TWI701046B - Drug delivery system - Google Patents
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Abstract
本發明係關於一種藥物傳遞系統，其包含水包油之微乳液，以提升親脂性活性成分之溶解度及生體可用率。本發明另提供一種包含厚朴酚微乳液之醫藥組合物，以及將厚朴酚及其微乳液用於製備治療中風之藥物的用途。The present invention relates to a drug delivery system comprising an oil-in-water microemulsion to improve the solubility and bioavailability of lipophilic active ingredients. The present invention also provides a pharmaceutical composition containing magnolol microemulsion, and the use of magnolol and its microemulsion to prepare drugs for treating stroke.
Description
本發明提供一種藥物傳遞系統，特別是用於提升親脂性活性成分之溶解度及生體可用率之微乳液。本發明另提供一種包含厚朴酚微乳液之醫藥組合物，以及將厚朴酚及其微乳液用於製備治療中風之藥物的用途。The present invention provides a drug delivery system, especially a microemulsion for improving the solubility and bioavailability of lipophilic active ingredients. The present invention also provides a pharmaceutical composition containing magnolol microemulsion, and the use of magnolol and its microemulsion to prepare drugs for treating stroke.
中風(Stroke)為全球死亡之第四大主因，並同時為長期致殘之主要成因。在台灣，中風於過去10年中為第三大死因。中風成因及類型複雜，以腦中血流受阻中斷為例，病患可能突然出現肢體癱瘓或麻木、語言能力受損、運動失調、眩暈，甚至是喪失視力。基於中風之高發病率和健康傷害，有研究顯示70％病患之工作能力受損，並有30%病患需要自我照護協助，不僅造成沉重之個人負擔，亦為重大之公衛挑戰。Stroke is the fourth leading cause of death worldwide, and it is also the leading cause of long-term disability. In Taiwan, stroke has been the third leading cause of death in the past 10 years. The causes and types of stroke are complex. Taking the interruption of blood flow in the brain as an example, the patient may suddenly experience paralysis or numbness, impaired language ability, movement disorders, dizziness, and even loss of vision. Based on the high incidence of stroke and health damage, studies have shown that 70% of patients have impaired work ability and 30% of patients require self-care assistance. This not only causes a heavy personal burden, but also poses a major public health challenge.
最近研究數據顯示，「缺血性腦中風」占約80-87％，「出血性腦中風」則占約9-13%。「出血性腦中風」包括腦出血和蛛網膜下腔出血，其致病之主要危險因素為高血壓，並通常無預警地發生於冬季，症狀包括頭痛、噁心或嘔吐、四肢麻痺或麻木、言語不清及運動失調等。「蛛網膜下腔出血」成因則通常為腦動靜脈血管畸形破裂，症狀包含頭痛、頸部僵硬、噁心或嘔吐、四肢麻痺或麻木、言語不清及運動失調等。Recent research data show that "ischemic stroke" accounts for about 80-87%, and "hemorrhagic stroke" accounts for about 9-13%. "Hemorrhagic stroke" includes cerebral hemorrhage and subarachnoid hemorrhage. The main risk factor for the disease is high blood pressure. It usually occurs in winter without warning. Symptoms include headache, nausea or vomiting, paralysis or numbness of limbs, and speech Unclear and movement disorders, etc. The cause of "subarachnoid hemorrhage" is usually the rupture of cerebral arteriovenous malformations. Symptoms include headache, neck stiffness, nausea or vomiting, paralysis or numbness of the limbs, slurred speech, and movement disorders.
「缺血性腦中風」包括腦血栓和腦栓塞。「腦血栓」為供給腦養分之動脈的粥狀硬化斑塊破裂所導致，「腦栓塞」則指病患體內其他部位之血凝塊或脂肪等形成栓子，藉由血液循環流入腦部，進而導致腦血管堵塞。「缺血性腦中風」具有多重及彼此加乘之危險因素，雖然高血壓和年齡為中風之重要危險因素，但最新研究顯示有中風之家族病史者，亦有較高之罹病風險。"Ischemic stroke" includes cerebral thrombosis and cerebral embolism. "Cerebral thrombosis" is caused by the rupture of atherosclerotic plaques in the arteries that supply brain nutrients. "Cerebral embolism" refers to the formation of emboli from blood clots or fat in other parts of the patient's body, which flow into the brain through blood circulation. This leads to blockage of cerebral blood vessels. "Ischemia stroke" has multiple and multiplying risk factors. Although hypertension and age are important risk factors for stroke, the latest research shows that people with a family history of stroke are also at higher risk of illness.
鑒於大多數「缺血性腦中風」係由大腦動脈(如總頸動脈)或其分支中有血栓，因栓塞性閉塞血管而造成者，且「雙側總頸動脈閉塞」之缺血性腦中風患者之預後較差，進而導致後續再次中風之罹病率及死亡率皆較高，而有開發新藥物之必要性。因市面上之藥物選項有限，且活性成分通常水溶性不佳，不易為病患所利用，而有開發新劑型，以提升病患生體可用率之需求。In view of the fact that most "ischemic strokes" are caused by thrombosis in cerebral arteries (such as common carotid artery) or its branches, caused by embolic occlusion of blood vessels, and "bilateral common carotid artery occlusion" ischemic brain The prognosis of stroke patients is poor, which leads to higher morbidity and mortality of subsequent strokes, and there is a need to develop new drugs. Due to the limited options of drugs on the market and the fact that the active ingredients are usually poorly soluble in water, they are not easily available to patients. Therefore, there is a need to develop new formulations to increase the availability of patients.
本發明提供一種藥物傳遞系統，包含：活性成分和載劑系統，並形成水包油(oil in water)之微乳液；該載劑系統包含水、油和乳化劑，其中以該載劑系統之總重為基準，該水之重量百分比為5%至60%，該油之重量百分比為5%至80%，以及該乳化劑之重量百分比為15%至90%，且該油包含脂肪酸油(fatty acid oil)，該乳化劑包含非離子界面活性劑(nonionic surfactant)。The present invention provides a drug delivery system comprising: an active ingredient and a carrier system, and forming an oil in water (oil in water) microemulsion; the carrier system comprises water, oil and emulsifier, wherein the carrier system Based on the total weight, the weight percentage of the water is 5% to 60%, the weight percentage of the oil is 5% to 80%, and the weight percentage of the emulsifier is 15% to 90%, and the oil contains fatty acid oil ( fatty acid oil), the emulsifier contains a nonionic surfactant.
較佳的，該藥物傳遞系統不包含二甲基亞碸(Dimethyl sulfoxide, DMSO)。Preferably, the drug delivery system does not contain dimethyl sulfoxide (DMSO).
較佳的，該載劑系統由水、油和乳化劑所組成。Preferably, the carrier system consists of water, oil and emulsifier.
更佳的，該藥物傳遞系統，由活性成分和載劑系統所組成。More preferably, the drug delivery system is composed of an active ingredient and a carrier system.
較佳的，該乳化劑不包含：陽離子界面活性劑(cationic surfactant)、陰離子界面活性劑(anionic surfactant)或雙離子/兩性界面活性劑(amphoteric / zwitterionic surfactant)。Preferably, the emulsifier does not include: cationic surfactant, anionic surfactant, or amphoteric/zwitterionic surfactant.
本發明所述之「微乳液(microemulsion)」係指一種將活性成分包埋至尺寸介於微米至奈米之間的微乳液液滴(emulsion droplet)的藥物傳遞系統，且該微乳液液滴包含油、水和乳化劑三種成分，為一熱力學穩定(thermodynamically stable)之等向性(isotropic)混合物，並通常為澄清的。The "microemulsion" in the present invention refers to a drug delivery system in which active ingredients are embedded in microemulsion droplets with a size between micrometers and nanometers, and the microemulsion droplets It contains three components: oil, water and emulsifier. It is a thermodynamically stable isotropic mixture and is usually clear.
此外，微乳液(microemulsion)與乳液(emulsion)並不相同，原因在於乳液係混濁的，且最終將出現相分離(phase separation)，而欠缺熱力學穩定性，以及乳液製作上亦較微乳液耗能。因此，微乳液與乳液在熱力學穩定性、外觀和製法等三方面皆不相同。In addition, microemulsion and emulsion are not the same. The reason is that the emulsion is turbid and will eventually undergo phase separation, lacks thermodynamic stability, and the production of emulsion is also more energy-consuming than microemulsion . Therefore, microemulsions and emulsions are different in terms of thermodynamic stability, appearance and preparation method.
較佳的，以該載劑系統之總重為基準，該水之重量百分比為5%、10%、15%、17%、18%、19%、20%、21%、22%、23%、25%、30%、35%、37%、40%、43%、45%、48%、49%、50%、51%、52%、55%、60%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total weight of the carrier system, the weight percentage of the water is 5%, 10%, 15%, 17%, 18%, 19%, 20%, 21%, 22%, 23% , 25%, 30%, 35%, 37%, 40%, 43%, 45%, 48%, 49%, 50%, 51%, 52%, 55%, 60%, any of their values The interval formed by two, or any value within the interval formed by any two of its equivalent values.
較佳的，以該載劑系統之總重為基準，該油之重量百分比為5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、18%、19%、20%、21%、22%、25%、30%、35%、40%、45%、48%、49%、50%、51%、52%、55%、60%、65%、70%、75%、80%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total weight of the carrier system, the weight percentage of the oil is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% , 15%, 18%, 19%, 20%, 21%, 22%, 25%, 30%, 35%, 40%, 45%, 48%, 49%, 50%, 51%, 52%, 55 Any one of %, 60%, 65%, 70%, 75%, 80%, an interval formed by any two of its equivalent values, or any value within an interval formed by any two of its equivalent values.
較佳的，以該載劑系統之總重為基準，該乳化劑之重量百分比為15%、18%、19%、20%、21%、22%、25%、30%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、48%、49%、50%、51%、52%、55%、60%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、80%、85%、90%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total weight of the carrier system, the weight percentage of the emulsifier is 15%, 18%, 19%, 20%, 21%, 22%, 25%, 30%, 35%, 36 %, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 48%, 49%, 50%, 51%, 52%, 55%, 60%, Any one of 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 80%, 85%, 90%, any two of these values The interval formed, or any value within the interval formed by any two of its equivalent values.
在一具體實例中，以該載劑系統之總重為基準，該水之重量百分比為37%至43%，及/或該油之重量百分比為8%至12%，及/或該乳化劑之重量百分比為45%至55%。In a specific example, based on the total weight of the carrier system, the weight percentage of the water is 37% to 43%, and/or the weight percentage of the oil is 8% to 12%, and/or the emulsifier The weight percentage is 45% to 55%.
較佳的，以該載劑系統之總重為基準，該水之重量百分比為40%，及/或該油之重量百分比為10%，及/或該乳化劑之重量百分比為50%。Preferably, based on the total weight of the carrier system, the weight percentage of the water is 40%, and/or the weight percentage of the oil is 10%, and/or the weight percentage of the emulsifier is 50%.
在另一具體實例中，以該載劑系統之總重為基準，該水之重量百分比為17%至23%，及/或該油之重量百分比為8%至12%，及/或該乳化劑之重量百分比為65%至75%。In another specific example, based on the total weight of the carrier system, the weight percentage of the water is 17% to 23%, and/or the weight percentage of the oil is 8% to 12%, and/or the emulsification The weight percentage of the agent is 65% to 75%.
較佳的，以該載劑系統之總重為基準，該水之重量百分比為18%、19%、20%、21%或22%，及/或該油之重量百分比為9%、10%或11%，及/或該乳化劑之重量百分比為66%、67%、68%、69%、70%、71%、72%、73%或74%。Preferably, based on the total weight of the carrier system, the weight percentage of the water is 18%, 19%, 20%, 21% or 22%, and/or the weight percentage of the oil is 9%, 10% Or 11%, and/or the weight percentage of the emulsifier is 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73% or 74%.
更佳的，以該載劑系統之總重為基準，該水之重量百分比為20%，及/或該油之重量百分比為10%，及/或該乳化劑之重量百分比為70%。More preferably, based on the total weight of the carrier system, the weight percentage of the water is 20%, and/or the weight percentage of the oil is 10%, and/or the weight percentage of the emulsifier is 70%.
在一具體實例中，該水為蒸餾水或無菌水。In a specific example, the water is distilled water or sterile water.
在另一具體實例中，該油包含油酸(Oleic acid，簡稱OA)、三酸甘油酯(Triglyceride，簡稱TG)、橄欖油(Olive oil)、甘油(Glycerol, 簡稱Gly)、α-次亞麻油酸(α-Linolenic acid, ALA)、二十一碳五烯酸(Heneicosapentaenoic acid, HPA)、二十碳五烯酸(Eicosapentaenoic acid, EPA)、二十二碳六烯酸(Docosahexaenoic acid, DHA)、二十碳四烯酸(Eicosatetraenoic acid, ETA)、二十碳三烯酸(Eicosatrienoic acid, ETE)、亞麻油酸(Linoleic acid)、γ-次亞麻油酸(γ-Linolenic acid, GLA)、花生四烯酸(Arachidonic acid, AA)之任一或組合。In another specific example, the oil includes oleic acid (OA), triglyceride (TG), olive oil, glycerol (Glycerol, Gly), α- Sesame oil (α-Linolenic acid, ALA), Eicosapentaenoic acid (Heneicosapentaenoic acid, HPA), Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA) ), Eicosatetraenoic acid (ETA), Eicosatrienoic acid (ETE), Linoleic acid, γ-Linolenic acid (GLA) , Arachidonic acid (Arachidonic acid, AA) any one or a combination.
較佳的，該油不包含硬脂酸(Stearic acid, STA)、蓖麻油酸(Ricinoleic acid)及/或芥子酸(Erucic acid)。其中，蓖麻油酸口服有腹瀉之副作用，硬脂酸則因於常溫下呈固態，具有操作上不方便之缺點，而迴避使用。Preferably, the oil does not contain stearic acid (STA), ricinoleic acid (Ricinoleic acid) and/or Erucic acid (Erucic acid). Among them, oral administration of ricinoleic acid has the side effect of diarrhea, and stearic acid is avoided because it is solid at room temperature and has the disadvantage of inconvenience in operation.
較佳的，該油包含三酸甘油酯和油酸，且三酸甘油酯和油酸之比例為5比1至1比5。Preferably, the oil contains triglyceride and oleic acid, and the ratio of triglyceride to oleic acid is 5:1 to 1:5.
更佳的，該油包含油酸和三酸甘油酯且比例為1比2.7、2.8、2.9、3.0、3.1、3.2、3.3之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。More preferably, the oil contains oleic acid and triglycerides and the ratio is 1 to any one of 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, an interval formed by any two of their values, or their equivalent values Any value in the interval formed by any two.
再更佳的，該油包含油酸和三酸甘油酯，且油酸和三酸甘油酯之比例為1比3。Even more preferably, the oil contains oleic acid and triglycerides, and the ratio of oleic acid to triglycerides is 1:3.
在一具體實例中，該乳化劑包含界面活性劑(surfactant)及助界面活性劑(cosurfactant)。In a specific example, the emulsifier includes a surfactant (surfactant) and a cosurfactant (cosurfactant).
助界面活性劑(cosurfactant)，例如：短鏈醇類(short chain alcohols)，具有幫助微乳液形成及提升藥物傳遞系統對水之增溶載量之功效，故界面活性劑(surfactant)，例如：吐溫(Polysorbates或Tween系列產品)常與其他非離子界面活性劑併用以製備微乳液。Cosurfactants, such as short chain alcohols, have the effect of helping the formation of microemulsions and increasing the solubilization capacity of the drug delivery system to water. Therefore, surfactants, such as: Tween (Polysorbates or Tween series products) is often used in combination with other non-ionic surfactants to prepare microemulsions.
較佳的，該界面活性劑為吐溫(Tween)，更佳的，該界面活性劑為吐溫80(Tween 80)。Preferably, the surfactant is Tween, and more preferably, the surfactant is Tween 80.
較佳的，該助界面活性劑包含丙二醇(Propylene glycol)、聚乙二醇(Polyethylene glycol, PEG)、二乙二醇單乙基醚（Diethylene glycol monoethyl ether）、辛酸癸酸聚乙二醇甘油酯(Labrasol)、聚氧乙烯氫化蓖麻油(Ethoxylated hydrogenated castor oil)、聚乙烯醇(Polyvinyl alcohol, PVA)之任一或組合。Preferably, the co-surfactant comprises propylene glycol (Propylene glycol), polyethylene glycol (PEG), diethylene glycol monoethyl ether (Diethylene glycol monoethyl ether), caprylic acid capric acid polyethylene glycol glycerin Any one or a combination of ester (Labrasol), polyoxyethylene hydrogenated castor oil (Ethoxylated hydrogenated castor oil), polyvinyl alcohol (PVA).
較佳的，該助界面活性劑不包含斯盤(Span)、聚乙二醇單辛基苯基醚(Triton X-100)和聚乙烯吡咯啶酮(Polyvinyl pyrrolidone, PVP)。其中，從後述實施例可知，助界面活性劑使用斯盤時之成果不佳，聚乙二醇單辛基苯基醚及聚乙烯吡咯啶酮則皆非屬常見用於人體之材料，而有生物安全性之疑慮，故配方設計上非作為優先對象。Preferably, the co-surfactant does not include Span, polyethylene glycol monooctyl phenyl ether (Triton X-100) and polyvinyl pyrrolidone (PVP). Among them, it can be seen from the following examples that the results of using Span as a co-surfactant are not good. Polyethylene glycol monooctylphenyl ether and polyvinylpyrrolidone are not commonly used materials for the human body. Biological safety concerns, so formula design is not a priority.
更佳的，該助界面活性劑為1,2-丙二醇(1,2-propylene glycol, 1,2-PG)及/或聚乙二醇400(PEG 400)。More preferably, the co-surfactant is 1,2-propylene glycol (1,2-PG) and/or polyethylene glycol 400 (PEG 400).
在一具體實例中，該乳化劑包含吐溫80(Tween 80)、1,2-丙二醇(1,2-propylene glycol, 1,2-PG)和聚乙二醇400(PEG 400)，且以乳化劑之總量為基準，吐溫80之重量百分比含量占5%至60%、1,2-丙二醇之重量百分比含量占5%至60%且聚乙二醇400之重量百分比含量占5%至60%。In a specific example, the emulsifier comprises Tween 80, 1,2-propylene glycol (1,2-propylene glycol, 1,2-PG), and polyethylene glycol 400 (PEG 400), and The total amount of emulsifier is based on the basis. The weight percentage of Tween 80 is 5% to 60%, the weight percentage of 1,2-propylene glycol is 5% to 60%, and the weight percentage of
較佳的，以乳化劑之總量為基準，該吐溫80之重量百分比為5%、10%、15%、20%、25%、30%、31%、32%、33%、33.3%、34%、35%、36%、40%、45%、50%、55%、60%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total amount of emulsifier, the weight percentage of the Tween 80 is 5%, 10%, 15%, 20%, 25%, 30%, 31%, 32%, 33%, 33.3% Any two of, 34%, 35%, 36%, 40%, 45%, 50%, 55%, 60%, or any two of its equivalent values, or any two of its equivalent values Any value.
較佳的，以乳化劑之總量為基準，該1,2-丙二醇之重量百分比為5%、10%、15%、20%、25%、30%、31%、32%、33%、33.3%、34%、35%、36%、40%、45%、50%、55%、60%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total amount of emulsifier, the weight percentage of 1,2-propanediol is 5%, 10%, 15%, 20%, 25%, 30%, 31%, 32%, 33%, Any two of 33.3%, 34%, 35%, 36%, 40%, 45%, 50%, 55%, 60%, or any two of its equivalent values, or any two of its equivalent values Any value within.
較佳的，以乳化劑之總量為基準，該聚乙二醇400之重量百分比為5%、10%、15%、20%、25%、30%、31%、32%、33%、33.3%、34%、35%、36%、40%、45%、50%、55%、60%之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。Preferably, based on the total amount of emulsifier, the weight percentage of the
在一具體實例中，該乳化劑包含：吐溫80、1,2-丙二醇及聚乙二醇400，且吐溫80、1,2-丙二醇及聚乙二醇400之比例為0.5至2.0比0.5至1.5比0.5至1.5。In a specific example, the emulsifier comprises:
較佳的，吐溫80、1,2-丙二醇及聚乙二醇400之比例為0.5至2.0比0.8至1.2比0.8至1.2。Preferably, the ratio of
更佳的，該乳化劑包含：吐溫80、1,2-丙二醇及聚乙二醇400，且吐溫80、1,2-丙二醇及聚乙二醇400之比例為0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8或1.9比0.9、1.0或1.1比0.9、1.0或1.1。More preferably, the emulsifier includes:
在另一具體實例中，該活性成分為親油性化合物。In another specific example, the active ingredient is a lipophilic compound.
較佳的，該活性成分包含厚朴酚(Magnolol)、薑黃素(Curcumin)或其可藥用的鹽之任一或組合。Preferably, the active ingredient contains any one or a combination of Magnolol, Curcumin or a pharmaceutically acceptable salt thereof.
更佳的，該活性成分包含厚朴酚。More preferably, the active ingredient contains magnolol.
在一具體實例中，該微乳液於室溫之黏稠度為15至200厘泊(cP)，較佳的，該微乳液之黏稠度為120至170厘泊(cP)，更佳的為140、145、150、151、152、153、154、155、156、157、158、159、160、165厘泊(cP)之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。In a specific example, the viscosity of the microemulsion at room temperature is 15 to 200 centipoise (cP), preferably, the viscosity of the microemulsion is 120 to 170 centipoise (cP), more preferably 140 Any one of, 145, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165 centipoise (cP), an interval formed by any two of its values, or any of its
再更佳的，該微乳液於室溫之黏稠度為155.72 ± 2.28 cP。Even better, the viscosity of the microemulsion at room temperature is 155.72 ± 2.28 cP.
在另一具體實例中，該微乳液所含液滴之直徑為50奈米至2500奈米；較佳的為400奈米至1000奈米；更佳的為650、660、670、680、690、700、710、720、730、740、750奈米之任一、其等數值任二所形成之區間，或其等數值任二所形成之區間內之任一數值。再更佳的為697.7 ± 208.3奈米。In another specific example, the diameter of the droplets contained in the microemulsion is 50 nm to 2500 nm; preferably 400 nm to 1000 nm; more preferably 650, 660, 670, 680, 690 Any one of, 700, 710, 720, 730, 740, 750 nm, an interval formed by any two of these values, or any value within an interval formed by any two of these values. Even better is 697.7 ± 208.3 nanometers.
本發明提供一種厚朴酚(Magnolol)在製備治療、改善或減緩中風或中風所引發症狀之藥物的用途。較佳的，該中風為腦中風；更佳的，該中風為缺血性腦中風。The present invention provides a use of Magnolol in preparing a medicine for treating, improving or alleviating stroke or symptoms caused by stroke. Preferably, the stroke is a cerebral stroke; even more preferably, the stroke is an ischemic stroke.
本發明另提供一種醫藥組合物，其包含上述之藥物傳遞系統，且該活性成分包含治療有效量之厚朴酚(Magnolol)。The present invention also provides a pharmaceutical composition, which comprises the above-mentioned drug delivery system, and the active ingredient comprises a therapeutically effective amount of Magnolol.
較佳的，該厚朴酚之人用治療有效量為每日投予至少4 mg/kg。更佳的為至少4.5 mg/kg、至少4.8 mg/kg或至少5.0 mg/kg。Preferably, the therapeutically effective human dose of magnolol is at least 4 mg/kg administered daily. More preferably, it is at least 4.5 mg/kg, at least 4.8 mg/kg, or at least 5.0 mg/kg.
厚朴酚若以DMSO作為溶劑，溶解度可達16mg/ml，而在本發明之一具體實例中，使用上述之藥物傳遞系統製備厚朴酚微乳液劑，其藥物溶解度至少可達10mg/ml，且無DMSO之高毒性。If magnolol uses DMSO as the solvent, the solubility can reach 16mg/ml, and in a specific example of the present invention, the above-mentioned drug delivery system is used to prepare magnolol microemulsion, and its drug solubility can reach at least 10mg/ml. And without the high toxicity of DMSO.
此外，使用乙醇與PBS之比例為1比5之混合液作為溶劑者，厚朴酚則僅有0.16mg/ml之溶解度，顯見上述之藥物傳遞系統能於兼顧材料毒性之前提下，有效提升溶解度。In addition, when using a mixture of ethanol and PBS with a ratio of 1:5 as a solvent, magnolol has a solubility of only 0.16mg/ml. It is obvious that the above-mentioned drug delivery system can effectively improve the solubility before taking into account the toxicity of the material. .
較佳的，本藥物傳遞系統之載藥量至少可達10、11、12、13、14、15、16、17、18、19、20、21、22、22.5、23或24 mg/ml。Preferably, the drug loading amount of the drug delivery system can reach at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 22.5, 23 or 24 mg/ml.
更佳的，本藥物傳遞系統所用之活性成分為厚朴酚，且活性成分之藥物最大載藥量為22.78 ± 0.43 mg/ml。More preferably, the active ingredient used in the drug delivery system is magnolol, and the maximum drug loading amount of the active ingredient is 22.78 ± 0.43 mg/ml.
在一具體實例中，該醫藥組合物為液劑，並以口服或注射之方法給藥。從後述實施例可知，採用腹腔注射及口服方式給藥皆無造成實驗大鼠死亡，故液劑可作成針劑或採用口服方式給藥。In a specific example, the pharmaceutical composition is a liquid and is administered by oral or injection methods. It can be seen from the following examples that neither intraperitoneal injection nor oral administration caused the death of experimental rats, so the liquid can be made into injections or oral administration.
較佳的，該注射之方法包含皮下注射、靜脈注射、肌肉注射，及/或腹腔注射。Preferably, the injection method includes subcutaneous injection, intravenous injection, intramuscular injection, and/or intraperitoneal injection.
本發明再提供一種微乳液在製備治療、改善或減緩中風或中風所引發症狀之藥物的用途，該微乳液包含上述之藥物傳遞系統，且活性成分包含治療有效量之厚朴酚(Magnolol)。The present invention further provides a use of a microemulsion in the preparation of a medicine for treating, ameliorating or alleviating the symptoms caused by stroke or stroke. The microemulsion contains the above-mentioned drug delivery system and the active ingredient contains a therapeutically effective amount of Magnolol.
更佳的，該中風為腦中風；再更佳的，該中風為缺血性腦中風。More preferably, the stroke is a cerebral stroke; even more preferably, the stroke is an ischemic stroke.
本發明所述之「缺血性腦中風」包括腦血栓和腦栓塞。The "ischemic stroke" in the present invention includes cerebral thrombosis and cerebral embolism.
較佳的，該缺血性腦中風所引發症狀包含腦血栓所引發之視線模糊、視力受損、手/腳麻木、麻痺或感覺無力，語言能力降低、理解能力降低、半身不遂之任一或組合；及/或腦栓塞所引發之半身不遂、一側視野不明，言語/聽覺障礙之任一或組合。Preferably, the symptoms caused by the ischemic stroke include any one or a combination of blurred vision, impaired vision, numbness, numbness or weakness of the hands/foot, decreased language ability, decreased understanding ability, and hemiplegia caused by cerebral thrombosis. ; And/or any one or a combination of hemiplegia caused by cerebral embolism, unclear vision on one side, speech/hearing impairment.
較佳的，該人用治療有效量為每日投予至少4 mg/kg。更佳的為至少4.5 mg/kg、至少4.8 mg/kg或至少5.0 mg/kg。Preferably, the therapeutically effective dose for humans is at least 4 mg/kg administered daily. More preferably, it is at least 4.5 mg/kg, at least 4.8 mg/kg, or at least 5.0 mg/kg.
本發明亦提供一種提升活性成分之溶解度(solubility)及/或生體可用率(bioavailability)之方法，其係使用前述之藥物傳遞系統。較佳的，該活性成分包含厚朴酚(Magnolol)、薑黃素(Curcumin)或其可藥用的鹽之任一或組合。The present invention also provides a method for improving the solubility and/or bioavailability of active ingredients, which uses the aforementioned drug delivery system. Preferably, the active ingredient contains any one or a combination of Magnolol, Curcumin or a pharmaceutically acceptable salt thereof.
本發明之微乳液之優點包含：一、以液體形式施用活性成分；二、藉由小液滴尺寸來提升活性成分之生體可用率和穩定性；三、可用於溶解和傳遞親脂性活性成分；以及四、所需原料相對簡單，且可自發性形成微乳液。The advantages of the microemulsion of the present invention include: 1. The active ingredient is applied in liquid form; 2. The bioavailability and stability of the active ingredient are improved by the small droplet size; 3. It can be used to dissolve and deliver lipophilic active ingredients ; And four, the required raw materials are relatively simple, and can spontaneously form a microemulsion.
實施例1：擬三元相圖繪製Example 1: Plotting of quasi-ternary phase diagram
為確定微乳液之存在區範圍，本實驗使用水性滴定法於室溫構建「擬三元相圖」(pseudo ternary phase diagram)。成分分三類：水、油和乳化劑，先將油與乳化劑按重量比例為1∶9，2∶8，3∶7，4∶6，5∶5，6∶4，7∶3，8∶2，9∶1之組別分別配成混合液，並以蒸餾水進行滴定，直至混合液變渾濁後，記錄所用水量。藉由繪製水相、油相和乳化劑(含界面活性劑及助界面活性劑)來構建擬三元相圖，並從所得之擬三元相圖選擇不同配方進行熱力學評估，以選出承載親脂性活性成分之微乳液最佳比例。各組配方如表1，且各成分係購自Sigma Aldrich, (France)。In order to determine the scope of the microemulsion, this experiment uses the aqueous titration method to construct a "pseudo ternary phase diagram" at room temperature. The ingredients are divided into three categories: water, oil and emulsifier. First, the weight ratio of oil and emulsifier is 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, The groups of 8:2 and 9:1 were prepared into mixed liquids respectively, and titrated with distilled water until the mixed liquid became turbid, and the water consumption was recorded. Construct a pseudo-ternary phase diagram by drawing the water phase, oil phase, and emulsifier (including surfactants and co-surfactants), and select different formulas from the resulting pseudo-ternary phase diagram for thermodynamic evaluation to select the carrier affinity The best ratio of the microemulsion of lipid active ingredients. The formulas of each group are shown in Table 1, and the ingredients are purchased from Sigma Aldrich, (France).
表1：微乳液配方與擬三元相圖表
從表1及圖1至3可知，從甲、乙和丙三組之油相選用橄欖油、OA、Gly和TG四者，可與乳化劑之Tween、PEG和1,2-PG相互搭配，皆可獲得低黏度、透明、具同向性及熱力學穩定之分散體，並以甲組能在最廣的比例範圍內獲得低黏度、透明、具同向性及熱力學穩定之分散體，而為最佳配方。It can be seen from Table 1 and Figures 1 to 3 that olive oil, OA, Gly and TG are selected from the oil phases of Groups A, B and C, which can be matched with emulsifiers Tween, PEG and 1,2-PG. Both can obtain low viscosity, transparent, isotropic and thermodynamically stable dispersions, and group A can obtain low viscosity, transparent, isotropic and thermodynamically stable dispersions in the widest range of proportions. The best formula.
從表1及圖2、4之比較可知，丁組以TG取代橄欖油，並提升OA之含量比例時，可自動微乳化之區域面積縮小。From the comparison of Table 1 and Figures 2 and 4, it can be seen that when the D group replaces olive oil with TG and increases the proportion of OA, the area of automatic microemulsification is reduced.
從表1及圖1、5之比較可知，甲組和戊組之差異為TG與OA之混合比例，可知OA與TG為1：3之比例時，可自動微乳化之區域面積較廣，而能在減少乳化劑用量、增加水的含量的同時，仍產生低黏度、透明、具同向性及熱力學穩定之分散體。From the comparison of Table 1 and Figures 1 and 5, it can be seen that the difference between group A and group E is the mixing ratio of TG and OA. It can be seen that when the ratio of OA to TG is 1:3, the area of automatic microemulsification is wider, and It can reduce the amount of emulsifier and increase the water content while still producing a dispersion with low viscosity, transparency, isotropy and thermodynamic stability.
從表1及圖6、7可知，己組和庚組使用Span，皆僅能在較窄的比例範圍內產生低黏度、透明、具同向性及熱力學穩定之分散體，顯示油項選用橄欖油、OA、Gly和TG四者時，不適合與Span相互搭配。It can be seen from Table 1 and Figures 6 and 7 that the use of Span in the Group H and Group G can only produce low viscosity, transparent, isotropic and thermodynamically stable dispersions within a narrow ratio range, indicating that olives are used as the oil item When oil, OA, Gly and TG are four, it is not suitable for matching with Span.
從表1、圖1至3及圖7、8和9可知，庚組、辛組和壬組之乳化劑僅使用兩種成分，且結果不佳，可知乳化劑選用Tween、PEG和1,2-PG具有重要性。From Table 1, Figures 1 to 3 and Figures 7, 8 and 9, it can be seen that the emulsifiers of the G, Xin and Ren groups only use two components, and the results are not good. It can be seen that the emulsifiers are Tween, PEG and 1, 2 -PG is important.
從表1、圖3、8和10可知，水相仍以僅包含蒸餾水為佳。It can be seen from Table 1, Figures 3, 8 and 10 that the water phase still preferably contains only distilled water.
綜上可知，油相選用橄欖油、OA、Gly和TG四者時，可與乳化劑之Tween、PEG和1,2-PG三者搭配，但不適合與Span相互搭配，且TG與OA之比例具有重要性。In summary, when olive oil, OA, Gly and TG are used as the oil phase, it can be matched with the emulsifier Tween, PEG and 1,2-PG, but it is not suitable for Span, and the ratio of TG to OA Is important.
實施例2：液滴粒徑(直徑)量測Example 2: Measurement of droplet size (diameter)
本實驗從圖1選取A、B兩點配製微乳液，配方如表2，並使用Zetasizer奈米粒度電位儀(1000HS，Malvern Instruments，UK)，藉「光子相關光譜法」之原理，分析液滴之布朗運動所引發之光散射波動，以測定滴液直徑。首先，取0.1毫升(ml)微乳液在容量瓶中分散於10毫升(ml)水，經劇烈搖動以充分混合後，在室溫下以90°角監測光散射，結果如圖11和12。This experiment selects two points A and B from Figure 1 to prepare a microemulsion. The formula is shown in Table 2, and the Zetasizer nanoparticle size potentiometer (1000HS, Malvern Instruments, UK) is used to analyze the droplets based on the principle of "photon correlation spectroscopy". The light scattering fluctuations caused by Brownian motion can be used to determine the drop diameter. First, take 0.1 milliliter (ml) of the microemulsion and disperse it in 10 milliliters (ml) of water in a volumetric flask, shake it vigorously for thorough mixing, and monitor the light scattering at a 90° angle at room temperature. The results are shown in Figures 11 and 12.
表2：微乳液配方與液滴粒徑(直徑)量測表
從圖11和12可知，在配方A之液滴直徑分佈中，其微乳液液滴直徑為111.2±27.3奈米，在配方B之液滴直徑分佈中，其微乳液液滴直徑為697.7±208.3奈米。It can be seen from Figures 11 and 12 that in the droplet diameter distribution of formula A, the microemulsion droplet diameter is 111.2±27.3 nm, and in the droplet diameter distribution of formula B, the microemulsion droplet diameter is 697.7±208.3 Nano.
此外，從表2可知，當水含量增加時，微乳液液滴直徑將變小，基於藥品服用至人體後，微乳液液滴將處於水溶液環境，使微乳液液滴於人體循環過程中逐漸變小，最終因難以完整包覆而釋出活性成分，故後續動物實驗選用配方B，藉由較高之緩衝含水量，提高微乳液液滴進入人體後之穩定性，並因液滴直徑將逐步微小化，而更有利於人體之吸收運用，以提高生體可用率。In addition, it can be seen from Table 2 that when the water content increases, the diameter of the microemulsion droplets will decrease. Based on the fact that the microemulsion droplets will be in an aqueous environment after the drug is administered to the human body, the microemulsion droplets will gradually change during the circulation of the body Because it is difficult to completely coat and release the active ingredients, the follow-up animal experiment uses formula B. With a higher buffer water content, the stability of the microemulsion droplets after entering the human body is improved, and the droplet diameter will gradually Miniaturization is more conducive to the absorption and utilization of the human body to improve the bioavailability.
實施例3：黏稠度量測Example 3: Viscosity measurement
製備上述配方A和配方B之微乳液，並使用Visco-895黏度計(Atago Co., Inc.，Tokyo，Japan)，轉針號碼為A3 RE-77106，於室溫下測定微乳化製劑黏度，量測結果為配方A之黏稠度為21.86 ± 1.31 cP，以及配方B之黏稠度為155.72 ± 2.28 cP。Prepare the microemulsions of the above formula A and formula B, and use a Visco-895 viscometer (Atago Co., Inc., Tokyo, Japan), with the needle number A3 RE-77106, and measure the viscosity of the microemulsion formulation at room temperature. The measurement result is that the viscosity of formula A is 21.86 ± 1.31 cP, and the viscosity of formula B is 155.72 ± 2.28 cP.
實施例4：最大載藥量Example 4: Maximum drug loading
製備上述配方B之微乳液，將過量的厚朴酚加入裝有一毫升配方B微乳液之小瓶中後，塞緊小瓶瓶口，並於室溫下以機械振盪器連續振盪72小時。將微乳液以10,000rpm離心10分鐘，分離出上清液。過濾上清液，並使用甲醇進行適當稀釋，藉由高效液相層析儀(HPLC)來定量厚朴酚含量，結果顯示厚朴酚之最大載藥量為22.78 ± 0.43 mg/ml。To prepare the microemulsion of the above formula B, add excess magnolol into a vial containing one milliliter of the microemulsion of formula B, close the vial, and continuously shake with a mechanical oscillator at room temperature for 72 hours. The microemulsion was centrifuged at 10,000 rpm for 10 minutes, and the supernatant was separated. The supernatant was filtered and diluted with methanol. The content of magnolol was quantified by high performance liquid chromatography (HPLC). The results showed that the maximum drug loading of magnolol was 22.78 ± 0.43 mg/ml.
實施例5：藥物代謝動力學參數量測Example 5: Measurement of pharmacokinetic parameters
(一)實驗動物：本實驗之實驗動物為史－道二氏大鼠(Sprague-Dawley rats，簡稱SD大鼠)，取自國泰綜合醫院動物中心(Cathay General Hospital Animal Center)，性別為雄性，體重約280±20公克(g)，並於濕度控制為40%、溫度控制為22±2℃及12小時之光暗循環週期之條件下飼養。本發明所有動物實驗均遵守公認之人道動物照護標準，以及依據國泰綜合醫院之機構動物照護和使用委員會(Institutional Animal Care and Use Committee, IACUC)所核准制定之標準流程進行。(1) Experimental animals: The experimental animals in this experiment are Sprague-Dawley rats (Sprague-Dawley rats, referred to as SD rats), taken from Cathay General Hospital Animal Center (Cathay General Hospital Animal Center), and the sex is male. The body weight is about 280±20 grams (g), and it is raised under the conditions of humidity control at 40%, temperature control at 22±2°C and a 12-hour light-dark cycle. All animal experiments of the present invention comply with recognized humane animal care standards and are performed in accordance with the standard procedures approved and formulated by the Institutional Animal Care and Use Committee (IACUC) of the Cathay General Hospital.
(二)藥品製備：實驗組依上述配方B調製藥品，活性成分為厚朴酚(Magnolol)，藥品濃度為10mg/ml，對照組則使用DMSO溶解厚朴酚(Magnolol)，藥品濃度亦為10mg/ml。實驗組與對照組各包含3隻SD大鼠，並以每公斤體重30毫克藥物，亦即30mg/kg之藥物進行腹腔注射，施打次數為1次。(2) Drug preparation: The experimental group prepared drugs according to the above formula B, the active ingredient is Magnolol, the drug concentration is 10mg/ml, and the control group uses DMSO to dissolve Magnolol, the drug concentration is also 10mg /ml. The experimental group and the control group each contained 3 SD rats, and were injected intraperitoneally with 30 mg of drug per kilogram of body weight, that is, 30 mg/kg of drug, and the number of injections was once.
(三)血液樣本製備：血液樣品分別於上述腹腔注射藥物後5分鐘、10分鐘、15分鐘、30分鐘、45分鐘、60分鐘、2小時、4小時、6小時及24小時進行取樣，於4℃下以4500 rpm離心3分鐘後分離出血清，並將上述所有樣品以-80℃儲存直至分析。上述血清添加「和厚朴酚(honokiol)」作為內標準品(購自：Sigma Aldrich)，並以血清與和厚朴酚(honokiol)之比例為100比1，亦即將200μl血清和2μl、濃度為0.1mg/ml之和厚朴酚混合，以進行高效液相層析(HPLC)分析。(3) Preparation of blood samples: blood samples were taken 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours and 24 hours after the above-mentioned intraperitoneal injection of the drug. After centrifugation at 4500 rpm for 3 minutes at ℃, the serum was separated, and all the above samples were stored at -80℃ until analysis. The above serum added "honokiol" as an internal standard (purchased from: Sigma Aldrich), and the ratio of serum to honokiol (honokiol) was 100 to 1, that is, 200μl serum and 2μl, concentration The 0.1mg/ml honokiol was mixed for high performance liquid chromatography (HPLC) analysis.
(四)腦樣本製備：鼠腦樣品分別於上述腹腔注射藥物後1小時和24小時後進行取樣及切片，並於量秤鼠腦切片之重量後，將鼠腦切片與0.6毫升(ml)之乙腈(acetonitrile)進行混合，以使蛋白質沉降(de-protein)，並於形成均質物(homogenate)後，添加和厚朴酚(honokiol)作為內標準品，再於室溫下以13200 rpm離心10分鐘，取上清液(20μl)進行高效液相層析(HPLC)分析。上述樣品於分析前皆以-80℃儲存。(4) Preparation of brain samples: The rat brain samples were taken and sliced 1 hour and 24 hours after the above-mentioned intraperitoneal injection of the drug, and after weighing the weight of the rat brain slices, the rat brain slices and 0.6 ml (ml) Acetonitrile was mixed to make the protein de-protein and homogenate was formed. Honokiol was added as an internal standard and centrifuged at 13200 rpm at room temperature for 10 Minutes, take the supernatant (20 μl) for high performance liquid chromatography (HPLC) analysis. The above samples were stored at -80°C before analysis.
(五)高效液相層析(HPLC)分析：以HPLC (Primaide 1110泵、Primaide 1410紫外光(UV)檢出器、Primaide 1210自動進樣器，Hitachi，Tokyo，Japan)進行分析，並使用mightysil RP-18管柱、4.6mm×250mm和粒徑5μm（Kanto chemical Co. Inc，Tokyo，Japan）。流動相為甲醇-水（80：20，v/v，pH：2.5-3，以正磷酸(ortho-phosphoric acid)調整），以0.45μm Millipore過濾膜過濾，並於使用前先除氣。HPLC流速設為1毫升(ml)/分鐘(min)，樣品進樣體積(即注射量)為20μl，並在室溫下以偵測波長292nm對厚朴酚進行檢測，以取得厚朴酚(Magnolol)之血中濃度，結果如圖13。(5) High performance liquid chromatography (HPLC) analysis: HPLC (Primaide 1110 pump, Primaide 1410 ultraviolet light (UV) detector, Primaide 1210 autosampler, Hitachi, Tokyo, Japan) was used for analysis, and mightysil RP-18 column, 4.6mm×250mm and particle size of 5μm (Kanto chemical Co. Inc, Tokyo, Japan). The mobile phase is methanol-water (80:20, v/v, pH: 2.5-3, adjusted with ortho-phosphoric acid), filtered with 0.45μm Millipore filter membrane, and degassed before use. The HPLC flow rate is set to 1 milliliter (ml)/minute (min), the sample injection volume (ie injection volume) is 20 μl, and magnolol is detected at a detection wavelength of 292 nm at room temperature to obtain magnolol ( Magnolol) blood concentration, the results are shown in Figure 13.
(六)血液藥物代謝動力學參數：藥物代謝動力學參數係使用為微軟Excel免費附加程式PKSolver 2.0的一室分佈模式進行計算，最高血中藥物濃度(Cmax)和達到Cmax所需時間(Tmax)係依據上述取樣之實際測量數據進行計算，而時間零至最終採血點時間之的曲線下面積（AUC 0-t）係依梯形面積法則計算，軟體擬合結果如表3，實驗組之結果顯示於圖14，對照組之結果顯示於圖15。其中，圖14與圖15之圓圈為3隻SD大鼠血中藥物濃度實際測得值之平均，曲線則為軟體擬合而得。 (6) Blood pharmacokinetic parameters: The pharmacokinetic parameters are calculated using the one-room distribution model of PKSolver 2.0, a free add-on program for Microsoft Excel. The maximum blood drug concentration (Cmax) and the time required to reach Cmax (Tmax) The calculation is based on the actual measurement data of the above sampling. The area under the curve (AUC 0-t ) from time zero to the final blood sampling point is calculated according to the trapezoidal area rule. The software fitting results are shown in Table 3. The results of the experimental group are shown In Figure 14, the results of the control group are shown in Figure 15. Among them, the circles in Figure 14 and Figure 15 are the average of the actual measured values of the drug concentration in the blood of 3 SD rats, and the curve is obtained by software fitting.
表3：藥物代謝動力學參數
t 1/2ka為吸收半衰期，t 1/2k10為清除半衰期，AUC為藥品血漿濃度與時間曲線下面積，AUMC為第一時刻曲線下面積，MRT為平均停留時間，指所給予之藥物停留於體內之平均總時間，並可藉第一時刻曲線下面積(AUMC)/曲線下面積(AUC)來計算，V/F為分布體積，CL/F為藥品清除率，CL為清除率，可由劑量除以AUC而得，F則為生體可用率。表3顯示實驗組之藥品血漿濃度與時間曲線下面積(AUC)及平均停留時間(MRT)皆有顯著較佳之數值，原因在於對照組之活性成分未獲包覆，故代謝明顯較快，停留人體內之時間較短。換句話說，本案之微乳液劑除載劑系統所用成分屬低毒性外，因活性成分包覆在微乳液液滴中，不易被人體代謝所清除，故可供人體使用之有效藥量與時間明顯較佳，而有較佳之生體可用率。此外，血中藥物濃度變化較平緩，亦有助於降低副作用之發生風險。 t 1/2ka is the absorption half-life, t 1/2k10 is the elimination half-life, AUC is the area under the curve of drug plasma concentration and time, AUMC is the area under the curve at the first moment, and MRT is the average residence time, which means that the administered drug stays in the body The average total time can be calculated by the area under the curve (AUMC)/area under the curve (AUC) at the first moment, V/F is the volume of distribution, CL/F is the drug clearance rate, and CL is the clearance rate, which can be divided by the dose It is derived from AUC and F is the bioavailability. Table 3 shows that the area under the plasma concentration vs. time curve (AUC) and mean residence time (MRT) of the experimental group of drugs have significantly better values. The reason is that the active ingredient in the control group is not coated, so the metabolism is significantly faster and the retention time The time in the human body is shorter. In other words, in addition to the low toxicity of the components used in the carrier system of the microemulsion in this case, the active ingredients are coated in the microemulsion droplets and are not easily removed by human metabolism, so the effective dose and time available for human use Obviously better, with better bioavailability. In addition, the blood concentration of the drug changes more slowly, which also helps to reduce the risk of side effects.
(七)劑型比較試驗：口服組之配方、取樣與分析方法皆與上述實驗組(即微乳液劑)相同，差別僅在於口服組係以口服方式提供微乳液，而非腹腔注射，且口服次數亦為1次，而腹腔注射組即上述實驗組。軟體擬合結果如表4，圖16之圓圈為3隻SD大鼠血中藥物濃度實際測得值之平均，曲線則為軟體擬合而得。(7) Dosage form comparison test: The formula, sampling and analysis methods of the oral group are the same as the above-mentioned experimental group (ie microemulsion). The difference is that the oral group provides microemulsion instead of intraperitoneal injection, and the number of oral administrations It is also once, and the intraperitoneal injection group is the above-mentioned experimental group. The software fitting results are shown in Table 4. The circle in Figure 16 is the average of the actual measured values of the drug concentration in the blood of 3 SD rats, and the curve is obtained by software fitting.
表4：藥物代謝動力學參數
其中，α為分布相速率常數，β為消除相速率常數。從表4可知，實驗組之藥品血漿濃度與時間曲線下面積(AUC)有顯著較佳之數值，但口服組有較佳的平均停留時間(MRT)，研判口服組AUC較低之原因在於活性成分易受消化道及肝臟之消化、吸收及轉化作用的影響，因本次實驗口服組厚朴酚濃度僅為10mg/ml，但本發明之微乳液配方可提升最大載藥量至22.78 ± 0.43 mg/ml，故預期提升口服組厚朴酚濃度後，將有更佳之數據表現。最後，從表3和表4之實驗數據可知，微乳液劑型之腹腔注射組有較佳的MRT，而口服組亦有優異的MRT與V/F藥物分布濃度，說明微乳液劑型不僅能有效提升藥物溶解度，亦能提升生體可利用率。Among them, α is the distributed phase rate constant, and β is the elimination phase rate constant. It can be seen from Table 4 that the area under the plasma concentration versus time curve (AUC) of the experimental group of drugs has a significantly better value, but the oral group has a better mean residence time (MRT). The reason for the lower AUC of the oral group is determined by the active ingredients It is easily affected by digestion, absorption and transformation of the digestive tract and liver, because the concentration of magnolol in the oral group in this experiment is only 10mg/ml, but the microemulsion formula of the present invention can increase the maximum drug loading to 22.78 ± 0.43 mg /ml, it is expected that after increasing the concentration of magnolol in the oral group, there will be better data performance. Finally, from the experimental data in Table 3 and Table 4, it can be seen that the intraperitoneal injection group of the microemulsion formulation has better MRT, and the oral group also has excellent MRT and V/F drug distribution concentrations, indicating that the microemulsion formulation can not only effectively improve The solubility of the drug can also improve the bioavailability.
(八)腦切片藥物濃度：HPLC分析結果如圖17。圖17顯示實驗組與對照組之藥物濃度並無顯著差異。可知，以微乳液作為載劑系統可用以取代具有高毒性之DMSO溶劑。(8) Drug concentration in brain slice: HPLC analysis result is shown in Figure 17. Figure 17 shows that there is no significant difference in drug concentration between the experimental group and the control group. It can be seen that the microemulsion as a carrier system can be used to replace the highly toxic DMSO solvent.
實施例6：中風治療效果評估Example 6: Evaluation of the treatment effect of stroke
(一)中風之實驗動物模型：本實驗之實驗動物同實施例5，並進一步依據Smith (1984)、Dittmar (2003)和Schmid-Elsaesser (1998)等人的方法進行中腦動脈（middle cerebral artery, MCA）阻塞手術，模擬缺血性腦中風。實驗組、DMSO組與對照組動物皆以手術阻塞SD大鼠之中腦動脈，以在限定之期間內誘發可逆性局部缺血(ischemia)。首先，先將氧氣與二氧化碳以氣體混合器混合2-4%異氟醚(isoflurane)，再使用氧氣罩讓SD大鼠吸入以進行麻醉後，以夾釘(clip)結紮SD大鼠之左側總頸動脈(left common carotid arteries, CCA)。取一段有機矽塗層的4-0單股尼龍線(RWD Life Science Co.，Shenzhen，China)引入左側總頸動脈(CCA)，並通過內頸動脈(internal carotid artery, ICA)輕輕前進，直至上述單股尼龍線尖端阻塞中腦動脈(MCA)之分支起點。在局部缺血發作後90分鐘取出上述4-0單股尼龍線。手術全程以電熱毯將SD大鼠之肛溫保持在37℃。(1) Experimental animal model of stroke: The experimental animal in this experiment was the same as that in Example 5, and the middle cerebral artery was performed according to the methods of Smith (1984), Dittmar (2003) and Schmid-Elsaesser (1998). , MCA) obstructive surgery to simulate ischemic stroke. The experimental group, the DMSO group and the control group were all surgically blocked the middle cerebral artery in SD rats to induce reversible ischemia (ischemia) within a limited period. First, mix 2-4% isoflurane (isoflurane) with oxygen and carbon dioxide in a gas mixer, and then use an oxygen mask to inhale SD rats for anesthesia, and then ligate the left side of SD rats with a clip. Carotid artery (left common carotid arteries, CCA). Take a piece of silicone-coated 4-0 single-stranded nylon thread (RWD Life Science Co., Shenzhen, China) into the left common carotid artery (CCA), and gently advance through the internal carotid artery (ICA), Until the beginning of the branch of the middle cerebral artery (MCA) blocked by the tip of the single-stranded nylon thread. Take out the 4-0 single-stranded
(二)藥品製備：實驗組與DMSO組所施打之藥品配方同實施例5，對照組則無使用任何藥物。(2) Preparation of medicines: The formulas of the medicines administered in the experimental group and the DMSO group were the same as those in Example 5, while the control group did not use any medicine.
(三)藥品施打：將SD大鼠隨機分配，實驗組與DMSO組之SD大鼠在缺血性中風發作後90分鐘以腹膜內給藥之方式提供30mg/kg之藥物，對照組則無施打任何藥物。(3) Drug administration: SD rats were randomly assigned. SD rats in the experimental group and DMSO group were given 30 mg/kg of drug by
(四)腦切片製備及分析：大鼠中風給藥後24小時斷頸犧牲，並使用大鼠鼠腦切片盒（Harvard Apparatus，MA，USA）將大鼠腦切成5個厚度為2mm之冠狀切片，並將鼠腦切片浸置於2%之2,3,5-三苯基氯化四唑鎓(2,3,5-Triphenyltetrazolium chloride, TTC，為氧化還原指示劑，可受活體細胞所含之脫氫酶氧化)(Sigma Chemical Co.)中30分鐘後，立即以10%甲醛(formaldehyde)進行固定。梗塞區域顯示為白色，並且使用ImageJ 1.48軟件（美國國立衛生研究院）測量鼠腦切片之後表面，中風區域面積計算方式如下：1. [框選白色中風區域 / 1平方公分區域 ] x 1cm 2= 實際中風面積；2. 實際中風面積 x 0.2cm(切片厚度) = 中風體積；3. 累加五個切片即取得總中風體積，結果如18所示。 (4) Preparation and analysis of brain slices: the rats were sacrificed by their necks severed 24 hours after the administration of stroke, and the rat brain was cut into 5 coronals with a thickness of 2mm using a rat brain slice box (Harvard Apparatus, MA, USA) Slice, and immerse the mouse brain slice in 2% 2,3,5-Triphenyltetrazolium chloride (2,3,5-Triphenyltetrazolium chloride, TTC, which is a redox indicator that can be affected by living cells). The contained dehydrogenase was oxidized (Sigma Chemical Co.) for 30 minutes, and then immediately fixed with 10% formaldehyde. The infarct area is displayed in white, and the surface of the mouse brain slice is measured using ImageJ 1.48 software (National Institutes of Health). The stroke area area is calculated as follows: 1. [Box select white stroke area / 1 cm2 area] x 1cm 2 = Actual stroke area; 2. Actual stroke area x 0.2cm (slice thickness) = stroke volume; 3. Accumulate five slices to get the total stroke volume. The result is shown in 18.
圖18A為對照組腦切片染色結果圖，顯示對照組因欠缺任何藥物治療，故白色區域之總中風體積為最高；圖18B為DMSO組腦切片染色結果圖，顯示DMSO組之總中風體積次之；圖18C為實驗組腦切片染色結果圖，顯示實驗組之總中風體積為最低。最後，圖18D為上述三組之總中風體積統計圖，可知對照組相較於DMSO組和實驗組具有顯著差異，顯示本發明之厚朴酚微乳液確實具有優異之缺血性腦中風治療效果，而從大鼠相對於人體之代謝係數為6.25之換算基準下，因大鼠注射量為30mg/kg，可推得4.8mg/kg之人體之有效劑量。Figure 18A is the result of staining of brain slices in the control group, showing that the total stroke volume in the white area is the highest due to lack of any medication in the control group; Figure 18B is the result of staining of brain slices in the DMSO group, showing that the total stroke volume in the DMSO group is the second Figure 18C is the result of staining of brain slices in the experimental group, showing that the total stroke volume in the experimental group is the lowest. Finally, Figure 18D is a statistical diagram of the total stroke volume of the above three groups. It can be seen that the control group has significant differences compared to the DMSO group and the experimental group, indicating that the magnolol microemulsion of the present invention does have an excellent therapeutic effect on ischemic stroke , And from the conversion basis of the metabolic coefficient of the rat relative to the human body of 6.25, since the injection dose of the rat is 30 mg/kg, the effective dose of 4.8 mg/kg of the human body can be inferred.
實施例7：穩定性測試Example 7: Stability test
將依上述配方B與厚朴酚所調製而得之藥品在室溫下儲存一個月，並分別於第0、14及30天結束時，使用甲醇適當地稀釋樣品，再藉由HPLC進行厚朴酚含量之定量，以觀察厚朴酚於高濃度/溶解度時之穩定性，結果如表5。The medicine prepared according to the above formula B and magnolol was stored at room temperature for one month, and at the end of the 0th, 14th, and 30th days, the samples were appropriately diluted with methanol, and then Magnolia was performed by HPLC The phenol content was quantified to observe the stability of magnolol at high concentration/solubility. The results are shown in Table 5.
表5：穩定性測試
從表5之結果可知，配方B之微乳液於30日內之濃度穩定而無劇烈變化，顯示配方B之微乳液具有優異之穩定性。From the results in Table 5, it can be seen that the concentration of the microemulsion of formula B is stable without drastic changes within 30 days, indicating that the microemulsion of formula B has excellent stability.
無no
圖1為甲組配方之擬三元相圖。Figure 1 is the pseudo-ternary phase diagram of the formula of Group A.
圖2為乙組配方之擬三元相圖。Figure 2 is the pseudo-ternary phase diagram of the B formula.
圖3為丙組配方之擬三元相圖。Figure 3 is the pseudo-ternary phase diagram of the C formula.
圖4為丁組配方之擬三元相圖。Figure 4 is the pseudo-ternary phase diagram of the D group formula.
圖5為戊組配方之擬三元相圖。Figure 5 is the pseudo-ternary phase diagram of the E-group formula.
圖6為己組配方之擬三元相圖。Figure 6 is the pseudo-ternary phase diagram of the formula.
圖7為庚組配方之擬三元相圖。Figure 7 is the pseudo-ternary phase diagram of the G formula.
圖8為辛組配方之擬三元相圖。Figure 8 is the pseudo-ternary phase diagram of the Xin formula.
圖9為壬組配方之擬三元相圖。Figure 9 is a pseudo-ternary phase diagram of the Ren group formula.
圖10為癸組配方之擬三元相圖。Figure 10 is the pseudo-ternary phase diagram of the Kui formula.
圖11為配方A微乳液之液滴粒徑(直徑)分布圖。Figure 11 is the droplet size (diameter) distribution diagram of the formulation A microemulsion.
圖12為配方B微乳液之液滴粒徑(直徑)分布圖。Figure 12 is the droplet size (diameter) distribution diagram of the formulation B microemulsion.
圖13為實驗組與對照組之血中藥品濃度圖。Figure 13 is a graph of drug concentration in blood of the experimental group and the control group.
圖14顯示實驗組之血中藥品濃度圖。Figure 14 shows a graph of the drug concentration in the blood of the experimental group.
圖15顯示對照組之血中藥品濃度圖。Figure 15 shows a graph of the drug concentration in the blood of the control group.
圖16顯示口服組之血中藥品濃度圖。Figure 16 shows a graph of the drug concentration in the blood of the oral group.
圖17為實驗組與對照組之腦中藥品濃度比較圖。Figure 17 is a comparison diagram of drug concentration in the brain between the experimental group and the control group.
圖18A為對照組腦切片染色結果圖；圖18B為DMSO組腦切片染色結果圖；圖18C為實驗組腦切片染色結果圖；以及圖18D為上述三組之總中風體積統計圖。Figure 18A is a graph of the staining results of brain sections in the control group; Figure 18B is a graph of the staining results of brain sections in the DMSO group; Figure 18C is a graph of the staining results of brain sections in the experimental group; and Figure 18D is a statistical graph of the total stroke volume of the above three groups.
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