in vitro erosion of the preparation and the drug release?r=0.9993?.Finally,it was found in the in vitro release test that the CTH solution releases drugs very quickly,with cumulative release of up to 88.0%in2 hours,while nasal in situ gels release less than 50.0%at the same time,and accumulate in 8hours.The release rate was only 92.0%,indicating that the CTH nasal in situ gel has a good sustained release effect.In the fifth chapter,the pharmacokinetics and bioavailability of CTH nasal gel in situ,first established the HPLC-UV detection method of CTH concentration in rat plasma;then,the CTH solution was administered by gavage as a reference.The blood drug concentration in the rat body after nasal administration of the nasal in situ gel was measured and the main pharmacokinetic parameters Tmax,Cmax,AUC,and relative bioavailability?Fr?were calculated.The results showed that the Tmax,Cmax,and AUC0-?of CTH nasal gel in situ were 0.095 h,2127.16 ng·m L-1,and 1970.81 ng·h·m L-1,respectively,while Tmax,Cmax,and AUC0-?were0.791h,576.83ng·m L-1,and 1215.86ng·h·m L-1,respectively,and there were significant statistical differences between different routes of administration?P<0.05?.In addition,the Fr of the CTH nasal in situ gel was found to be as high as 167.75%.The above results show that the absorption rate of CTH is significantly accelerated and the bioavailability is significantly improved by nasal administration.In the sixth chapter,the brain targeting of CTH nasal in situ gel was studied.First,the HPLC-UV detection method for CTH concentration in rat brain tissue was established.Then,the administration was determined by intragastric administration.After nasal administration of CTH nasal in situ gel,the drug concentration in rat brain tissue was calculated and the main pharmacokinetic parameters were calculated.The results showed that the Tmax of CTH nasal in situ gel was 0.08 h,Cmax was 17660 ng·g-1,AUC0-?was 17263.45 ng·h·g-1,and Tmax,Cmax and AUC0-?were administered by gavage.There were significant differences between the two at 0.75 h,1171.68 ng·g-1 and 3735.05 ng·h·g-1?P<0.01?.In addition,the brain targeting index of CTH nasal in situ gel was calculated to be 2.50,indicating that the preparation has obvious brain targeting propertiesIn the seventh chapter,in the study of nasal mucociliary toxicity of CTH thermosensitive in situ gel,toad palate mucosa model was used in vitro and in vivo to evaluate its ciliary toxicity.The ciliary toxicity of CTH solution,blank prescription and intact prescription to nasal mucosa was investigated.The results showed that CTH solution,complete prescription and blank prescription had certain toxicity to nasal mucosal cilia,but the toxicity was reversible.Among them,the CTH solution is similar to the complete prescription,and the blank prescription is least toxic to cilia... |
PDF Full Text Request