The Study Of Strychnine And Its Ion-pair Patch

Strychnine is a weak alkaline indole Alkaloids.It can excite spinal cord and medullary center and also stimulate the cerebral cortex at low dose levels.It is clinically useful for the treatment of hemiplegia,amblyopia and barbiturate poisoning.As a glycine receptor antagonist,it can cause paralysis of the respiratory muscles when it is used excessively,eventually causing the patient to suffocate and die.At present,strychnine hydrochloride or strychnine nitrate is commonly used in clinical practice and administered by oral or injection.It can be quickly absorbed by the gastrointestinal tract,and its absorption rate in the body is greater than its metabolic rate,which can also quickly penetrate the blood-brain barrier and cause neurotoxicity.Transdermal drug delivery system?TDDS?has the advantages of maintaining blood concentration,reducing the number of administrations and improving the safety of medication.This topic explored the effect of ion-pair technology on the transdermal penetration of strychnine,developed a patch containing strychnine,and preliminarily discussed the formation of ion pair and percutaneous penetration mechanism from the molecular level by molecular simulation.Firstly,seven different organic acids were employed with the aim of ion-pair forming with strychnine.The ion-pair formation was confirmed by ¹H-NMR and FTIR spectroscopy.From the ¹H-NMR spectral data,shift changes were observed on protons adjacent to N of Str in all complexes after Str reacted with different organic acids.Chemical shift values increase and downfield shift change were observed in H?16?,H?17?,H?18?,H?20?and H?22?of Str.From the FTIR spectra,when Str reacted with organic acids,the stretching vibration of the C=O group(?_C=O)from C₁₀,C₁₂,C₁₄,C₁₆ and C₁₈ got blue shifted to 1722?88?^?11716?88?^?1.Furthermore,stretching vibration of the C=O group??C=O?of C₄ and C₆ overlaped with the?C=O of Str and a broad?C=O absorption peak was appeared.The stretching vibration of the C=O group(?_C=O)from C₄ and C₆ also got blue shift compared with the?C=O of Str.What's more,a new peak occurred among 1567?88?^?11556?88?^?1,which was attributed to the absorption band of the COO^-group??COO^-?that was a symbol of the interaction between carboxyl group in organic acids and N in Str.Thus,these changes in ¹H-NMR and FTIR spectroscopy provided evidence for the formation of Str ion pairs complexes between the organic acids and Str.Secondly,established a method for determining strychnine content by HPLC.The in vitro transdermal permeation of str and its ion-pair complexes were investigated.In this study,the Q_14h of str ion-pair complexes increased significantly,and str-C₁₀ was the most potential candidate with the Q_14h being 315.47±22.00?g·cm^?2.In this paper,the transdermal performance of str or str ion-pair complexes in different types of hot melt pressure sensitive adhesives were investigated.It was found that the transdermal performance of str ion-pair complexes in hot melt pressure sensitive adhesives was worse than that of str.Subsequently,the patch prescription was optimized.The best prescription of str patch is:SJ hot melt pressure sensitive adhesive as matrix,3%str?w/w?drug loading and with 3%Azone.Finally,molecular modeling was used to explore the formation of str organic acid ion pair and percutaneous penetration mechanism at a molecular level.Molecular modeling revealed that hydrogen bond ion pair was formed between str and organic acids.Upon the formation of ion pairs,the H-bonding interaction between str and the ceramide 2 in SC was apparently weakened and hardly detected,which increased amounts of ion-pair complex entering the viable epidermis.When the ion-pair complex entered the active epidermis,due to the presence of the aqueous environment,the interaction between strychnine and the organic acid was weakened,and even str ion-pair complexes may be dissociated in the VED.Therefore,the transdermal amount of strychnine was increased.