| Postoperative pain is an acute injury pain happened after the surgery,which is a complex physiological and psychological reaction during the body’s tissue injury and repair processes,and seen in almost all patients.Postoperative pain time mainly focus on 2448h,some sustainable 7d,if processing is not timely,it may not only cause a series of adverse effects and postoperative complications to the body,but also lead to the development of acute pain to long-term chronic pain in patients.Currently there are a lot of drugs can control postoperative pain,above them the local anesthetics play an important role in postoperative analgesia for it’s low addiction and less side effects,etc.Ropivacaine hydrochloride is a novel long-acting amide local anesthetic,compared to other local anesthetics,it has a fast metabolism,low toxicity of the central nervous system and cardiovascular system,and can separate sensory block and motor block more obvious,so it is more suitable for postoperative analgesia.Currently there is only ropivacaine hydrochloride injection on the market,for it’s short half-life,it normally takes 4 to 6 hours or continuous infusion administered once to get a satisfactory analgesic effect,which is inconvenient to use for the patient.In order to increase the local concentration of the drug,to prolonged drug action and improved patient compliance,this subject has developd a ropivacaine hydrochloride transdermal gel that can 24h administered once,which use carbopol as gel carrier material,propylene glycol as humectant and solubilizer,triethanolamine as a pH adjusting agent,and azo-ne as transmural skin penetration enhancers.This paper mainly reports the prescription screening,in vitro percutaneous penetration,stability,pharma-codynamic and irritating evaluation of the ropivacaine hydrochloride transdermal gel.Preformulation study established the content determination method of ropivacaine hydrochloride in gel,and the analysis method of in vitro percutaneous permeation tests.In formulation screening study,this paper firstly through the single factor studies showed that the drug cumulative penetration and steady transdermal rate were increased with the increase of drug content in the gel,and ultimately determine the amount of ropivacaine hydrochloride in gel was 5%.According to the production process,forming appearance,smear feeling and stability of the drug-containing gel,we ultimately establish the optimum amount range of carbomer and propylene glycol in prescription were2%to 3%and 10%to 20%respectively.Then took drug cumulative penetration and steady transdermal rate as index to optimize the dosage of carbomer,propylene glycol and azone in prescription by in vitro transdermal release test and orthogonal design.The results showed that the influence order on drug cumulative penetration and steady transdermal rate of these three factors was carbomer>propylene>azone;the optimal prescription of gel was content of 2%carbomer,10%propylene glycol and 5%azone;the cumulative transdermal percentage at 24 hours and steady transdermal rate of optimal prescription were 91.04%and 0.6951mg·cm-2·h-1 respectively.With appearance,pH,traits after centrifugation and drug content as indexes to preliminary evaluated the stability of the optimal prescription of ropivacaine hydrochloride gel.The results showed that ropivacaine hydrochloride gel was unstable at high temperatures and high humidity conditions.Accelerated testing and long-term stability test results showed that ropivacaine hydrochloride gel had good stability in the accelerated and natural conditions.The gel was translucent,the colour was pale white,the viscosity was moderate,the pH value was about 6.2 to 6.4,there were no mildew phenomenon such as corruption,and the content showed no obvious change.Hot plate test and writhing test in mice was applied to evaluated the pharmacodynamic of ropivacaine hydrochloride gel,and to studied the effect and duration of analgesia.The results showed that compared to the blank control group and the positive control group,ropivacaine hydrochloride gel has a longer analgesia duration,in which the analgesia duration of 1%ropivacaine hydrochloride gel was about 8h,the analgesia duration of 3%ropivacaine hydrochloride gel was more than 12h and the analgesia duration of 5%ropivacaine hydrochloride gel could sustainable 24h.With the improvement of ropivacaine hydrochloride content in the gel,the intensity of pain relief was improved,compared to 1%and 3%ropivacaine hydrochloride gel,5%ropivacaine hydrochloride gel has the most significant analgesic effect in each time point.Using rat’s epilation abdominal skin as the test object to investigated skin irritation of ropivacaine hydrochloride gel and blank gel.The standard stimulus xylene was used as positive control,the physiological saline was used as negative control.Observing the skin situation of each coated area within72h,after 72h the rats were executed and each coated area of skin was collected to make pathological sections.The results showed that ropivacaine hydrochloride gel and blank gel showed no apparent skin irritation.To sum up,the hydrochloride ropivacaine transdermal gels by this study had stable quality,good analgesic effect,and can sustained release 24h with non-irritating to the skin.Therefore,this project is expected to provide a better option for postoperative analgesia. |
