Preparation Of Desmopressin Acetate Thermosensitive Ophthalmic Gel And Its Intraocular Systemic Transport

Objective:?1?Desmopressin acetate was used as a model drug.poloxamer 407 and carboxymethyl chitosan used as gel matrix to prepare an ophthalmic thermosensitive gel,select the best prescription and evaluate it in vitro.?2?We compared the pharmacokinetic and pharmacodynamic profiles of desmopressin acetate after intraocular,intravenous and intragastric administration in rabbits to better understand the systemic delivery of peptide drugs through intraocular administration.?3?We prepared the ophthalmic thermosensitive gel for pharmacokinetic and pharmacodynamic experiments in rabbits,and investigate its sustained release effect.Method:?1?The thermosensitive gel was prepared by cold method,the sol-gel transition temperature was measured by precision thermometer;selects the appropriate dosage of poloxamer 407 through the gelation temperature,adds a series of concentrations of carboxymethyl chitosan to prepare carboxymethyl chitosan thermosensitive ophthalmic gel,and characterizes the prepared gel through rheology,in vitro release and differential scanning calorimetry experimentso and selects the appropriate concentration of carboxymethyl chitosan;the retention time and eye irritation of rabbits were studied.?2?15 rabbits were randomly divided into three groups(intravenous administration,7?g·kg^-1;intraocular administration,0.7?g·kg^-1;intragastric administration,7?g·kg^-1).Blood samples were taken from the heart at predetermined time points up to 12 h after dosing,the plasma desmopressin acetate level were analyzed by Enzyme-Linked Immunosorbent Assay?ELISA?.Another 21 rabbits were randomly divided into three groups(intravenous administration,7?g·kg^-1;intraocular administration,0.7?g·kg^-1;intragastric administration,7?g·kg^-1)for pharmacodynamics study.Urine volume was collected in predetermined intervals before and until 12 h after dosing.?3?5 rabbits were given desmopressin acetate thermosensitive ophthalmic gel in parallel,blood samples were taken from the heart at predetermined time points up to 12 h after dosing,the plasma desmopressin acetate concentration were analyzed by Enzyme-Linked Immunosorbent Assay?ELISA?.Another 7 rabbits for pharmacodynamics study.Urine volume was collected in predetermined intervals before and 12 h after dosing.Results:?1?The best prescription of the ophthalmic thermosensitive gel was selected:poloxamer 407?F127?concentration was 20%,carboxymethyl chitosan concentration was 1.5%.In vitro release experiments showed that with the increase of carboxymethyl chitosan concentration,drug release gradually slowed down.Rheological experiments show that the gel has good thixotropy and the viscosity of gel increases with the increase of carboxymethyl chitosan concentration.Rheological experiments show that the viscosity of gel increases with the increase of chitosan concentration.Differential scanning calorimetry results showed that the drug was encapsulated in hydrogel matrix.The gel can detained in the eyes of rabbits for more than 40 min.?2?Pharmacokinetics and pharmacodynamic parameters of desmopressin acetate in vivo after different routes of administration:Area under the plasma concentration-time curve for desmopressin(AUC_0-t)was 999.94 pg·h·m L^-1,C_max was 143.12 pg·m L^-1;The Pharmacokinetic parameters after intraocular administration,t_max was 5min,C_maxwas125.64 pg·m L^-1,AUC_0-t was 873.10 pg·h·m L^-1,absolute bioavailablility?F?was 8.73%;The Pharmacokinetic parameters after intragastric administration,t_maxwas 10 min,C_maxwas 104.10 pg·m L^-1,AUC_0-twas 451.79 pg·h·m L^-1,absolute bioavailablility was4.51%.Intraocular administration and intravenous administration of one tenth of the dosage showed similar effect,and the urine volume remained decreased for 12 h,but the urine volume increased significantly in the second collection period after intragastric administration,and there was no decrease effect 12 h after dosing.?3?The pharmacokinetic parameters of desmopressin acetate ophthalmic thermosensitive gel after intraocular administration in rabbits:t_max was 15 min,C_maxwas145.06 pg·m L^-1,AUC_0-twas 1017.94 pg·ml^-1,F was 10.18%,The prepared desmopressin acetate ophthalmic thermosensitive gel has the similar drug effect as eye drops.Conclusion:In this experiment,poloxamer 407?20%?and carboxymethyl chitosan?1.5%?were used as gel matrix to prepare desmopressin acetate ophthalmic thermosensitive gel,which was converted into gel at intraocular temperature.The gel has good in vitro release,with a cumulative release of 70.55%within 12 h and a certain viscosity.The gel has a good release in vitro,with a cumulative release of 70.55%within 12 h and a certain viscosity.Pharmacokinetics and pharmacodynamics of eye drop administration of desmopressin acetate were better than that of intragastric administration.Pharmacokinetics and pharmacodynamics results of desmopressin acetate ophthalmic thermosensitive gel showed that compared with eye drops,the gel prepared could prolong the eye retention time of the drug,increase the drug concentration in rabbits plasma,and has therapeutic effect.