| Local chronic pain is very common in clinical,such as nerve pain,surgical pain,joint pain and so on,and a long-term effective local analgesic preparation is needed.Although there are many topical formulations,such as liniment,patch,plaster and so on,the skin effect is poor,can not reach the deeper part,the local effect is not lasting,the analgesic effect is not ideal,and the long-term use will have certain irritation to the skin.Therefore,a powerful,long-term and safe local analgesic preparation is needed.Postherpetic neuralgria(PHN)is a serious sequela of herpes zoster,which is a neuropathic pain.It is a world-class refractory chronic neuropathic pain syndrome,which seriously affects the quality of life of the patients.At present,the methods and drugs for effective clinical treatment are limited.On the basis of current clinical routine treatment,this paper intends to develop a long effect local injection,which aims to play a strong,long-term and safe local analgesic effect on the related neural pathways,reduce the long-term pain of patients and improve the life quality of patients.Amide narcotic drugs play an indispensable role in the clinical treatment of PHN due to their relatively low addiction and side effects.In this paper,Lidocaine Hydrochloride(LH)is selected as a model drug.It is one of the main local anesthetics commonly used in clinic.It has the characteristics of large penetration,quick action,long time,wide spread and stable nature.The main clinical application on PHN is local injection block anesthesia.Because of its short time,many multiple injections are often needed,which can increase the pain for patients.This article is to make long-acting local injection of lidocaine hydrochloride,which can reduce injection times and pain,and improve patient's compliance.The long acting local injection matrix selects Sodium Hyaluronate(SH)or its crosslinking with PEG.SH is a widely distributed macromolecular mucopolysaccharide,which is easily soluble in water,has good biocompatibility and can be completely hydrolyzed by hyaluronidase in the body.It is an ideal biomaterial material.It has been used in the prevention of postoperative adhesions and soft tissue filling.The sustained release properties of SH and cross-linked SH as matrix material were compared in the study.In this study,the concentration range of sodium hyaluronate and the range of PEG dosage were determined by single factor test,and the orthogonal experiment was used to determine the optimal prescription.This study investigated by simple sodium hyaluronate injection as a matrix and a sodium hyaluronate and PEG cross-linking reaction after gel as two kinds of injection preparations in vitro matrix accumulated release results,investigate the in vitro long-term local injection of lidocaine hydrochloride gel cumulatereleaserate by dialysis bag method.The optimal formulation of the optimized prescription gel matrix SH content is 1%,the cross-linking agent PEG4000 content is 0.07%,the reaction temperature is 60 degrees,the main drug lidocaine hydrochloride content is 20mg/mL.The cross-linked sodium hyaluronate injection for cumulative release gel matrix in 120 h and 144 h was 95.2% and 95.2% respectively,while in non cross-linked sodium hyaluronate gel matrix for injection in cumulative release of 120 h is 102%,indicating that both showed significant sustained release effect,gel matrix sustained longer.Chromatographic method was developed to establish the quality control method of lidocaine hydrochloride long-acting local injection by high performance liquid,and the evaluation of the quality of 3 batches of samples,the contents were 100.82%,99.80% and 101.26%(n=6),indicating the contents of main components were in the range of 90.0%~110.0%,to meet the requirements.Through influencing factors test and long-term stability test,the initial stability of the preparation was evaluated by appearance,pH and main content.The results showed that the preparation had good stability.In this paper,SD rats were selected as the subjects,and the internationally accepted sciatic nerve chronic compression injury models(CCI)were selected.The rats were randomly divided into 4 groups,the control group was given normal saline,the positive control group was given lidocaine hydrochloride solution,and the drug delivery group was divided into two groups,respectively,lidocaine hydrochloride,sodium hyaluronate gel and lidocaine hydrochloride cross-linked sodium hyaluronate gel.After the preparation of the pain model,the corresponding drug was injected by the sciatic nerve in the rat,and the pharmacodynamics of the four groups of rats was studied.The results show that with the blank control and positive controls compared to that of lidocaine hydrochloride crosslinked and non-crosslinked sodium hyaluronate gel after administration of 72 h can significantly improve the mechanical withdrawal threshold,prolong the thermal pain threshold and reduce the cumulative pain scores,efficacy significantly prolongs the duration of analgesia,with obvious sustained release effect in vivo.The biocompatibility tests using SD rats as experimental objects,making the model of chronic compression injury of the sciatic nerve after fifth days after administration,the rats were sacrificed and the incision site of administration were observed and collected rats were administered at muscle and sciatic nerve and were stained by HE,on each section of pathological changes were observed by optical microscope.The results showed that there was no significant difference between the 5 groups after three days.There were no obvious pathological changes in sciatic nerve in the three groups.There were only a few inflammatory reactions in the three groups,indicating that the lidocaine hydrochloride cross linked sodium hyaluronate gel had good biocompatibility. |
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