Study On Aitong Cataplasm Which Is A Traditional Chinese Medicine Compound Transdermal Drug Delivery Prescription

Cancer pain is caused by the cancer itself or generated during the treatment of cancer. Currently, cancer has become the first cause of death, and the number of fatal cases caused by it has exceeded the sum of the ones caused by AIDS, tuberculosis, malaria. Cancer pain is one of the most important issues the cancer patients are facing in the cancer clinical manifestations. But because of the problems such as the side effects of the anti-cancer pain drug, the expensive treatment costs, etc. they resulted in a serious shortage of clinical treatment of cancer pain. Aitong Paste is an experienced prescription of the treatment of the pain caused by various malignant tumors in the clinical practice, in the second Chinese Medicine Hospital of Guangdong Province. Aitong Paste is of the effect of warming the meridians, eliminating the tumor, releasing the pain, and is mainly used for the cure of the pain caused by a variety of malignancies. Aitong Paste has been in clinical use for many years. The number of clinical curative effect cases is over one thousand. It has good clinical efficacy, and no serious side effects have been found. Aiming at the clinical characteristics of the cancer pain and the existing shortcomings in the therapy of the cancer pain, and under the guidance by the theory of "internal diseases treated with external therapy" in traditional Chinese Medicine, the study compounds the treatment characteristics of the cancer pain and the transdermal drug delivery formulations and exploits it with the the modern technique of drug for Chinese herbal compound transdermal drug delivery formulations—Aitong cataplasm with the efficacy of a unique, easy to use, less toxicity, and non-invasive administration. In this thesis, the extraction process, matrix optimization, penetration enhancers screening and optimization, manufacturing process, quality standards, stability, the main pharmacodynamic and safety pharmacology and toxicology are also studied for Aitong cataplasm.1. Research on the Extraction Process of Aitong cataplasmAccording to modern chemical composition, pharmacological and clinical research of all Chinese herbal medicine in Aitong cataplasm, it decided to extract and separate of the main active site with a certain concentration of ethanol or water1.1 The results of Cinnamon, ginger essential oil extracted optimize:cinnamon and ginger are crushed into coarse powder, and is extracted by steam distillation for 5h. It can reach up to 97% of the total oil 1.2 Study of water extraction process of Paeoniae, Safflower, and Cinnamon and Ginger residue after oil extractionThe amount of water added, extraction time and extraction times were investigated as the main factors. the extraction percentage of Paeoniflorin and HSYA assessment were used as evaluating indicator, three factors and three level orthogonal design were used to optimize the best water extraction process, and the optimum extraction conditions were:8 times per volume of water added, boiled 3 times and 1.5h each time.1.3 Study of ethanol extraction process of Aconitum, Arisaematis, Dahuricae and FrankincenseThe main pharmacological components of Aconitum, Arisaematis, Dahuricae, Frankincense are mostly fat-soluble components, so the extraction percentage of Alkaloids Aconitine and Imperatorin were used as evaluating indicator, and investigated the best extract alcohol concentration and extraction time. Also the orthogonal design method was used to optimize the extraction alcohol process, the best alcohol selection extraction process was to add 10 times 60% ethanol, boiled 2 times and 1h each time.2. Study on screening and optimizing the matrix prescription of Aitong CataplasmAppearance, bubble number, pool time and the surface viscosity as the index for evaluation, single factor was used for screening matrix and determined:sodium polyacrylate, glycerin, polyvinyl alcohol, gelatin, kaolin, Aluminum glycinate, citric acid, castor oil for the matrix composition of Aitong Cataplasm, the initial viscosity, peel strength and appearance of the comprehensive score as the index, Uniform design U17(1716) was used to optimize the matrix formulation of Aitong Cataplasm, and the results of quadratic polynomial stepwise regression equation of the optimization the experimental design shows that the matrix of Aitong cataplasm composed of the optimal ratio of matrix was:Sodium polyacrylate:Gelatin:Kaolin:Aluminium glycinate:Castor oil:Glycerol: Polyvinyl alcohol (6.46:6.0:4.1:0.08:0.1:56:0.05). The results showed that the Aitong Cataplasm prepared in the optimum conditions has a good scalability, smooth appearance, moderate viscosity, good moisture retention and good compatibility with Aitong Cataplasm powder.3. Study on Optimize penetration enhancers of Aitong Cataplasm3.1 Established the in-vitro percutaneous penetration test method of Aitong Cataplasm.By examining the influence of the different receiving medium, the skin of different animals, magnetic stir speed, test temperature on in vitro percutaneous permeation behavior of the paeoniflorin in the Aitong cataplasm, establish experimental methods of Paeoniflorin in vitro percutaneous absorption:the abdominal skin of mice hair removal is for the study object, saline is for receiving medium, test temperature is 32℃, and the magnetic stir bar rotation speed is 200r/min respectively. 3.2 Study on the influence of the different transdermal penetration enhancers on transdermal absorption of Aitong CataplasmThe most commonly used Azone, Oleic acid, Propylene glycol, Menthol, Borneol etc. permeation enhancers were used as the research object, respectively, in vitro percutaneous absorption, study the influence of 0%,1%,2%,3%,5%Azone; 0%,1%,2%,3%,5%, 7.5%,10%oleic acid; 0%,5%,6%,7.5%,8%,10%propylene glycol; 0%,0.5%,0.75%, 1%,1.5%,1.75%,2% menthol; 0%,0.5%,0.75%,1%,1.5%,1.75%,2% of borneol on the Paeoniflorin dose transdermal absorption of Aitong Cataplasm, calculating Qn, Q, J, ER and TLAG, and drew the penetration curve. The results show that adding oleic acid (1%) causes cause Aitong Cataplasm paste leakage phenomenon, and it is not fit to enhance paeoniflorin penetration of Aitong Cataplasm; besides, the Azone (0%～3%), propylene glycol (5%～8%), Menthol (0.5%～1.5%), Borneol (0.75%～1.5%) in a certain range of concentration with different levels enhancement of Paeoniflorin penetration effect, and cannot cause serious change of the appearance characteristics of Aitong Cataplasm3.3 Optimize the multiple penetration enhancers of Aitong Cataplasm with the Uniform Design MethodTransdermal absorption enhancers alone are not effective, often combined elements from the hydrophilic and hydrophobic molecules or two or three or even multiple composite transdermal penetration system. Depending on the single factor results of the concentration of Azone, propylene glycol, menthol, borneol, the appearance of an integrated score, initial adhesion, continued adhesion, Paeoniflorin transdermal absorption rate constants (J) are used as evaluating indicators, and uniform design U7 (74) was used to optimize the prescription of multiple penetration enhancers. The results showed that optimal composite ratio of multiple penetration enhancers of Aitong cataplasm was:Azone (1.54%)-Propylene glycol (7.53%)-Menthol (1.26%)-Borneol (1.50%), and the validation test results showed that the multi-compound penetration enhancers on the promotion of Aitong Cataplasm absorption is better than the single species of penetration enhancers.4. Study on Molding Process of Aitong CataplasmAfter the extraction process, matrix formulation and the penetration enhancers formula had been determined, study on the extract moisture and the influence of the matrix strength, viscosity and gelling time performance caused by adding the penetration enhancers into matrix etc. In the meantime study on appropriate prescription drug matrix can loading, the addition of drug substrates in order, stirring speed and time, the method of reduce bubble number, coating method, coating time, coating thickness, drying temperature and method of Aitong Cataplasm. Cataplasm molding process are:bring the amount of polyvinyl alcohol of prescription, adding 150-fold (g/ml) distilled water, record the weight and solution it in heating 90℃water bath (with a small amount of added water), let cool, and make up weight, adding gelatin, standing swelling, dissolved in 50℃water bath set to include kaolin,50℃water bath and stir well, get A-phase; bring sodium polyacrylate, mix in a small amount of glycerol and mix by adding appropriate amount of distilled water, stir quickly, standing to full swelling, mix well, get B-phase; take a small amount of citric acid dissolved in distilled water, Aluminium Glycinate and residual glycerol and mix, adding cinnamon, ginger essential oil, castor oil, penetration enhancers, then add extract, mix well, get C-phase; add the A-phase into B-phase under 50℃water bath,, mix well, then add C-phase, mix well; the modulation Paste coating with machine and regulate the coating specifications, coating molding, dry and cut specification 8.5cm×12cm of sheet material, quality control, packaging.5. Study on the Quality Standard of Aitong CataplasmThe quality standard of Aitong Cataplasm was developed according to the common requirement of patch described in the appendix of Chinese Pharmacopoeia (Part One) (Edition 2005) and specific character of cataplasm. TLC was used to identify the Aconitum, Dahuricae, Cinnamon, Paeoniae, Safflower, Frankincense, Ginger, etc the qualitative in Aitong cataplasm. Results of experiments show that the identification methods that can be identifiable, reliable, specific, negative control without interference; it should contain the amount of ointment not less than 9.8g per 100cm2, Adhesion test according to adhesion assay (Appendix XII E 1st law) to take on the 7th ball, shall comply with provisions; according to adhesion test assay (Appendix XII E Second Law), cataplasm slipped to the time off should be more than 40 seconds; and study on shaping, weight variation, microbial limit qualification; HPLC were used to determine the content of the Aconitum alkaloids, Paeoniflorin, HSYA A, Imperatorin. According to the experimental results, the provisions of each piece, containing Aconitum calculated by the total amount of aconitine (C34H47NO11), hypaconitine (C33H45NO10) and mesaconitine (C33H45NO11) should be 3mg-15mg; containing Paeoniae calculated by Paeoniflorin (C23H2gO11) should not be less than 18.5mg; containing Dahuricae calculated by imperatorin (C16H14O4) should not be less than 1.2mg; containing Safflower calculated by HSYA A (C27H30O15) should not be less than 7.4mg.6. Investigate Stability of Aitong CataplasmThe three batches of Aitong Cataplasm are packaged with aluminum bag. In accordance with the quality standards draft, regard the appearance of character, identification, ointment content, initial Adhesion, Continued Adhesion, microbiological examination, Aconitum alkaloids, Paeoniflorin, Imperatorin, HSYA A determination of indicators as assessment, carried out accelerated stability test and long-term stability test for 6 months. The results showed that the Aitong Cataplasm is stable within 6 months.7. Study on comparative experiment in vitro transdermal between Aitong Paste and Aitong cataplasm.The results of experiments show that the accumulated percentage of Aitong Cataplasm paeoniflorin after 24h in vitro percutaneous absorption significantly increased, reaching to 62.38%. Compared to the 30.74% of Aitong Paste, it increased by 2.03 times; The transdermal absorption constant is up to 7.64μg·cm-2·h-1 and it is 2.70 times as large as the percutaneous absorption constant 2.83μg·cm-2·h-1; The average lag time was 0.75h, which is 2.78 times as large as 0.27h of Aitong Paste.8. Experimental Study of Pain Cataplasm Pharmacodynamics and safety8.1 In the experiments, Shexiang Zhuifeng Paste and piroxicam patch were used as positive control groups, matrix was used as blank control group, established the Aitong Paste group, and observed Aitong Cataplasm writhing induced by glacial acetic acid-induced inhibition of writhing response in mice. The results showed that the high, medium and low doses of Aitong cataplasm can reduced writhing response in mice writhing reaction to glacial acetic acid-induced; the analgesic effect of high dose group was better than Aitong paste and Shexiang Zhuifeng paste, and analgesic effect of low-dose group was slightly better than Aitong paste; it prompt that there is a certain relationship between pain analgesic effect and dose.8.2 Animal experiments showed that obvious skin irritation was not be found on New Zealand rabbits; obvious acute skin toxicityin was not be found on New Zealand rabbits; and skin significantly allergenic effect was not be found on guinea pig.