TW202042800A - Pharmaceutical composition comprising omega fatty acids, and infusion preparation comprising the same - Google Patents

Pharmaceutical composition comprising omega fatty acids, and infusion preparation comprising the same Download PDF

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TW202042800A
TW202042800A TW109102752A TW109102752A TW202042800A TW 202042800 A TW202042800 A TW 202042800A TW 109102752 A TW109102752 A TW 109102752A TW 109102752 A TW109102752 A TW 109102752A TW 202042800 A TW202042800 A TW 202042800A
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omega
compartment
fatty acids
acid
pharmaceutical composition
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TWI749451B (en
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金東圭
曺泰根
黃道錫
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韓商怡諾安有限公司
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Abstract

The present invention relates to a pharmaceutical composition and an infusion preparation comprising omega-3 and omega-6 fatty acids, and the composition of the present invention comprises omega-3 and omega-6 fatty acids in a certain weight ratio to enhance an anti-inflammatory and immune-boosting effect, and thus exhibits an excellent effect on inflammatory diseases and immuno-compromised diseases, caused by nutritional deficiency. An infusion preparation of the present invention not only exhibits an excellent clinical validity, but also shows an effect of remarkably improving stability of the preparation.

Description

包含Ω脂肪酸的醫藥組合物及包含彼之輸液製劑Pharmaceutical composition containing omega fatty acid and infusion preparation containing it

本發明係關於用於預防或治療發炎性疾病或免疫受損疾病之包含Ω脂肪酸之醫藥組合物，及更特定言之，係關於醫藥組合物及包含彼之輸液製劑，其中該醫藥組合物不僅提供脂質營養素，且亦具有極佳抗發炎及免疫增強效應，且因此具有極佳之預防或治療由營養缺乏引起之發炎性疾病或免疫功能下降之效果。The present invention relates to a pharmaceutical composition containing omega fatty acids for the prevention or treatment of inflammatory diseases or immunocompromised diseases, and more specifically, to pharmaceutical compositions and infusion preparations containing them, wherein the pharmaceutical composition is not only Provides lipid nutrients, and also has excellent anti-inflammatory and immune enhancement effects, and therefore has an excellent effect of preventing or treating inflammatory diseases or decreased immune function caused by nutritional deficiency.

輸液補充嚴重脫水之人生理必需之電解質或水分，且輸液製劑為一種人工溶液，其可以靜脈內投與以非經腸地提供水分及營養素。特別定言之，消化器官有問題或意識喪失之患者容易陷入營養缺乏狀態，及因此，輸液用作為此類患者提供必需營養素之重要手段。The infusion solution supplements the physiologically necessary electrolytes or water for severely dehydrated people, and the infusion preparation is an artificial solution that can be administered intravenously to provide water and nutrients parenterally. In particular, patients with digestive organ problems or loss of consciousness are likely to fall into a state of nutritional deficiency, and therefore, infusion is used as an important means for such patients to provide essential nutrients.

營養缺乏狀態係指至少一種必需營養素或卡路里缺乏之狀態。若此類營養缺乏狀態持續，則會發生發炎性疾病或由免疫功能下降引起之疾病。為抑制此類疾病之發生，在用於提供營養素之輸液製劑中亦一起包含諸如抗發炎劑及免疫強化劑之藥物。The state of nutritional deficiency refers to the state of lack of at least one essential nutrient or calorie. If such a state of nutritional deficiency persists, inflammatory diseases or diseases caused by decreased immune function will occur. In order to suppress the occurrence of such diseases, infusion preparations used to provide nutrients also include drugs such as anti-inflammatory agents and immune boosters.

作為輸液製劑中所包含之營養素，存在碳水化合物、蛋白質、脂肪等，其中少量脂肪提供大量能量(1 g = 9 kcal)。用於全非經腸營養(TPN)以完全經由靜脈提供營養素之輸液製劑包含靜脈內脂質乳液，以防止因過量投與碳水化合物而引起之併發症並提供不可能在人體中合成之必需脂肪酸。As the nutrients contained in infusion preparations, there are carbohydrates, proteins, fats, etc., among which a small amount of fat provides a lot of energy (1 g = 9 kcal). The infusion preparation used for total parenteral nutrition (TPN) to provide nutrients completely through the vein contains intravenous lipid emulsion to prevent complications caused by excessive carbohydrate administration and provide essential fatty acids that cannot be synthesized in the human body.

第一種脂質乳液為大豆油，其迄今為止已被商業開發並用於多種產品中。然而，在使用一些大豆油作為脂質乳液之情況下，據報導會發生與免疫功能障礙及肝功能障礙相關聯之副作用。大豆油中所含之亞油酸為花生四烯酸之前體。若血液中亞油酸之濃度增加，則由此產生類二十烷酸，從而影響人體之免疫功能、發炎反應、血管功能、血小板聚集等，及因此引起發展併發症之風險增加。The first lipid emulsion is soybean oil, which has so far been commercially developed and used in various products. However, in the case of using some soybean oils as lipid emulsions, side effects associated with immune dysfunction and liver dysfunction have been reported to occur. The linoleic acid contained in soybean oil is the precursor of arachidonic acid. If the concentration of linoleic acid in the blood increases, eicosanoids will be produced, which will affect the body's immune function, inflammatory response, vascular function, platelet aggregation, etc., and thus increase the risk of developing complications.

為克服此類風險，最近之脂質乳液傾向於以衍生自多種物質諸如橄欖油、魚油等之油之混合形式開發。最近受關注之脂質乳液為從水生動物中收集之魚油。作為魚油，存在鯊魚肝油、鱈魚肝油、鯨魚油、烏賊油、鯷魚油等，其包含大量以二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)形式之Ω-3脂肪酸。To overcome such risks, recent lipid emulsions tend to be developed in the form of a mixture of oils derived from multiple substances such as olive oil and fish oil. The lipid emulsion that has recently received attention is fish oil collected from aquatic animals. As fish oil, there are shark liver oil, cod liver oil, whale oil, squid oil, anchovy oil, etc., which contain a large amount of omega-3 fatty acids in the form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) .

為重症監護病房(ICU)之患者選擇靜脈內脂質乳液時，絕對量之Ω脂肪酸及某些多不飽和脂肪酸(PUFA)是重要的。根據歐洲非經腸及腸內營養學會(ESPEN)之指南，建議向ICU患者提供之Ω-3脂肪酸之量應為0.1至0.2 g/kg/d。When choosing intravenous lipid emulsions for patients in the intensive care unit (ICU), absolute amounts of omega fatty acids and certain polyunsaturated fatty acids (PUFA) are important. According to the guidelines of the European Society of Parenteral and Enteral Nutrition (ESPEN), it is recommended that the amount of omega-3 fatty acids provided to ICU patients should be 0.1 to 0.2 g/kg/d.

在此種背景下，本發明者試圖開發包含Ω脂肪酸之醫藥組合物及輸液製劑，其可減輕由於營養缺乏所致之各種發炎性疾病及免疫疾病，並同時充分提供必需之脂質營養素。In this context, the present inventors tried to develop pharmaceutical compositions and infusion preparations containing omega fatty acids, which can alleviate various inflammatory diseases and immune diseases caused by nutritional deficiencies, and at the same time fully provide essential lipid nutrients.

[先前技術參考] [專利文獻] (專利文獻1)專利文獻1：韓國專利公開案第2011-0107615號[Prior Technical Reference] [Patent Literature] (Patent Document 1) Patent Document 1: Korean Patent Publication No. 2011-0107615

技術問題 本發明之目標係欲提供一種用於預防或治療發炎性疾病或免疫受損疾病之包含Ω脂肪酸之醫藥組合物。 Technical Problem The object of the present invention is to provide a pharmaceutical composition containing omega fatty acids for the prevention or treatment of inflammatory diseases or immunocompromised diseases.

本發明之另一目標係欲提供一種包含Ω脂肪酸之輸液製劑，其不僅可向缺乏營養之個體提供脂質營養素，且亦可減輕由營養缺乏引起之發炎性疾病或免疫受損疾病。Another object of the present invention is to provide an infusion preparation containing omega fatty acids, which can not only provide lipid nutrients to individuals lacking nutrition, but also alleviate inflammatory diseases or immunocompromised diseases caused by nutritional deficiency.

技術解決方案 此詳細描述於下文中。同時，本發明中揭示之各描述及實施例亦可分別應用於其他描述及其實施例。換言之，本發明中揭示之各種要素之所有組合均落入本發明之範圍內。同樣，亦不能看出為本發明之範圍限於下面描述之具體描述。 Technical solution This is described in detail below. At the same time, the descriptions and embodiments disclosed in the present invention can also be applied to other descriptions and embodiments, respectively. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Likewise, it cannot be seen that the scope of the present invention is limited to the specific description described below.

在本發明之一個態樣中，提供一種用於預防或治療發炎性疾病及免疫受損疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。In one aspect of the present invention, there is provided a pharmaceutical composition containing omega-3 and omega-6 fatty acids for preventing or treating inflammatory diseases and immunocompromised diseases.

本發明之組合物可藉由以Ω脂肪酸中之最佳比例包含Ω-3及Ω-6脂肪酸，對發炎性疾病或免疫受損疾病展現顯著效應。特定言之，該組合物可以1:0.75至1:1.25之重量比，較佳1:1之重量比包含Ω-3及Ω-6。The composition of the present invention can exhibit significant effects on inflammatory diseases or immunocompromised diseases by including omega-3 and omega-6 fatty acids in an optimal ratio among omega fatty acids. Specifically, the composition may include Ω-3 and Ω-6 in a weight ratio of 1:0.75 to 1:1.25, preferably a weight ratio of 1:1.

本發明之組合物中所包含之Ω-3及Ω-6脂肪酸之含量可為47至53 mg/mL，其中特別是Ω-3可以23至27 mg/mL之量包含其中，且Ω-6脂肪酸可以20至30 mg/mL之量包含其中。此種含量可在維持Ω-3及Ω-6脂肪酸之重量比之範圍內適當地調整。The content of omega-3 and omega-6 fatty acids contained in the composition of the present invention can be 47 to 53 mg/mL, in particular omega-3 can be contained in an amount of 23 to 27 mg/mL, and omega-6 The fatty acid may be contained in an amount of 20 to 30 mg/mL. This content can be appropriately adjusted within the range of maintaining the weight ratio of omega-3 and omega-6 fatty acids.

Ω-3為在自脂肪酸之甲基末端算起第三個碳原子上具有雙鍵之一系列脂肪酸，其中有亞麻酸、二十碳五烯酸及二十二碳六烯酸。Ω-3脂肪酸最常見於芥花籽油、亞麻籽油、紫蘇籽油或外來藍色魚中，且Ω-3藉由抑制肝臟中之中性脂肪及VLDL合成來降低血液中之中性脂肪含量。另外，已知Ω-3藉由改變會合成中性脂肪之核受體之表現程度來抑制中性脂肪之合成。Omega-3 is a series of fatty acids with a double bond on the third carbon atom from the methyl end of the fatty acid, including linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. Omega-3 fatty acids are most commonly found in canola oil, linseed oil, perilla seed oil or exotic blue fish. Omega-3 reduces neutral fat in the blood by inhibiting the synthesis of neutral fat in the liver and VLDL content. In addition, it is known that omega-3 inhibits the synthesis of neutral fat by changing the degree of expression of nuclear receptors that synthesize neutral fat.

在本發明中，Ω-3可為天然或合成之Ω-3脂肪酸、其醫藥上可接受之鹽及其混合物及例如可為α-亞麻酸(ALA)、二十碳五烯酸(EPA)或二十二碳六烯酸(DHA)，但不限於此。In the present invention, omega-3 can be natural or synthetic omega-3 fatty acids, pharmaceutically acceptable salts and mixtures thereof, and can be, for example, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) Or docosahexaenoic acid (DHA), but not limited to this.

由本發明之組合物提供之Ω-3脂肪酸之每日量可為0.1至0.2 g/kg/天，特別是0.125 g/kg或更高。The daily amount of omega-3 fatty acids provided by the composition of the present invention can be 0.1 to 0.2 g/kg/day, especially 0.125 g/kg or higher.

在本發明中，Ω-6為在自脂肪酸之甲基末端算起第6個碳原子上具有雙鍵之一系列脂肪酸，其中其大量係包含在雞蛋、乳製品、核桃、堅果、種子、大豆油、紅花油及玉米油中。Ω-6為體內產生皮膚及頭髮並維持膽固醇代謝及生殖功能之重要組分。In the present invention, omega-6 is a series of fatty acids with a double bond on the 6th carbon atom from the methyl end of the fatty acid, and a large amount of it is contained in eggs, dairy products, walnuts, nuts, seeds, Soybean oil, safflower oil and corn oil. Omega-6 is an important component in the body to produce skin and hair and maintain cholesterol metabolism and reproductive functions.

本發明之Ω-6可為天然或合成之Ω-6脂肪酸、其醫藥上可接受之鹽及其混合物，且例如可為亞油酸、γ亞麻酸、金盞酸、二十碳二烯酸、二高-γ-亞麻酸、花生四烯酸、二十二碳二烯酸、二十二碳四烯酸、二十二碳五烯酸、二十四碳四烯酸或二十四碳五烯酸，但不限於此。The omega-6 of the present invention can be natural or synthetic omega-6 fatty acids, pharmaceutically acceptable salts and mixtures thereof, and can be, for example, linoleic acid, gamma linolenic acid, calendic acid, eicosadienoic acid , Two high-γ-linolenic acid, arachidonic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosatetraenoic acid, or twenty-four carbon Pentaenoic acid, but not limited to this.

特定言之，本發明提供用於預防或治療發炎性疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。Specifically, the present invention provides pharmaceutical compositions containing omega-3 and omega-6 fatty acids for preventing or treating inflammatory diseases.

發炎性疾病可為由營養缺乏引起且其特徵可為感染區域出現疼痛、發紅現象、腫脹、發熱及最終功能喪失。發炎性疾病可為選自由以下組成之群之至少一者：胃炎、腸炎、腎炎、肝炎、慢性阻塞性肺病(COPD)、肺纖維化、腸激躁症候群、發炎疼痛、偏頭痛、頭痛、背痛、纖維肌痛、筋膜病、病毒感染、細菌感染、真菌感染、燒傷、由外科手術或牙科手術造成之傷害、PGE過高症候群、動脈粥樣硬化、痛風、霍奇金氏病(Hodgkin's disease)、胰臟炎、結膜炎、虹膜炎、鞏膜炎、葡萄膜炎及急性及慢性發炎性疾病。Inflammatory diseases can be caused by nutritional deficiencies and can be characterized by pain, redness, swelling, fever, and eventual loss of function in the infected area. The inflammatory disease may be at least one selected from the group consisting of gastritis, enteritis, nephritis, hepatitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back Pain, fibromyalgia, fascial disease, viral infections, bacterial infections, fungal infections, burns, injuries caused by surgical or dental procedures, PGE syndrome, atherosclerosis, gout, Hodgkin's disease disease), pancreatitis, conjunctivitis, iritis, scleritis, uveitis and acute and chronic inflammatory diseases.

根據本發明之一個實驗實例，已確定具有經調整之Ω-3及Ω-6脂肪酸比例之組合物可藉由顯著抑制IL-1β (亦即，發炎性疾病指數)來有效地用於預防或治療發炎性疾病。According to an experimental example of the present invention, it has been determined that a composition with an adjusted ratio of omega-3 and omega-6 fatty acids can be effectively used for prevention or prevention by significantly inhibiting IL-1β (ie, inflammatory disease index) Treat inflammatory diseases.

特定言之，本發明提供用於預防或治療免疫受損疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。Specifically, the present invention provides a pharmaceutical composition containing omega-3 and omega-6 fatty acids for preventing or treating immunocompromised diseases.

在本發明中，免疫受損疾病可源於由營養缺乏引起之免疫功能下降，且可為例如選自由以下組成之群之至少一者：哮喘、季節性或常年性鼻炎、過敏性鼻炎、結膜炎、異位性皮膚炎、蕁麻疹、紅細胞溶血、急性腎小球腎炎、流感、慢性疲勞及癌症。In the present invention, the immunocompromised disease may be derived from a decline in immune function caused by nutritional deficiency, and may be, for example, at least one selected from the group consisting of asthma, seasonal or perennial rhinitis, allergic rhinitis, and conjunctivitis , Atopic dermatitis, urticaria, hemolysis of red blood cells, acute glomerulonephritis, influenza, chronic fatigue and cancer.

另外，本發明提供用於增強免疫力之包含Ω-3及Ω-6脂肪酸之組合物。In addition, the present invention provides a composition containing omega-3 and omega-6 fatty acids for enhancing immunity.

根據本發明之一個實驗實例，已經確定，具有經調整之Ω-3及Ω-6脂肪酸比例之組合物可藉由顯著減少脾臟之重量損失(亦即，關鍵之免疫系統)及恢復血細胞免疫功能指數而有效地用於免疫受損疾病。According to an experimental example of the present invention, it has been determined that a composition with an adjusted ratio of omega-3 and omega-6 fatty acids can significantly reduce the weight loss of the spleen (ie, the key immune system) and restore the immune function of blood cells Exponentially and effectively used in immunocompromised diseases.

就組合物之總重量而言，本發明之醫藥組合物可包含22至30%之Ω-3及Ω-6脂肪酸。In terms of the total weight of the composition, the pharmaceutical composition of the present invention may contain 22 to 30% of omega-3 and omega-6 fatty acids.

除了Ω-3及Ω-6之外，本發明之醫藥組合物亦可另外包含至少一種類型之用於其投與之醫藥上可接受之載劑。作為醫藥上可接受之載劑，可使用以下：鹽水溶液、無菌水、林格氏溶液、緩衝鹽水、葡萄糖溶液、麥芽糖糊精溶液、甘油及其至少一種組分之組合，及若需要，可向其中添加其他習知添加劑諸如抗氧化劑、緩衝溶液、抑菌劑等。In addition to omega-3 and omega-6, the pharmaceutical composition of the present invention may additionally contain at least one type of pharmaceutically acceptable carrier for its administration. As pharmaceutically acceptable carriers, the following can be used: saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerin and a combination of at least one component thereof, and if necessary, Add other conventional additives such as antioxidants, buffer solutions, bacteriostatic agents and so on.

本發明之醫藥組合物可根據預期方法進行非經腸投與(例如靜脈內、皮下、腹膜內或局部施用)，特定言之靜脈內投與，及更特定言之向中央靜脈或外周靜脈內投與。劑量可根據患者之體重、年齡、性別、健康狀況、飲食、投與時間、投與方法、排泄速率、疾病之嚴重程度等在其範圍內進行各種調整。The pharmaceutical composition of the present invention can be administered parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical administration), specifically intravenous administration, and more specifically into the central vein or peripheral vein according to the intended method Vote. The dosage can be adjusted in various ranges according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, severity of disease, etc.

在將本發明之醫藥組合物調配成可注射溶液之情況下，本發明之醫藥組合物可以製備成溶液或懸浮液，製備方式為使得本發明之組合物與穩定劑或緩衝液一起在水中混合，但是調配方法不限於此。作為使用本發明之醫藥組合物之可注射劑型之一個實例，可將本發明之組合物調配成用於瓶之單位劑型之製劑。When the pharmaceutical composition of the present invention is formulated into an injectable solution, the pharmaceutical composition of the present invention can be prepared as a solution or suspension, and the preparation method is such that the composition of the present invention is mixed with a stabilizer or buffer in water , But the deployment method is not limited to this. As an example of an injectable dosage form using the pharmaceutical composition of the present invention, the composition of the present invention can be formulated into a unit dosage form of a bottle.

在本發明之醫藥組合物中，其劑量可基於目標個體之體重按照年齡來計算。作為一個較佳之實例，對於成人，醫藥組合物之投與劑量可量為5至10 mL/kg/天之輸液，其對應1至2 g/kg/天之每日攝入脂肪。In the pharmaceutical composition of the present invention, the dosage can be calculated by age based on the weight of the target individual. As a preferred example, for adults, the dosage of the pharmaceutical composition may be 5 to 10 mL/kg/day for infusion, which corresponds to a daily fat intake of 1 to 2 g/kg/day.

另外，本發明之醫藥組合物之醫藥上有效量及有效劑量可根據用於調配醫藥組合物之方法、投與方式、投與時間及/或投與途徑等而變化，且可根據各種因素多樣化，該等因素包括欲藉助投與醫藥組合物所達成之反應之類型及程度，進行投與之個體之類型，諸如個體之年齡、體重、一般健康狀況、疾病症狀或嚴重程度、性別、飲食及排泄，欲在同一時間或不同時間用於對應個體之其他藥物組合物之組分等，以及在醫藥領域眾所周知之其他類似因素，及熟習此項技術者可確定並開處方在預期之治療範圍內之劑量。舉例而言，本發明之醫藥組合物之投與可每天進行一次，但不限於此。本發明之醫藥組合物可作為個別治療劑或與其他治療劑組合投與，且可以與習知治療劑依序或同時投與。考慮到以上所有因素，本發明之醫藥組合物可以使得可以最小量達成最大效果而沒有副作用之量投與，且該量可由熟習本發明所屬技術者輕易地確定。In addition, the pharmaceutically effective amount and effective dose of the pharmaceutical composition of the present invention may vary according to the method, administration method, administration time, and/or administration route used to formulate the pharmaceutical composition, and may vary according to various factors. These factors include the type and extent of the response to be achieved by the administration of the pharmaceutical composition, and the type of the individual administered, such as the individual’s age, weight, general health, disease symptoms or severity, gender, and diet And excretion, components of other pharmaceutical compositions to be used in the corresponding individual at the same time or at different times, and other similar factors well known in the medical field, and those familiar with the technology can determine and prescribe the expected treatment range Within the dose. For example, the administration of the pharmaceutical composition of the present invention can be carried out once a day, but it is not limited thereto. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. Taking all the above factors into consideration, the pharmaceutical composition of the present invention can be administered in a minimum amount to achieve the maximum effect without side effects, and the amount can be easily determined by those skilled in the present invention.

本發明之醫藥組合物可包含至少一種選自由以下組成之群之油：魚油、大豆油、橄欖油、棉籽油、紅花油、芝麻油、椰子油及玉米油。特定言之，本發明之組合物中所包含之Ω-3及Ω-6脂肪酸可源自至少一種選自由以下組成之群之油：魚油、大豆油、橄欖油、棉籽油、紅花油、芝麻油、椰子油及玉米油。The pharmaceutical composition of the present invention may contain at least one oil selected from the group consisting of fish oil, soybean oil, olive oil, cottonseed oil, safflower oil, sesame oil, coconut oil and corn oil. In particular, the omega-3 and omega-6 fatty acids contained in the composition of the present invention can be derived from at least one oil selected from the group consisting of fish oil, soybean oil, olive oil, cottonseed oil, safflower oil, and sesame oil , Coconut oil and corn oil.

魚油可藉由混合水產動物油作為提供Ω-3脂肪酸之主要來源而獲得，該等油例如富含脂肪之魚油，諸如鯷科(Engraulidae)、鯵科(Carangidae)、鯡科(Clupeidae)、胡瓜魚科(Osmeridae)、鮭科(Salmonidae)及鯖科(Scombridae)。Fish oil can be obtained by mixing aquatic animal oils as the main source of omega-3 fatty acids, such as fatty fish oils such as Engraulidae, Carangidae, Clupeidae, and Smelt Family (Osmeridae), Salmonidae (Salmonidae) and Scombridae (Scombridae).

該油可另外包含合成油諸如中鏈三酸甘油酯。The oil may additionally contain synthetic oils such as medium chain triglycerides.

特定言之，醫藥組合物可包含基於總100 ml該組合物計3.0 g至5.0 g大豆油、3.5 g至4.5 g中鏈三酸甘油酯、5.0 g至6.0 g橄欖油及6.0 g至7.0 g魚油，且更特定言之可包含基於總100 ml該組合物計4 g大豆油、4 g中鏈三酸甘油酯、5.5 g橄欖油及6.5g魚油，其可在維持Ω-3及Ω-6脂肪酸重量比之範圍內適當調整。In particular, the pharmaceutical composition may include 3.0 g to 5.0 g soybean oil, 3.5 g to 4.5 g medium chain triglycerides, 5.0 g to 6.0 g olive oil, and 6.0 g to 7.0 g based on the total 100 ml of the composition. Fish oil, and more specifically, may include 4 g soybean oil, 4 g medium-chain triglycerides, 5.5 g olive oil and 6.5 g fish oil based on the total 100 ml of the composition, which can maintain omega-3 and omega- Adjust appropriately within the range of fatty acid weight ratio.

本發明之醫藥組合物可另外包含至少一種選自由乳化劑、滲透調節劑、pH調節劑及抗氧化劑組成之群之添加劑。The pharmaceutical composition of the present invention may additionally contain at least one additive selected from the group consisting of emulsifiers, osmotic regulators, pH regulators and antioxidants.

乳化劑為形成穩定之油顆粒並維持所形成之顆粒之穩定性之材料，且可為選自由蛋黃卵磷脂、氫化蛋黃卵磷脂、大豆卵磷脂、氫化大豆卵磷脂、油酸鈉等組成之群之至少一者。較佳地，乳化劑可為蛋黃卵磷脂及油酸鈉，其可為基於100 ml用於靜脈內投與之該組合物計0.6至1.8% (w/v)蛋黃卵磷脂及0.01至0.05% (w/v)油酸鈉，但不限於此。Emulsifier is a material that forms stable oil particles and maintains the stability of the formed particles, and can be selected from the group consisting of egg yolk lecithin, hydrogenated egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, sodium oleate, etc. At least one of them. Preferably, the emulsifier can be egg yolk lecithin and sodium oleate, which can be 0.6 to 1.8% (w/v) egg yolk lecithin and 0.01 to 0.05% based on 100 ml of the composition for intravenous administration. (w/v) Sodium oleate, but not limited to this.

滲透調節劑可為選自由氯化鈉、葡萄糖、D-甘露糖醇、山梨糖醇、海藻糖及甘油組成之群之至少一者，且較佳可為基於100 ml用於靜脈內投與之該組合物計1.7至2.5% (w/v)甘油，但不限於此。The osmotic regulator may be at least one selected from the group consisting of sodium chloride, glucose, D-mannitol, sorbitol, trehalose and glycerin, and preferably may be based on 100 ml for intravenous administration The composition accounts for 1.7 to 2.5% (w/v) glycerin, but is not limited thereto.

pH調節劑可為選自由氫氧化鈉、鹽酸、磷酸、磷酸鹽及檸檬酸組成之群之至少一者，但不限於此。抗氧化劑可為選自由抗壞血酸、二丁基羥基茴香醚、二丁基羥基甲苯、山梨糖醇及生育酚組成之群之至少一者，但不限於此。The pH adjuster may be at least one selected from the group consisting of sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, and citric acid, but is not limited thereto. The antioxidant may be at least one selected from the group consisting of ascorbic acid, dibutylhydroxyanisole, dibutylhydroxytoluene, sorbitol, and tocopherol, but is not limited thereto.

抗氧化劑可為選自由抗壞血酸及其鹽、二丁基羥基茴香醚、二丁基羥基甲苯、山梨糖醇及生育酚組成之群之至少一者，但不限於此。The antioxidant may be at least one selected from the group consisting of ascorbic acid and its salts, dibutylhydroxyanisole, dibutylhydroxytoluene, sorbitol, and tocopherol, but is not limited thereto.

在本發明之另一態樣中，為達成上述目標，提供包含Ω-3及Ω-6脂肪酸之輸液製劑。In another aspect of the present invention, in order to achieve the above goal, an infusion preparation containing omega-3 and omega-6 fatty acids is provided.

本發明之輸液製劑可包含具有Ω-3及Ω-6脂肪酸之組合物。The infusion preparation of the present invention may include a composition having omega-3 and omega-6 fatty acids.

本發明之輸液製劑可包含一定比例之Ω-3及Ω-6脂肪酸，及因此不僅可顯示其臨床有效性，諸如抗發炎、減緩免疫力下降，等等，且亦可顯示顯著改良製劑穩定性之效果，諸如減緩由多不飽和脂肪酸引起之脂質過氧化，等等。特定言之，該輸液製劑可以包含1:0.75至1:1.25之重量比，特定言之1:1之重量比之Ω-3與Ω-6。The infusion preparation of the present invention can contain a certain proportion of omega-3 and omega-6 fatty acids, and therefore can not only show its clinical effectiveness, such as anti-inflammatory, slow down immunity, etc., but also show a significant improvement in the stability of the preparation Its effects, such as slowing down lipid peroxidation caused by polyunsaturated fatty acids, etc. In particular, the infusion formulation may contain Ω-3 and Ω-6 in a weight ratio of 1:0.75 to 1:1.25, specifically a weight ratio of 1:1.

在輸液製劑中，Ω-3及Ω-6脂肪酸可包含在單一隔室中，且該隔室可另外包含胺基酸、電解質及糖。In infusion preparations, omega-3 and omega-6 fatty acids may be contained in a single compartment, and the compartment may additionally contain amino acids, electrolytes, and sugars.

另外，輸液製劑可接收在複數個隔室中，該等隔室以可連接方式彼此分隔開，以便在使用時可混合製劑。Ω-3及Ω-6脂肪酸或包含彼之組合物可接收在其中一個隔室中。特定言之，本發明之輸液製劑可接收在被分成第一隔室、第二隔室及第三隔室之隔室中。第一隔室可接收用於提供胺基酸及電解質之第一隔室流體；第二隔室可接收用於提供糖之第二隔室流體；及第三隔室可接收用於提供脂肪之第三隔室流體。In addition, the infusion preparation can be received in a plurality of compartments, which are separated from each other in a connectable manner, so that the preparation can be mixed during use. Omega-3 and omega-6 fatty acids or compositions containing them can be received in one of the compartments. Specifically, the infusion preparation of the present invention can be received in a compartment divided into a first compartment, a second compartment, and a third compartment. The first compartment can receive the first compartment fluid for providing amino acids and electrolytes; the second compartment can receive the second compartment fluid for providing sugar; and the third compartment can receive the fluid for providing fat The third compartment fluid.

電解質可係指以下意義中之電解質，該電解質係在輸液領域中使用，特定言之包含在體液(例如血液及細胞內液)中之電解質，及更特定言之鈣、磷、鈉、鎂、鉀、鋅、氯等，但不限於此。Electrolytes can refer to electrolytes in the following meanings, which are used in the field of transfusion, specifically electrolytes contained in body fluids (such as blood and intracellular fluid), and more specifically calcium, phosphorus, sodium, magnesium, Potassium, zinc, chlorine, etc., but not limited to this.

鈣可為葡萄糖酸鈣、氯化鈣、甘油磷酸鈣或泛酸鈣；鹽可為無機鹽，包括磷酸鈣及磷酸鎂；或有機鹽，包括甘油磷酸鈉及甘油磷酸鉀；鈉可為氯化鈉、乳酸鈉、乙酸鈉、硫酸鈉、甘油磷酸鈉、檸檬酸鈉或其水合物形式；鎂可為硫酸鎂、氯化鎂或乙酸鎂；鉀可為氯化鉀、乙酸鉀、甘油磷酸鉀、硫酸鉀、乳酸鉀或其水合物形式；鋅可為硫酸鋅、氯化鋅或其水合物形式；氯可為氯化鈉、氯化鉀、氯化鎂或氯化鈣，但不限於此。Calcium can be calcium gluconate, calcium chloride, calcium glycerophosphate or calcium pantothenate; the salt can be an inorganic salt, including calcium phosphate and magnesium phosphate; or an organic salt, including sodium glycerophosphate and potassium glycerophosphate; the sodium can be sodium chloride , Sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, sodium citrate or its hydrate form; magnesium can be magnesium sulfate, magnesium chloride or magnesium acetate; potassium can be potassium chloride, potassium acetate, potassium glycerophosphate, potassium sulfate, Potassium lactate or its hydrate form; zinc may be zinc sulfate, zinc chloride or its hydrate form; chlorine may be sodium chloride, potassium chloride, magnesium chloride or calcium chloride, but is not limited thereto.

特定言之，電解質可為選自由二水合氯化鈣、甘油磷酸鈉、水合乙酸鈉、七水合硫酸鎂、氯化鉀及七水合硫酸鋅組成之群之至少一者。電解質可為72至76 mg二水合氯化鈣、400至440 mg無水甘油磷酸鈉、555至570 mg水合乙酸鈉、245至250 mg七水合硫酸鎂、445至451 mg氯化鉀及2.0至2.6 mg七水合硫酸鋅，且較佳74 mg二水合氯化鈣、418 mg無水甘油磷酸鈉、562 mg水合乙酸鈉、247 mg七水合硫酸鎂、448 mg氯化鉀及2.3 mg七水合硫酸鋅，基於100 mL第一隔室流體計，但不限於此。In particular, the electrolyte may be at least one selected from the group consisting of calcium chloride dihydrate, sodium glycerophosphate, sodium acetate hydrate, magnesium sulfate heptahydrate, potassium chloride, and zinc sulfate heptahydrate. Electrolytes can be 72 to 76 mg calcium chloride dihydrate, 400 to 440 mg sodium glycerophosphate anhydrous, 555 to 570 mg sodium acetate hydrate, 245 to 250 mg magnesium sulfate heptahydrate, 445 to 451 mg potassium chloride and 2.0 to 2.6 mg zinc sulfate heptahydrate, and preferably 74 mg calcium chloride dihydrate, 418 mg sodium glycerophosphate anhydrous, 562 mg sodium acetate hydrate, 247 mg magnesium sulfate heptahydrate, 448 mg potassium chloride and 2.3 mg zinc sulfate heptahydrate, Based on a 100 mL first compartment fluid meter, but not limited to this.

胺基酸包括游離胺基酸及胺基酸鹽形式。游離胺基酸形式可為選自由以下組成之群之至少一者：L-丙胺酸、L-精胺酸、甘胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、牛磺酸、L-蘇胺酸、L-色胺酸、L-酪胺酸、L-纈胺酸及L-穀胺酸。胺基酸鹽形式可為選自由無機鹽諸如L-精胺酸鹽酸鹽、L-組胺酸鹽酸鹽、L-離胺酸鹽酸鹽等；L-離胺酸乙酸鹽；及L-離胺酸蘋果酸組成之群之至少一者。Amino acids include free amino acids and amino acid salt forms. The free amino acid form may be at least one selected from the group consisting of: L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine Acid, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, taurine, L-threonine, L-tryptophan, L- Tyrosine, L-valine and L-glutamate. The amino acid salt form may be selected from inorganic salts such as L-arginine hydrochloride, L-histamine hydrochloride, L-lysine hydrochloride, etc.; L-lysine acid acetate; and L -At least one of the group consisting of lysine malic acid.

從提供營養之觀點來看，該輸液製劑可包含至少兩種胺基酸，且可有效地包含必需胺基酸，亦即L-精胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸、L-甲硫胺酸、L-苯丙胺酸、牛磺酸、L-蘇胺酸、L-色胺酸及L-纈胺酸。From the point of view of providing nutrition, the infusion preparation can contain at least two amino acids, and can effectively contain essential amino acids, namely L-arginine, L-histidine, and L-isoleucine , L-leucine, L-lysine, L-methionine, L-phenylalanine, taurine, L-threonine, L-tryptophan and L-valine.

特定言之，此類製劑可包含基於100 mL第一隔室流體計2.05至2.10 g L-丙胺酸、1.10至1.20 g L-精胺酸、0.98至1.08 g甘胺酸、0.45至0.50 g L-組胺酸、0.50至0.70 g L-異白胺酸、0.68至0.78 g L-白胺酸、0.715至0.735 g L-離胺酸鹽酸鹽、0.30至0.50 g L-甲硫胺酸、0.50至0.62 g L-苯丙胺酸、0.63至0.73 g L-脯胺酸、0.40至0.60 g L-絲胺酸、0.05至0.15 g牛磺酸、0.37至0.47 g L-蘇胺酸、0.13至0.23 g L-色胺酸、0.03至0.05 g L-酪胺酸及0.53至0.63 g L-纈胺酸，及較佳基於100 mL第一種隔室液流體計2.07 g L-丙胺酸、1.15 g L-精胺酸、1.03 g甘胺酸、0.48 g L-組胺酸、0.60 g L-異白胺酸、0.73 g L-白胺酸、0.725 g L-離胺酸鹽酸鹽、0.40 g L-甲硫胺酸、0.56 g L-苯丙胺酸、0.68 g L-脯胺酸、0.50 g L-絲胺酸、0.10 g牛磺酸、0.42 g L-蘇胺酸、0.18 g L -色胺酸、0.04 g L-酪胺酸及0.58 g L-纈胺酸。In particular, such formulations may contain 2.05 to 2.10 g L-alanine, 1.10 to 1.20 g L-arginine, 0.98 to 1.08 g glycine, 0.45 to 0.50 g L-alanine based on a 100 mL first compartment fluid meter -Histidine, 0.50 to 0.70 g L-isoleucine, 0.68 to 0.78 g L-leucine, 0.715 to 0.735 g L-lysine hydrochloride, 0.30 to 0.50 g L-methionine, 0.50 to 0.62 g L-phenylalanine, 0.63 to 0.73 g L-proline, 0.40 to 0.60 g L-serine, 0.05 to 0.15 g taurine, 0.37 to 0.47 g L-threonine, 0.13 to 0.23 g L-tryptophan, 0.03 to 0.05 g L-tyrosine and 0.53 to 0.63 g L-valine, and preferably based on 100 mL of the first compartment fluid meter 2.07 g L-alanine, 1.15 g L-arginine, 1.03 g glycine, 0.48 g L-histidine, 0.60 g L-isoleucine, 0.73 g L-leucine, 0.725 g L-lysine hydrochloride, 0.40 g L-methionine, 0.56 g L-phenylalanine, 0.68 g L-proline, 0.50 g L-serine, 0.10 g taurine, 0.42 g L-threonine, 0.18 g L-tryptamine Acid, 0.04 g L-tyrosine and 0.58 g L-valine.

第一隔室流體可另外包含pH調節劑。當第一隔室流體與第二隔室流體及第三隔室流體混合時，pH調節劑包含在其中且因此可以維持最佳pH，足夠穩定以不破壞其中所包含之胺基酸。pH調節劑可選自習知類別。較佳地，可使用乙酸酐。The first compartment fluid may additionally contain a pH adjusting agent. When the first compartment fluid is mixed with the second compartment fluid and the third compartment fluid, the pH adjusting agent is contained therein and therefore the optimal pH can be maintained, which is stable enough not to destroy the amino acid contained therein. The pH adjusting agent can be selected from a conventional category. Preferably, acetic anhydride can be used.

輸液製劑可包含糖，其可為還原糖諸如葡萄糖、果糖、麥芽糖等，及非還原糖諸如木糖醇、山梨糖醇等，且較佳可為最輕易吸收至體內之葡萄糖。The infusion preparation may contain sugar, which may be reducing sugars such as glucose, fructose, maltose, etc., and non-reducing sugars such as xylitol, sorbitol, etc., and preferably may be glucose that can be most easily absorbed into the body.

第二隔室流體可另外包含pH調節劑，且pH調節劑可為鹽酸、磷酸、乙酸、檸檬酸或硫酸。The second compartment fluid may additionally contain a pH adjusting agent, and the pH adjusting agent may be hydrochloric acid, phosphoric acid, acetic acid, citric acid, or sulfuric acid.

本發明之輸液製劑可以投與給中心靜脈或外周靜脈。若將輸液製劑投與給中心靜脈，則第二隔室流體可包含基於100 ml該第二隔室流體計46.1至46.3 g一水合葡萄糖，較佳46.2 g其。若將輸液製劑投與給外周靜脈，則第二隔室流體可包含基於100 ml該第二隔室流體計14.2至14.4 g單水合葡萄糖，較佳14.3 g其。The infusion preparation of the present invention can be administered to a central vein or a peripheral vein. If the infusion preparation is administered to the central vein, the second compartment fluid may contain 46.1 to 46.3 g glucose monohydrate based on 100 ml of the second compartment fluid, preferably 46.2 g thereof. If the infusion preparation is administered to a peripheral vein, the second compartment fluid may contain 14.2 to 14.4 g glucose monohydrate based on 100 ml of the second compartment fluid, preferably 14.3 g thereof.

第三隔室流體包含油、乳化劑、滲透調節劑、pH調節劑及抗氧化劑，且為用於靜脈內投與之本發明組合物。The third compartment fluid contains oil, emulsifier, osmotic regulator, pH regulator and antioxidant, and is used for intravenous administration of the composition of the present invention.

在本發明之輸液製劑中，第三隔室流體(即，用於靜脈內投與之組合物)可單獨使用，或可以使得第一隔室流體及第二隔室流體係混合在一起之方式使用，端視需要輸液投與之個體之狀態而定。In the infusion preparation of the present invention, the third compartment fluid (that is, for intravenous administration of the composition) can be used alone, or the first compartment fluid and the second compartment fluid system can be mixed together The use depends on the state of the individual who needs infusion to be administered.

若將用於靜脈內投與之本發明組合物與第一隔室流體及第二隔室流體混合，則其混合比例及總劑量可根據各患者之營養狀態及卡路里需求適當地調整。若將本發明之輸液製劑投與給中心靜脈，則第一隔室流體、第二隔室流體及第三隔室流體之體積比可為2.66:1.59:1.00。若將本發明之輸液製劑投與給外周靜脈，則第一隔室流體、第二隔室流體及第三隔室流體之體積比可為2.24:3.86:1.00。然而，第一隔室流體、第二隔室流體及第三隔室流體之體積比不限於此，且可根據營養卡路里之標準良好地進行各種細分。If the composition of the present invention is to be mixed with the fluid of the first compartment and the fluid of the second compartment for intravenous administration, the mixing ratio and total dosage can be appropriately adjusted according to the nutritional status and calorie requirements of each patient. If the infusion preparation of the present invention is administered to the central vein, the volume ratio of the first compartment fluid, the second compartment fluid and the third compartment fluid can be 2.66:1.59:1.00. If the infusion preparation of the present invention is administered to a peripheral vein, the volume ratio of the first compartment fluid, the second compartment fluid, and the third compartment fluid can be 2.24:3.86:1.00. However, the volume ratio of the first compartment fluid, the second compartment fluid, and the third compartment fluid is not limited to this, and various subdivisions can be made according to the standard of nutrient calories.

本發明之輸液製劑可經由頸靜脈為需要營養提供之患者提供卡路里、胺基酸、必需脂肪酸及Ω-3脂肪酸，因為口服或胃腸營養提供係不可能、不充足或受限的。另外，本發明之輸液製劑可用於管理創傷患者之營養，該等創傷患者經歷主要外科手術諸如癌症、AIDS、缺血性腸病、吸收不良、支氣管阻斷/移除、腸梗阻、嚴重肝功能障礙、嚴重急性胰臟炎等。The infusion preparation of the present invention can provide calories, amino acids, essential fatty acids and omega-3 fatty acids to patients who need nutrition via the jugular vein, because oral or gastrointestinal nutrition is impossible, insufficient or limited. In addition, the infusion preparation of the present invention can be used to manage the nutrition of trauma patients who have undergone major surgical operations such as cancer, AIDS, ischemic bowel disease, malabsorption, bronchial block/removal, intestinal obstruction, severe liver function Disorders, severe acute pancreatitis, etc.

本發明提供用於預防或治療發炎性疾病或免疫受損疾病之方法，其包括將包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物投與給需要治療之個體之步驟。The present invention provides a method for preventing or treating inflammatory diseases or immunocompromised diseases, which comprises administering a composition containing omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25 to the need for treatment The individual steps.

如本文所用，術語̚「需要治療之個體」指包括人類之哺乳動物，且術語「投與」意指藉助任何適當之方法向個體提供預定物質。術語「治療有效量」意指誘導動物或人類顯示由研究者、獸醫、醫生或臨床醫生所考量之生物學或醫學反應之活性組分或醫藥組合物之量，且該量包括用於誘導欲治療之疾病或病症之症狀減輕之其量。熟習此項技術者應知曉，本發明之有效組分之治療有效劑量及投與次數可根據所需效果而變化。As used herein, the term "individual in need of treatment" refers to mammals including humans, and the term "administration" means to provide a predetermined substance to the individual by any appropriate method. The term "therapeutically effective amount" means the amount of the active ingredient or pharmaceutical composition that induces an animal or human to show a biological or medical response considered by the researcher, veterinarian, doctor or clinician, and this amount includes the amount used to induce desire The amount by which the symptoms of the disease or condition being treated are reduced. Those familiar with the art should know that the therapeutically effective dose and the number of administrations of the effective components of the present invention can vary according to the desired effect.

本發明之醫藥組合物可每天一次或以一定時間間隔每天至少兩次進行投與。The pharmaceutical composition of the present invention can be administered once a day or at least twice a day at certain intervals.

本發明提供一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物在預防或治療發炎性疾病或免疫受損疾病中之用途。The present invention provides a use of a composition comprising omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25 in the prevention or treatment of inflammatory diseases or immunocompromised diseases.

本發明提供一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物在製備用於預防或治療發炎性疾病或免疫受損疾病之醫藥製劑中之用途。The present invention provides a use of a composition containing omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25 in the preparation of pharmaceutical preparations for the prevention or treatment of inflammatory diseases or immunocompromised diseases.

若彼此不矛盾，則在本發明之醫藥組合物、治療方法及用途中所提及之物質適用相同。If they are not inconsistent with each other, the substances mentioned in the pharmaceutical composition, treatment method and use of the present invention are applicable to the same.

有利效應 本發明之醫藥組合物可以一定重量比包含Ω-3及Ω-6脂肪酸，且因此可增強抗發炎及免疫增強效應，且因此可預防或治療由營養缺乏引起之發炎性疾病及免疫受損疾病。另外，本發明之輸液製劑可不僅展現極佳臨床有效性，且亦可顯示顯著改良製劑之穩定性。 Advantageous effects The pharmaceutical composition of the present invention can contain omega-3 and omega-6 fatty acids in a certain weight ratio, and therefore can enhance anti-inflammatory and immune-enhancing effects, and therefore can prevent or treat inflammatory diseases and immune disorders caused by nutritional deficiency Damage to disease. In addition, the infusion formulation of the present invention can not only exhibit excellent clinical effectiveness, but also exhibit significantly improved stability of the formulation.

本發明之模式 在下文中，本發明之構型及效果將藉由實例更詳細地描述。以下實例係僅出於說明本發明之目的提供，且因此本發明之範圍不限於此。 Modes of the present invention Hereinafter, the configuration and effects of the present invention will be described in more detail with examples. The following examples are provided only for the purpose of illustrating the present invention, and therefore the scope of the present invention is not limited thereto.

製備實例 1 ：醫藥組合物之製法 根據本發明，實例及比較實例之組合物係藉助以下方法製備。 Preparation Example 1 : Preparation method of pharmaceutical composition According to the present invention, the compositions of Examples and Comparative Examples were prepared by the following methods.

準備兩個製備用槽，使得一個用作製備水相之槽，及另一個用作製備油相之槽。Prepare two preparation tanks such that one is used as a tank for preparing the water phase and the other is used as a tank for preparing the oil phase.

將注射用水及滲透調節劑(即甘油)插入混合水相之槽中及隨後混合在一起，然後將純化大豆油、純化橄欖油、中鏈三酸甘油酯、純化魚油、純化蛋黃卵磷脂、油酸鈉及生育酚插入混合油相之槽中及隨後用均質混合器(例如IKA均質器)均勻混合。Insert the water for injection and the osmotic regulator (i.e. glycerin) into the tank of the mixed water phase and then mix them together, and then combine the purified soybean oil, purified olive oil, medium chain triglycerides, purified fish oil, purified egg yolk lecithin, oil Sodium and tocopherol are inserted into the tank of the mixed oil phase and then uniformly mixed with a homomixer (such as an IKA homogenizer).

根據上述製備方法製備之實例及比較實例之詳細組成示於下表1中。 【表1】 組 分 (g/100ml) 實例1 比較實例1 比較實例2 比較實例3 比較實例4 比較實例5 比較實例6 純化大豆油 4.0 9.7 6.8 5.6 2.0 6.0 6.0 中鏈三酸甘油酯 4.0 4.0 4.0 4.0 4.0 6.0 5.0 純化橄欖油 5.5 4.1 4.8 5.1 5.7 5.0 5.0 純化魚油 6.5 2.2 4.4 5.3 8.3 3.0 4.0 純化蛋黃卵磷脂 1.2 1.2 1.2 1.2 1.2 1.2 1.2 油酸鈉 0.03 0.03 0.03 0.03 0.03 0.03 0.03 甘油 2.5 2.5 2.5 2.5 2.5 2.5 2.5 生育酚 0.0194 0.0194 0.0194 0.0194 0.0194 0.0194 0.0194 氫氧化鈉 適宜量 適宜量 適宜量 適宜量 適宜量 適宜量 適宜量 注射用水 適宜量 適宜量 適宜量 適宜量 適宜量 適宜量 適宜量 The detailed composition of the examples prepared according to the above preparation method and the comparative examples are shown in Table 1 below. 【Table 1】 Component (g / 100ml) Example 1 Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Purified soybean oil 4.0 9.7 6.8 5.6 2.0 6.0 6.0 Medium chain triglycerides 4.0 4.0 4.0 4.0 4.0 6.0 5.0 Purified olive oil 5.5 4.1 4.8 5.1 5.7 5.0 5.0 Purified fish oil 6.5 2.2 4.4 5.3 8.3 3.0 4.0 Purified egg yolk lecithin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Sodium Oleate 0.03 0.03 0.03 0.03 0.03 0.03 0.03 glycerin 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Tocopherol 0.0194 0.0194 0.0194 0.0194 0.0194 0.0194 0.0194 Sodium hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Water for Injection Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

將所得各混合物在一個槽中攪拌以混合預乳液，及隨後在600至1,400巴壓力條件下用高壓均質器(APV-2000，Demark)進行乳化，然後用1N氫氧化鈉調節pH。The resulting mixtures were stirred in a tank to mix the pre-emulsion, and then emulsified with a high-pressure homogenizer (APV-2000, Demark) under a pressure of 600 to 1,400 bar, and then adjusted the pH with 1N sodium hydroxide.

中鏈三酸甘油酯、純化大豆油、純化橄欖油及純化魚油中所含之Ω-3、Ω-6及Ω-9脂肪酸各係實務上根據歐洲藥典標準進行測量。中鏈三酸甘油酯、純化大豆油、純化橄欖油及純化魚油之量係根據Ω-3、Ω-6及Ω-9脂肪酸之含量進行調節。The omega-3, omega-6 and omega-9 fatty acids contained in medium-chain triglycerides, purified soybean oil, purified olive oil and purified fish oil are actually measured in accordance with European Pharmacopoeia standards. The amount of medium chain triglycerides, purified soybean oil, purified olive oil and purified fish oil is adjusted according to the content of omega-3, omega-6 and omega-9 fatty acids.

上文製備之實例1及比較實例1至6中之Ω脂肪酸之比例及含量如下表2所示。 【表2】 實例1 比較實例1 比較實例2 比較實例3 比較實例4 比較實例5 比較實例6 Ω-6/-3 之比例 1.0 / 1.0 4.0 / 1.0 2.0 / 1.0 1.5 / 1.0 0.5/ 1.0 2.5 / 1.0 2.0 / 1.0 Ω-3脂肪酸 (mg/mL) 25.0 13.4 19.4 21.8 30.1 14.0 17.5 Ω-6脂肪酸(mg/mL) 25.1 53.3 39.0 33.0 15.1 34.8 34.9 Ω-9脂肪酸(mg/mL) 58.8 58.6 58.6 58.7 56.9 56.9 57.8 The ratio and content of omega fatty acids in Example 1 and Comparative Examples 1 to 6 prepared above are shown in Table 2 below. 【Table 2】 Example 1 Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Ω-6/-3 ratio 1.0 / 1.0 4.0 / 1.0 2.0 / 1.0 1.5 / 1.0 0.5/ 1.0 2.5 / 1.0 2.0 / 1.0 Omega-3 fatty acids (mg/mL) 25.0 13.4 19.4 21.8 30.1 14.0 17.5 Omega-6 fatty acid (mg/mL) 25.1 53.3 39.0 33.0 15.1 34.8 34.9 Omega-9 fatty acid (mg/mL) 58.8 58.6 58.6 58.7 56.9 56.9 57.8

製備實例 2 ：輸液製劑之製法 為製備根據本發明之輸液製劑，分別製備第一隔室流體及第二隔室流體及隨後以使得在上述製備實例1中所獲得之實例1之組合物用作第三隔室流體之方式進行混合。 Preparation Example 2 : The preparation method of the infusion preparation is to prepare the infusion preparation according to the present invention. The first compartment fluid and the second compartment fluid are prepared separately and then the composition of Example 1 obtained in the above preparation example 1 is used as The third compartment is mixed by means of fluid.

在第一隔室流體中，將以下物質插入注射用水：L-丙胺酸、L-精胺酸、甘胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸鹽酸鹽、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、牛磺酸、L-蘇胺酸、L-色胺酸、L-酪胺酸、L-纈胺酸、二水合氯化鈣、無水甘油磷酸鈉、水合乙酸鈉、七水合硫酸鎂、氯化鉀及七水合硫酸鋅，及隨後完全溶解，然後用乙酸調節pH。In the first compartment fluid, insert the following substances into the water for injection: L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L -Lysine hydrochloride, L-methionine, L-phenylalanine, L-proline, L-serine, taurine, L-threonine, L-tryptophan, L- Tyrosine, L-valine, calcium chloride dihydrate, sodium glycerophosphate anhydrous, sodium acetate hydrate, magnesium sulfate heptahydrate, potassium chloride and zinc sulfate heptahydrate, and then completely dissolved, and then the pH is adjusted with acetic acid.

在第二隔室流體中，插入單水合葡萄糖並使其完全溶解，然後用鹽酸調節pH。In the second compartment fluid, insert glucose monohydrate and dissolve it completely, and then adjust the pH with hydrochloric acid.

將以上獲得之第一隔室流體、第二隔室流體及第三隔室流體填充至輸液用塑膠袋中，將輸液用塑膠袋分成三個隔室。之後，經由充氮將其填充流體上方之空隙密封，隨後將其與脫氧劑一起裝入多層膜之外包裝中，及隨後密封。此後，根據習知已知方法在高壓下對所得產品進行蒸汽滅菌。The first compartment fluid, the second compartment fluid, and the third compartment fluid obtained above are filled into a plastic bag for infusion, and the plastic bag for infusion is divided into three compartments. After that, the gap above the filling fluid is sealed by nitrogen filling, and then it is packed in a multilayer film outer package together with a deoxidizer, and then sealed. Thereafter, the resulting product is steam sterilized under high pressure according to a conventionally known method.

根據上述製備方法製備之實例2及3之組合物如下表3所示。 【表3】 分類 組分名稱 實例2 實例3 含量(g/100 mL) 第一隔室流體 (胺基酸及電解質) L-丙胺酸 2.07 2.07 L-精胺酸 1.15 1.15 甘胺酸 1.03 1.03 L-組胺酸 0.48 0.48 L-異白胺酸 0.60 0.60 L-白胺酸 0.73 0.73 L-離胺酸鹽酸鹽 0.725 0.725 L-甲硫胺酸 0.40 0.40 L-苯丙胺酸 0.56 0.56 L-脯胺酸 0.68 0.68 L-絲胺酸 0.50 0.50 牛磺酸 0.10 0.10 L-蘇胺酸 0.42 0.42 L-色胺酸 0.18 0.18 L-酪胺酸 0.04 0.04 L-纈胺酸 0.58 0.58 二水合氯化鈣 0.074 0.074 甘油磷酸鈉 0.418 0.418 七水合硫酸鎂 0.247 0.247 氯化鉀 0.448 0.448 水合乙酸鈉 0.562 0.562 七水合硫酸鋅 0.0023 0.0023 乙酸 (100) 適宜量 適宜量 注射用水 適宜量 適宜量 第二隔室流體 單水合葡萄糖 46.20 14.30 鹽酸 適宜量 適宜量 注射用水 適宜量 適宜量 The compositions of Examples 2 and 3 prepared according to the above preparation method are shown in Table 3 below. 【table 3】 classification Component name Example 2 Example 3 Content (g/100 mL) First compartment fluid (amino acid and electrolyte) L-Alanine 2.07 2.07 L-Arginine 1.15 1.15 Glycine 1.03 1.03 L-histidine 0.48 0.48 L-Isoleucine 0.60 0.60 L-Leucine 0.73 0.73 L-lysine hydrochloride 0.725 0.725 L-methionine 0.40 0.40 L-phenylalanine 0.56 0.56 L-Proline 0.68 0.68 L-serine 0.50 0.50 Taurine 0.10 0.10 L-threonine 0.42 0.42 L-tryptophan 0.18 0.18 L-tyrosine 0.04 0.04 L-Valine 0.58 0.58 Calcium chloride dihydrate 0.074 0.074 Sodium glycerophosphate 0.418 0.418 Magnesium Sulfate Heptahydrate 0.247 0.247 Potassium chloride 0.448 0.448 Sodium acetate hydrate 0.562 0.562 Zinc Sulfate Heptahydrate 0.0023 0.0023 Acetic acid (100) Appropriate amount Appropriate amount Water for Injection Appropriate amount Appropriate amount Second compartment fluid Glucose monohydrate 46.20 14.30 hydrochloric acid Appropriate amount Appropriate amount Water for Injection Appropriate amount Appropriate amount

實驗實例 1 ：根據 Ω 脂肪酸之組成比例評估抗發炎效應 評估發炎細胞激素之抑制能力以評定根據本發明之實例及比較實例之組合物之抗發炎效應。 Experimental Example 1 : Evaluation of the anti-inflammatory effect based on the composition ratio of omega fatty acids The inhibitory ability of inflammatory cytokines was evaluated to evaluate the anti-inflammatory effect of the compositions according to the examples of the present invention and comparative examples.

特定言之，從人類外周血單核細胞(PBMC)分離單核細胞，然後將2×105 個單核細胞插入各孔中，及隨後培養。在16小時後，各孔用20 μl實例及比較實例之組合物處理，及隨後在30分鐘後用脂多醣(LPS)處理，使得其最終濃度可達到1 μg/ml。在24小時後，利用酶聯免疫測定法(ELISA)測定IL-1β之表現程度，其結果示於圖1中。Specifically, monocytes are separated from human peripheral blood mononuclear cells (PBMC), and then 2×10 5 monocytes are inserted into each well, and then cultured. After 16 hours, each well was treated with 20 μl of the composition of Examples and Comparative Examples, and then treated with lipopolysaccharide (LPS) after 30 minutes, so that its final concentration could reach 1 μg/ml. After 24 hours, the expression level of IL-1β was measured by enzyme-linked immunoassay (ELISA). The results are shown in Figure 1.

如圖1中所示，已確認IL-1β表現程度隨著Ω-3脂肪酸比例增加而受到抑制。As shown in Fig. 1, it has been confirmed that the degree of expression of IL-1β is suppressed as the ratio of omega-3 fatty acids increases.

實驗實例 2 ：根據 Ω 脂肪酸之組成比例評估免疫增強功效 實驗實例 2-1 ：測量脾臟重量 評估涉及動物模型之免疫力之脾臟重量變化及免疫細胞變化，以評定根據本發明之實例及比較實例之組合物之免疫增強效應。 Experimental example 2 : Evaluation of immune enhancement effect based on the composition ratio of omega fatty acids. Experimental example 2-1 : Measurement of spleen weight. Evaluation of spleen weight changes and immune cell changes related to the immunity of animal models to evaluate the examples according to the present invention and comparative examples The immune enhancement effect of the composition.

特定言之，使用大鼠(七週齡雄性SD大鼠，Hallym Experimental Animals, Inc.)作為動物模型，及隨後以25 mg/kg輸注環磷醯胺(CP)以誘導免疫力之急劇下降，之後，在CP投與後之30分鐘、8小時及24小時內，對各大鼠靜脈內給藥0.4 g實例1及比較實例4及6之各組合物。此後，從動物模型中收集關鍵性免疫系統(亦即脾臟)，以判別其體重變化，其結果示於圖2中。Specifically, a rat (seven-week-old male SD rat, Hallym Experimental Animals, Inc.) was used as an animal model, and then cyclophosphamide (CP) was infused at 25 mg/kg to induce a sharp decline in immunity. Thereafter, within 30 minutes, 8 hours, and 24 hours after CP administration, 0.4 g of each composition of Example 1 and Comparative Examples 4 and 6 was intravenously administered to each rat. After that, the critical immune system (ie, the spleen) was collected from the animal model to determine the change in body weight. The results are shown in Figure 2.

如圖2中所示，已確定經環磷醯胺處理之對照組顯示脾臟重量減少，而經本發明實例1之組合物處理之組顯示脾臟重量增加，以顯著地抑制免疫力下降，因此與比較實例4及6相比為極佳。As shown in Figure 2, it has been determined that the control group treated with cyclophosphamide showed a decrease in spleen weight, while the group treated with the composition of Example 1 of the present invention showed an increase in spleen weight, which significantly suppressed the decrease in immunity, so compared with The comparison between Examples 4 and 6 is excellent.

實驗實例 2-2 ：血細胞指數之測量 在實例2-1之動物模型中測量血細胞指數，以評估根據本發明之實例及比較實例之組合物之免疫增強效應。 Experimental Example 2-2 : Measurement of Blood Cell Index The blood cell index was measured in the animal model of Example 2-1 to evaluate the immune enhancing effect of the composition according to the examples of the present invention and the comparative examples.

特定言之，給大鼠以25 mg/kg給藥環磷醯胺(CP)以誘導免疫力之急劇下降，及隨後給藥實例1及比較實例4及6之組合物。在投與後48小時內，從各大鼠心臟收集血液，及隨後用肝素處理，用自動血液分析儀測量免疫功能相關細胞(亦即，嗜中性粒細胞、嗜酸性粒細胞及淋巴細胞)之數量，使得其結果示於圖3中。Specifically, cyclophosphamide (CP) was administered to rats at 25 mg/kg to induce a sharp decline in immunity, and then the compositions of Example 1 and Comparative Examples 4 and 6 were administered. Within 48 hours after administration, blood was collected from the heart of each rat, and then treated with heparin, and immune function-related cells (ie, neutrophils, eosinophils, and lymphocytes) were measured with an automatic blood analyzer. The number of results is shown in Figure 3.

如圖3所示，已確定經本發明之實例1之組合物處理之組顯著增強中性粒細胞、嗜酸性粒細胞及淋巴細胞，該等細胞已由於免疫力下降而減少，因此與具有不同Ω脂肪酸比例之比較實例4及6相比為極佳。As shown in Figure 3, it has been determined that the group treated with the composition of Example 1 of the present invention significantly enhanced neutrophils, eosinophils and lymphocytes. These cells have been reduced due to decreased immunity, and therefore have different Ω The fatty acid ratios of Comparative Examples 4 and 6 are excellent.

實驗實例 3 ：根據 Ω 脂肪酸之組成比例確定血清生化指數變化 根據Ω脂肪酸比例，評估對血清生化指數(亦即乳酸脫氫酶(LDH)及肌酐(CREA))之影響。 Experimental example 3 : Determine the change of serum biochemical index according to the composition ratio of omega fatty acids. According to the ratio of omega fatty acids, evaluate the influence on serum biochemical index (ie lactate dehydrogenase (LDH) and creatinine (CREA)).

特定言之，在CP投與後48小時內，從各大鼠心臟收集血液以從中分離血清，然後用血清生化分析儀測量各血清指數，使得其結果示於圖4中。Specifically, within 48 hours after CP administration, blood was collected from each rat heart to separate serum therefrom, and then each serum index was measured with a serum biochemical analyzer, so that the results are shown in FIG. 4.

如圖4所示，已確定經本發明之實例1之組合物處理之組顯著抑制LDH及CREA。As shown in Figure 4, it has been determined that the group treated with the composition of Example 1 of the present invention significantly inhibits LDH and CREA.

實驗實例 4 ：單次靜脈內投與之毒性測試 為評估根據本發明之用於靜脈內投與之組合物之安全性，將動物模型用其靜脈內注射以評定其安全性。 Experimental Example 4 : Single intravenous administration and toxicity test In order to evaluate the safety of the composition for intravenous administration according to the present invention, an animal model was injected intravenously to assess its safety.

將實例1之用於靜脈內投與之組合物一次性靜脈內投與至比格犬(雄性，28個月大，約11 kg)中。關於臨床投與劑量(基於成人60 kg)，以三倍劑量投與該組合物持續至多八小時。投與後，無動物死亡，及未觀測到體重、臨床症狀存在及血液組成之變化。The composition for intravenous administration of Example 1 was administered to Beagle dogs (male, 28 months old, approximately 11 kg) once intravenously. Regarding the clinical administration dose (based on 60 kg for adults), the composition was administered in a triple dose for up to eight hours. After the administration, no animals died, and no changes in body weight, clinical symptoms and blood composition were observed.

實驗實例 5 ：對脂質輸液製劑之穩定性測試 1 在加速條件(40℃/RH 75%)下，對上述實例1及比較實例2至6進行一個月穩定性評估。用NICOMP設備測量脂質乳液之粒度。關於按項脂質營養素輸注之標準，適用脂質可注射乳液專論之標準，但詳細設定與脂肪酸氧化引起之降解產物有關的游離脂肪酸及溶血磷脂醯膽鹼(LPC)之標準。乳液之脂質顆粒均勻地形成並保持，而與Ω脂肪酸比例無關。另外，如在下表4中所見，所需穩定性標準係例如藉由不顯示根據Ω脂肪酸比例之脂肪酸氧化指數大差異來滿足。 【表4】 項 標準 實例1 比較實例2 比較實例3 初始 1 個月 初始 1 個月 初始 1 個月 pH 6.0~9.0 8.3 8.2 8.2 8.2 8.1 8.2 游離脂肪酸 ≤8.0 mg/mL 2.4 2.9 2.3 2.8 2.4 2.9 平均顆粒 ≤500 nm 192 214 180 199 198 205 最大顆粒 ≤1 μm 0.30 0.35 0.38 0.27 0.34 0.30 分散度 ≤0.25 0.04 0.05 0.12 0.02 0.06 0.03 溶血磷脂醯膽鹼 ≤2 mg/mL 小於0.5 小於0.5 小於0.5 小於0.5 - 小於0.5 項 標準 比較實例4 比較實例5 比較實例6 初始 1 個月 初始 1 個月 初始 1 個月 pH 6.0~9.0 8.3 8.2 8.3 8.2 8.1 8.1 游離脂肪酸 ≤8.0 mg/mL 2.6 3.1 2.3 2.8 2.2 2.8 平均顆粒 ≤500 nm 200 197 200 210 190 195 最大顆粒 ≤1 μm 0.39 0.30 0.35 0.32 0.33 0.41 分散度 ≤0.25 0.09 0.04 0.06 0.04 0.06 0.12 溶血磷脂醯膽鹼 ≤2 mg/mL 小於0.5 小於0.5 小於0.5 小於0.5 小於0.5 小於0.5 Experimental Example 5 : Stability Test 1 of Lipid Infusion Preparation Under accelerated conditions (40° C./RH 75%), the above-mentioned Example 1 and Comparative Examples 2 to 6 were evaluated for stability for one month. The particle size of the lipid emulsion was measured with NICOMP equipment. Regarding the standard for lipid nutrient infusion, the standard of the Lipid Injectable Emulsion Monograph applies, but the free fatty acid and lysophospholipid choline (LPC) standards related to the degradation products caused by fatty acid oxidation are set in detail. The lipid particles of the emulsion are uniformly formed and maintained regardless of the ratio of omega fatty acids. In addition, as seen in Table 4 below, the required stability criterion is met, for example, by not showing a large difference in fatty acid oxidation index according to the ratio of omega fatty acids. 【Table 4】 item standard Example 1 Comparative example 2 Comparative example 3 initial 1 month initial 1 month initial 1 month pH 6.0~9.0 8.3 8.2 8.2 8.2 8.1 8.2 Free fatty acid ≤8.0 mg/mL 2.4 2.9 2.3 2.8 2.4 2.9 Average particle ≤500 nm 192 214 180 199 198 205 Largest particle ≤1 μm 0.30 0.35 0.38 0.27 0.34 0.30 Dispersion ≤0.25 0.04 0.05 0.12 0.02 0.06 0.03 Lysophospholipid Choline ≤2 mg/mL Less than 0.5 Less than 0.5 Less than 0.5 Less than 0.5 - Less than 0.5 item standard Comparative example 4 Comparative example 5 Comparative example 6 initial 1 month initial 1 month initial 1 month pH 6.0~9.0 8.3 8.2 8.3 8.2 8.1 8.1 Free fatty acid ≤8.0 mg/mL 2.6 3.1 2.3 2.8 2.2 2.8 Average particle ≤500 nm 200 197 200 210 190 195 Largest particle ≤1 μm 0.39 0.30 0.35 0.32 0.33 0.41 Dispersion ≤0.25 0.09 0.04 0.06 0.04 0.06 0.12 Lysophospholipid Choline ≤2 mg/mL Less than 0.5 Less than 0.5 Less than 0.5 Less than 0.5 Less than 0.5 Less than 0.5

實驗實例 6 ：對脂質營養素輸注之穩定性測試 2 在長期(25℃/RH 60%)、加速(40℃/RH 75%)儲存條件下，對上述實例1及比較實例4至6進行六個月穩定性評估，使得其結果示於下表5中。 【表5】 項 標準 實例1 比較實例4 初始 長期6M 加速6M 初始 長期6M 加速6M pH 6.0~9.0 8.3 8.2 7.2 8.3 8.1 7.1 游離脂肪酸 ≤8.0 mg/mL 2.4 3.3 6.0 2.6 3.3 6.6 平均顆粒 ≤500 nm 192 223 219 200 220 232 最大顆粒 ≤1 μm 0.30 0.29 0.47 0.39 0.35 0.39 分散度 ≤0.25 0.04 0.01 0.13 0.09 0.04 0.06 溶血磷脂醯膽鹼 ≤2 mg/mL 小於 0.5 0.54 1.18 小於 0.5 0.49 1.35 項 標準 比較實例5 比較實例6 初始 長期6M 加速6M 初始 長期6M 加速6M pH 6.0~9.0 8.3 8.0 7.1 8.1 8.1 7.0 游離脂肪酸 ≤8.0 mg/mL 2.3 3.3 5.8 2.2 3.3 5.8 平均顆粒 ≤500 nm 201 236 224 190 213 221 最大顆粒 ≤1 μm 0.35 0.39 0.43 0.33 0.55 0.35 分散度 ≤0.25 0.06 0.05 0.09 0.06 0.20 0.04 溶血磷脂醯膽鹼 ≤2 mg/mL 小於 0.5 0.64 1.18 小於 0.5 0.56 1.14 Experimental example 6 : Stability test for lipid nutrient infusion 2 Under long-term (25°C/RH 60%) and accelerated (40°C/RH 75%) storage conditions, six of the above example 1 and comparative examples 4 to 6 are performed The monthly stability was evaluated so that the results are shown in Table 5 below. 【table 5】 item standard Example 1 Comparative example 4 initial Long-term 6M Speed up 6M initial Long-term 6M Speed up 6M pH 6.0~9.0 8.3 8.2 7.2 8.3 8.1 7.1 Free fatty acid ≤8.0 mg/mL 2.4 3.3 6.0 2.6 3.3 6.6 Average particle ≤500 nm 192 223 219 200 220 232 Largest particle ≤1 μm 0.30 0.29 0.47 0.39 0.35 0.39 Dispersion ≤0.25 0.04 0.01 0.13 0.09 0.04 0.06 Lysophospholipid Choline ≤2 mg/mL Less than 0.5 0.54 1.18 Less than 0.5 0.49 1.35 item standard Comparative example 5 Comparative example 6 initial Long-term 6M Speed up 6M initial Long-term 6M Speed up 6M pH 6.0~9.0 8.3 8.0 7.1 8.1 8.1 7.0 Free fatty acid ≤8.0 mg/mL 2.3 3.3 5.8 2.2 3.3 5.8 Average particle ≤500 nm 201 236 224 190 213 221 Largest particle ≤1 μm 0.35 0.39 0.43 0.33 0.55 0.35 Dispersion ≤0.25 0.06 0.05 0.09 0.06 0.20 0.04 Lysophospholipid Choline ≤2 mg/mL Less than 0.5 0.64 1.18 Less than 0.5 0.56 1.14

從上表5中可見，已確定，儘管包含大量多不飽和脂肪酸，但與比較實例5及6相比，實例1就品質而言係穩定的。然而，從包含相對最多量Ω-3脂肪酸之比較實例4之結果判斷，在考慮實際產物有效期(從製造日期起24個月)之情況下，可假定Ω-3脂肪酸之濃度存在限制(表5)。As can be seen from Table 5 above, it has been determined that, despite containing a large amount of polyunsaturated fatty acids, compared to Comparative Examples 5 and 6, Example 1 is stable in terms of quality. However, judging from the results of Comparative Example 4 containing the relatively largest amount of omega-3 fatty acids, considering the actual product expiration date (24 months from the date of manufacture), it can be assumed that there is a limit to the concentration of omega-3 fatty acids (Table 5 ).

實驗實例 7 ：對輸液製劑之品質評估 對以上實例2及3中製備之輸液之各隔室流體及與第一至第三隔室流體混合之流體進行品質評估，使得其結果示於下表6中。 【表6】 分類 項 標準 實例2 實例3 第一隔室流體 性質 透明及無色至淺黃色溶液 適宜 適宜 pH 5.4 - 5.8 5.6 5.6 第二隔室流體 性質 無色及透明溶液 適宜 適宜 pH 3.5 - 5.5 4.1 4.5 純度 0.25或更小之吸光度 0.04 0.01 第三隔室流體 性質 象牙白均質乳液 適宜 適宜 pH 6.0 - 9.0 8.5 8.2 脂肪總量 199 – 219 mg/mL 208 207 游離脂肪酸 ≤8.0 mEq/L 2.5 2.5 分散度 平均顆粒: ≤500 nm 247 232 最大顆粒: ≤1 μm 0.46 0.39 分散度: ≤0.25 0.07 0.04 粒度 1.5 μm或更大： ≤2% 0.57 0.39 5 μm或更大：≤0.05% 0.00 0.00 溶血磷脂醯膽鹼 ≤2 mg/mL 0.6 0.6 混合物 性質 白色乳液 適宜 適宜 pH 5.5 ~ 5.7 5.6 5.6 粒度 最大顆粒7 μm或更大：0% 0 0 無菌法 無菌生長 適宜 適宜 內毒素 ≤0.5 EU/mL 0.25或更小 0.25或更小 Experimental Example 7 : Evaluation of the quality of infusion preparations. The quality of each compartment fluid of the infusion prepared in the above examples 2 and 3 and the fluids mixed with the first to third compartment fluids were evaluated, and the results are shown in Table 6 below in. 【Table 6】 classification item standard Example 2 Example 3 First compartment fluid nature Transparent and colorless to light yellow solution suitable suitable pH 5.4-5.8 5.6 5.6 Second compartment fluid nature Colorless and transparent solution suitable suitable pH 3.5-5.5 4.1 4.5 purity Absorbance of 0.25 or less 0.04 0.01 Third compartment fluid nature Ivory homogeneous emulsion suitable suitable pH 6.0-9.0 8.5 8.2 Total fat 199 – 219 mg/mL 208 207 Free fatty acid ≤8.0 mEq/L 2.5 2.5 Dispersion Average particle: ≤500 nm 247 232 Largest particle: ≤1 μm 0.46 0.39 Dispersion: ≤0.25 0.07 0.04 granularity 1.5 μm or more: ≤2% 0.57 0.39 5 μm or more: ≤0.05% 0.00 0.00 Lysophospholipid Choline ≤2 mg/mL 0.6 0.6 mixture nature White emulsion suitable suitable pH 5.5 ~ 5.7 5.6 5.6 granularity Largest particles 7 μm or larger: 0% 0 0 Aseptic method Aseptic growth suitable suitable Endotoxin ≤0.5 EU/mL 0.25 or less 0.25 or less

從上表6中可見，已確定，本發明之輸液製劑適用於所有針對品質所評估之項。特定言之，已確定，穩定性沒有問題，因為0.00%為顆粒5 μm或更大之比例(PFAT 5，直徑＞5 μm之脂肪小球之百分比)，與產物之安全性密切相關(在一些動物測試模型(豚鼠模型)中之組織學轉化，在肝及肺中出現疾病症狀(大鼠模型)等)。It can be seen from Table 6 above that it has been determined that the infusion preparation of the present invention is suitable for all items evaluated for quality. In particular, it has been determined that there is no problem with stability, because 0.00% is the proportion of particles 5 μm or larger (PFAT 5, the percentage of fat globules with a diameter> 5 μm), which is closely related to the safety of the product (in some Histological transformation in animal test model (guinea pig model), disease symptoms in liver and lung (rat model), etc.).

圖1為顯示根據Ω脂肪酸比例之抗發炎效應之圖。Figure 1 is a graph showing the anti-inflammatory effect according to the ratio of omega fatty acids.

圖2為顯示根據Ω脂肪酸比例對免疫力下降之抑制效應之圖。Figure 2 is a graph showing the inhibitory effect of omega fatty acid ratio on immunity decline.

圖3為顯示根據Ω脂肪酸比例之血細胞指數之圖。Figure 3 is a graph showing the blood cell index according to the ratio of omega fatty acids.

圖4為顯示根據Ω脂肪酸比例之血清生化指數之圖。Figure 4 is a graph showing the serum biochemical index according to the ratio of omega fatty acids.

Claims (21)

一種預防或治療發炎性疾病或免疫受損疾病之醫藥組合物，其包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸。A pharmaceutical composition for preventing or treating inflammatory diseases or immunocompromised diseases, which comprises omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25. 如請求項1之醫藥組合物，其中Ω-3及Ω-6脂肪酸之重量比為1:1。The pharmaceutical composition of claim 1, wherein the weight ratio of omega-3 and omega-6 fatty acids is 1:1. 如請求項1之醫藥組合物，其中該等Ω-3脂肪酸為選自由α-亞麻酸(ALA)、二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)組成之群之至少一者。The pharmaceutical composition of claim 1, wherein the omega-3 fatty acids are selected from the group consisting of α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) At least one of them. 如請求項1之醫藥組合物，其中所提供之該等Ω-3脂肪酸之每日量為0.1至0.2 g/kg/天。The pharmaceutical composition of claim 1, wherein the daily amount of the omega-3 fatty acids provided is 0.1 to 0.2 g/kg/day. 如請求項1之醫藥組合物，其中該等Ω-6脂肪酸為選自由亞油酸、γ-亞麻酸、金盞酸、二十碳二烯酸、二高-γ-亞麻酸、花生四烯酸、二十二碳二烯酸、二十二碳四烯酸、二十二碳五烯酸、二十四碳四烯酸及二十四碳五烯酸組成之群之至少一者。The pharmaceutical composition of claim 1, wherein the omega-6 fatty acids are selected from the group consisting of linoleic acid, γ-linolenic acid, calendic acid, eicosadienoic acid, dihomo-γ-linolenic acid, and arachidene At least one of the group consisting of acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosatetraenoic acid, and docosapentaenoic acid. 如請求項1之醫藥組合物，其中該等發炎性疾病係選自由以下組成之群：胃炎、腸炎、腎炎、肝炎、慢性阻塞性肺病(COPD)、肺纖維化、腸激躁症候群、發炎性疼痛、偏頭痛、頭痛、背痛、纖維肌痛、筋膜病、病毒感染、細菌感染、真菌感染、燒傷、由外科手術或牙科手術造成之傷害、PGE過高症候群、動脈粥樣硬化、痛風、霍奇金氏病(Hodgkin's disease)、胰臟炎、結膜炎、虹膜炎、鞏膜炎、葡萄膜炎及急慢性發炎性疾病。The pharmaceutical composition of claim 1, wherein the inflammatory diseases are selected from the group consisting of gastritis, enteritis, nephritis, hepatitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, inflammatory Pain, migraine, headache, back pain, fibromyalgia, fascial disease, viral infection, bacterial infection, fungal infection, burns, injury caused by surgery or dental surgery, PGE syndrome, atherosclerosis, gout , Hodgkin's disease, pancreatitis, conjunctivitis, iritis, scleritis, uveitis and acute and chronic inflammatory diseases. 如請求項1之醫藥組合物，其中該組合物抑制IL-1β之表現。The pharmaceutical composition of claim 1, wherein the composition inhibits the expression of IL-1β. 如請求項1之醫藥組合物，其中該等免疫受損疾病係選自由以下組成之群：哮喘、季節性或常年性鼻炎、過敏性鼻炎、結膜炎、異位性皮膚炎、蕁麻疹、紅細胞溶血、急性腎小球腎炎、流感、慢性疲勞及癌症。The pharmaceutical composition of claim 1, wherein the immunocompromised diseases are selected from the group consisting of asthma, seasonal or perennial rhinitis, allergic rhinitis, conjunctivitis, atopic dermatitis, urticaria, hemolysis of red blood cells , Acute glomerulonephritis, influenza, chronic fatigue and cancer. 如請求項1之醫藥組合物，其中該組合物為非經腸投與。The pharmaceutical composition of claim 1, wherein the composition is administered parenterally. 如請求項1之醫藥組合物，其中該組合物包含選自由魚油、大豆油、橄欖油、棉籽油、紅花油、芝麻油、椰子油及玉米油組成之群之至少一種油。The pharmaceutical composition of claim 1, wherein the composition comprises at least one oil selected from the group consisting of fish oil, soybean oil, olive oil, cottonseed oil, safflower oil, sesame oil, coconut oil, and corn oil. 如請求項1之醫藥組合物，其中該組合物包含選自由乳化劑、滲透調節劑、pH調節劑及抗氧化劑組成之群之至少一種添加劑。The pharmaceutical composition of claim 1, wherein the composition comprises at least one additive selected from the group consisting of an emulsifier, an osmotic regulator, a pH regulator, and an antioxidant. 一種輸液製劑，其包含Ω-3及Ω-6脂肪酸。An infusion preparation containing omega-3 and omega-6 fatty acids. 如請求項12之輸液製劑，其中該輸液製劑中所包含之Ω-3及Ω-6脂肪酸之重量比為1:0.75至1:1.25。The infusion preparation of claim 12, wherein the weight ratio of omega-3 and omega-6 fatty acids contained in the infusion preparation is 1:0.75 to 1:1.25. 如請求項12之輸液製劑，其中該輸液製劑中所包含之Ω-3及Ω-6脂肪酸之重量比為1:1。The infusion preparation of claim 12, wherein the weight ratio of omega-3 and omega-6 fatty acids contained in the infusion preparation is 1:1. 如請求項12之輸液製劑，其中該輸液製劑係接收在單個隔室中。The infusion preparation of claim 12, wherein the infusion preparation is received in a single compartment. 如請求項12之輸液製劑，其中該輸液製劑係接收在複數個隔室中，該等複數個隔室以可連接方式彼此分隔，以便在使用時可混合製劑。For example, the infusion preparation of claim 12, wherein the infusion preparation is received in a plurality of compartments, and the plurality of compartments are separated from each other in a connectable manner so that the preparation can be mixed during use. 如請求項16之輸液製劑，其中該隔室係被分成第一隔室、第二隔室及第三隔室，且其中該第一隔室接收用於提供胺基酸及電解質之第一隔室流體；該第二隔室接收用於提供糖之第二隔室流體；及該第三隔室接收用於提供脂肪之第三隔室流體。The infusion preparation of claim 16, wherein the compartment is divided into a first compartment, a second compartment and a third compartment, and wherein the first compartment receives the first compartment for providing amino acid and electrolyte Chamber fluid; the second compartment receives the second compartment fluid for providing sugar; and the third compartment receives the third compartment fluid for providing fat. 如請求項17之輸液製劑，其中該第一隔室接收該第一隔室流體，基於100 mL該第一隔室流體計，該第一隔室流體包含2.07 g L-丙胺酸、1.15 g L-精胺酸、1.03 g甘胺酸、0.48 g L-組胺酸、0.60 g L-異白胺酸、0.73 g L-白胺酸、0.725 g L-離胺酸鹽酸鹽、0.40 g L-甲硫胺酸、0.56 g L-苯丙胺酸、0.68 g L-脯胺酸、0.50 g L-絲胺酸、0.10 g牛磺酸、0.42 g L-蘇胺酸、0.18 g L-色胺酸、0.04 g L-酪胺酸、0.58 g L-纈胺酸、74 mg二水合氯化鈣、418 mg無水甘油磷酸鈉、562 mg水合乙酸鈉、247 mg七水合硫酸鎂、448 mg氯化鉀及2.3 mg七水合硫酸鋅； 其中該第二隔室接收該第二隔室流體，基於100 mL該第二隔室流體計，該第二隔室流體包含14.3 g或46.2 g一水合葡萄糖；及 其中該第三隔室接收該第三隔室流體，基於100 ml該第三隔室流體計，該第三隔室流體包含4.0 g純化大豆油、4.0 g中鏈三酸甘油酯、5.5 g純化橄欖油及6.5 g純化魚油。The infusion preparation of claim 17, wherein the first compartment receives the first compartment fluid, and based on 100 mL of the first compartment fluid meter, the first compartment fluid contains 2.07 g L-alanine, 1.15 g L -Arginine, 1.03 g glycine, 0.48 g L-histidine, 0.60 g L-isoleucine, 0.73 g L-leucine, 0.725 g L-lysine hydrochloride, 0.40 g L -Methionine, 0.56 g L-phenylalanine, 0.68 g L-proline, 0.50 g L-serine, 0.10 g taurine, 0.42 g L-threonine, 0.18 g L-tryptophan , 0.04 g L-tyrosine, 0.58 g L-valine acid, 74 mg calcium chloride dihydrate, 418 mg sodium glycerophosphate anhydrous, 562 mg sodium acetate hydrate, 247 mg magnesium sulfate heptahydrate, 448 mg potassium chloride And 2.3 mg zinc sulfate heptahydrate; Wherein the second compartment receives the second compartment fluid, based on the 100 mL of the second compartment fluid meter, the second compartment fluid contains 14.3 g or 46.2 g monohydrate glucose; and Wherein the third compartment receives the third compartment fluid, based on 100 ml of the third compartment fluid meter, the third compartment fluid contains 4.0 g purified soybean oil, 4.0 g medium chain triglycerides, 5.5 g purified Olive oil and 6.5 g purified fish oil. 一種預防或治療發炎性疾病或免疫受損疾病之方法，其包括將包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物投與給需要治療之個體之步驟。A method for preventing or treating inflammatory diseases or immunocompromised diseases, which comprises the step of administering a composition containing omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25 to an individual in need of treatment . 一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物之用途，其用於預防或治療發炎性疾病或免疫受損疾病。A use of a composition comprising omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25, which is used for the prevention or treatment of inflammatory diseases or immunocompromised diseases. 一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物之用途，其用於製備用於預防或治療發炎性疾病或免疫受損疾病之醫藥製劑。A use of a composition comprising omega-3 and omega-6 fatty acids in a weight ratio of 1:0.75 to 1:1.25, which is used to prepare pharmaceutical preparations for the prevention or treatment of inflammatory diseases or immunocompromised diseases.
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