Study On The Transdermal Delivery Systerm Of Tulobuterol Based On Drug Crystallization Behaviro Control

Objective:Tulobuterol?TBR?,as a selective?₂ adrenal receptor agonist,has strong and long-lasting effect of expansion the bronchial smooth muscle,promotes bronchial ciliary movement and antitussive,it also has less excitability to the heart and good transdermal absorption properties.Generally,the human respiratory function changes in circadian rhythm.In the nighttime sleep stage,asthmatic patients have significantly weaker respiratory function,which is the most susceptible to onset,leading to asthmatic attacks with obvious circadian rhythm.However,oral tulobuterol before bedtime,the peak time of the drug is not consistent with the time of asthma,the effect is short,and it has the large adverse reactions.This project aims to combine the advantages of circadian rhythm changes in asthmatic diseases,combined with pharmacological,chronological pharmacology and the advantages of transdermal preparations to avoid liver first pass effect,reduce the number of doses and improve medication compliance.The principle of recrystallization was designed to prepare a transdermal patch of toloterol crystal reservoir for pre-sleep dosing,nocturnal asthma prone to peak time,and long-term effective blood drug concentration.And explore the drug crystallization behavior and in vitro release mechanism,characterize the crystallization-related properties and conduct the in vitro and in vivo evaluation.Methods:The polyisobutylene,polybutene and petroleum resin are used as auxiliary materials,and the transdermal patch is prepared according to the principle of drug recrystallization.The crystallization behavior and in vitro release mechanism of the drug in the preparation were studied by means of a microscope;the in vitro test drug content was analyzed by high performance liquid chromatography.The drug crystallization was used as an indicator to screen and optimize the preparation process.The f₂ similarity factor was used as an indicator to conduct prescription research using orthogonal design experiments.The dissolution and transdermal properties in vitro were evaluated by a dissolution tester and a transdermal tester.The crystallization-related properties were characterized by differential thermal analysis and Fourier transform infrared spectroscopy.The quality of the patch was evaluated using a microscope,an initial adhesion tester,a viscosity tester,a peel tester,etc.New Zealand rabbits were used as experimental animals to investigate the pharmacokinetic behavior in vivo.Results:A drug crystal depot system in the tulobuterol patch was established.The drug crystals in the patch are uniformly distributed in the form of transparent filaments.The average crystal width is about?4.4±1.8??m,and the average length is about?26.6±17.5??m.The characteristics of DSC and MATR spectra of self-made patches are similar to reference preparations.In the dissolution medium of water or phosphate buffer solution of pH=7.4,6.8,4.0,f₂ was 72.516,94.840,90.905,81.760,all of them are above 50,in line with the Higuchi release process.The in vitro transdermal test conforms to the zero-order kinetic equation and belongs to the Fick's diffusion mechanism.The average permeability on 24h is 92.0%,the ratio of the average permeability to the reference preparation is 1.02,and the ratio of skin retention is 0.88.And the correlation between transdermal and dissolution in vitro is better;it is proved that the consistency of in vitro evaluation meets the requirements.Under the hindrance of migration by polymer excipients,there is no visible crystallization in the drying stage;under the influence of temperature and supersaturation,the initial crystallization is controlled for 12h,and then matured at room temperature;the crystal size and growth direction are limited by the back layer and the bonding layer space;After 7 days,the relative steady state of"crystallization-redissolution equilibrium"was reached;42.86%⁵7.14%of the drugs were uniformly dispersed in the bonding layer in crystalline form,and the remaining drugs were dissolved in the bonding layer in the form of drug molecules to form a drug crystal depot system.After the patch used,the drug is slowly released into the dissolution medium,while the tulobuterol crystals are redissolved to continuously replenish the supplied drug.Through the crystallization re-dissolution process and the polymer adjuvants to control the release behavior of the patch in vitro,the general law of drug release in vitro was revealed.The quality evaluation index and method system of the transdermal patch of the tulobuter crystal reservoir were established.Pharmacokinetics showed that the preparation reached a peak at?6.67±3.06?h,and the peak plasma concentration was?3.08±1.32?ng·mL^-1,which was maintained for 24h.The sustained release effect was obvious and there was no skin irritation.Conclusion:This project successfully prepared a transdermal patch of tulobuterol crystal reservoir,and proved the general drug crystallization behavior and drug release law in the preparation.The transdermal performance of the preparation was good,and the drug release in vivo and in vitro had obvious sustained release characteristics.The conformity evaluation of the reference preparations was in compliance with the requirements.To a certain extent,it is expected to achieve pre-sleep dosing,nighttime sleep-time asthma prone to peak time,prevent and treat nighttime asthma-like disease episodes,reduce the occurrence of adverse reactions,to achieve the purpose of drug treatment.Provide theoretical and experimental references for this type of transdermal drug delivery system research.