TW201338805A - Hormone containing emulsion - Google Patents

Abstract

The present invention relates to a hormone containing oil-in-water emulsion for parenteral administration comprising (a) progestogen and/or estrogen and (b) fish oil triglycerides, wherein the fish oil triglyceride consists of glycerol which is esterified with fatty acids wherein said fatty acids comprise eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in an amount of at least 45 % by weight of said fatty acids.

Description

含荷爾蒙的乳劑 Hormone-containing emulsion

本發明係關於一種非經口投與之含有荷爾蒙的水包油型乳劑，其係包含助孕激素(progestogen)及/或***(estrogen)、魚油三酸甘油脂；以及一種醫藥組合物，其係包含該水包油型乳劑或由該水包油型乳劑所組成。該醫藥組合物特別是用於治療或預防中風及/或創傷後之神經傷害，及/或用於治療或預防腦震盪後之神經傷害及/或中樞神經系統的創傷性損傷。 The present invention relates to a hormone-containing oil-in-water emulsion for parenteral administration comprising a progestogen and/or estrogen, fish oil triglyceride, and a pharmaceutical composition. It comprises or consists of the oil-in-water emulsion. The pharmaceutical composition is particularly useful for treating or preventing neurological damage after stroke and/or trauma, and/or for treating or preventing neurological damage following concussion and/or traumatic injury of the central nervous system.

創傷性腦部損傷(TBI)是一種非退化性、非先天性，腦部遭受外部物理性力量後，可能造成之永久性或暫時性的認知、身體以及心理功能的損傷，並伴隨著意識的衰減或是狀態變化。有些TBI病患須要長期或是終生的照護，以維持日常生活活動。 Traumatic brain injury (TBI) is a non-degenerate, non-congenital, permanent or temporary impairment of cognitive, physical, and psychological functions that may be caused by external physical forces in the brain, accompanied by consciousness. Attenuation or state change. Some TBI patients require long-term or lifelong care to maintain activities of daily living.

儘管TBI所造成的問題影響深遠，但目前仍缺乏經證實之有效減少死亡率或是改善TBI後果的藥物治療。然而，最近有兩個臨床試驗已證實，類固醇荷爾蒙助孕酮(progesterone)可成功治療TBI(Xiao等人所著之2008,Crit.Care,12：R61；Wright等人所著之Ann.Emerg.Med.2007,49：391-402)。二個研究都顯示助孕酮對TBI病患來說是安全的且TBI病患對助孕酮具有很好的耐受 性，且將助孕酮投與TBI病患可降低死亡率。此外，專利申請案WO2006/102644、WO2006102596、WO2008/039898、US 2011/0262494以及US 2011/0262495概述經口服投與助孕激素治療TBI的方法。 Despite the far-reaching implications of TBI, there is still a lack of proven drug treatment to reduce mortality or improve the consequences of TBI. However, two recent clinical trials have confirmed that steroid hormone progesterone can successfully treat TBI (Xiao et al., 2008, Crit. Care, 12: R61; Wright et al. Ann. Emerg. Med. 2007, 49: 391-402). Both studies have shown that progesterone is safe for TBI patients and that TBI patients are well tolerated with progesterone Sexuality, and the administration of progesterone to TBI patients can reduce mortality. In addition, patent applications WO2006/102644, WO2006102596, WO2008/039898, US 2011/0262494 and US 2011/0262495 outline methods for the treatment of TBI by oral administration of a progestogen.

此外，Alkayed等人所著之in Stroke 31,161(2003)記載經皮下投與中風病患***與助孕酮後的正面影響。 In addition, Alkayed et al., In Stroke 31, 161 (2003), describes the positive effects of subcutaneous administration of estrogen and progesterone in stroke patients.

中風，又稱作腦血管病變(cerebrovascular accident，CVA)，是因為腦部血液供給出現障礙而快速失去大腦功能。腦部血液供給出現障礙的原因可能是阻塞(血栓、動脈栓塞)所造成的局部缺血(缺乏血流)或是出血(流血)。因腦部功能無法運作的區域，可能會導致無法移動身體一側的四肢(一或多者)、無法理解或闡述談話，或是無法看到視野一側。 Stroke, also known as cerebrovascular accident (CVA), is a rapid loss of brain function due to impediments to the blood supply to the brain. The cause of impaired blood supply to the brain may be ischemia (lack of blood flow) or bleeding (bleeding) caused by obstruction (thrombosis, arterial embolism). Areas where brain function is inoperable may result in the inability to move the limbs (one or more) on one side of the body, the inability to understand or articulate the conversation, or the inability to see the side of the field of view.

中風是一種醫學上的緊急突發事件，會造成永久性神經傷害、併發症以及死亡。中風，在美國及歐洲，是導致成人失能的首要原因，而在全世界則是造成死亡的次要原因。中風的危險因子包括年長、高血壓、曾經中風、或是短暫性腦缺血發作(transient ischemic attack，TIA)、糖尿病、高膽固醇、抽菸、以及動脈纖維化。其中，高血壓是中風最主要的危險因子。 Stroke is a medical emergency that can cause permanent nerve damage, complications, and death. Stroke, in the United States and Europe, is the leading cause of adult disability, and the world is the secondary cause of death. Risk factors for stroke include elderly, high blood pressure, previous stroke, or transient ischemic attack (TIA), diabetes, high cholesterol, smoking, and arterial fibrosis. Among them, hypertension is the most important risk factor for stroke.

助孕激素(例如助孕酮)及/或***(例如***)之最有效的投與途徑為非經口服(例如靜脈管內給法)的投與方式。然而，由於助孕酮及/或***分子的疏水性質致使其於水中的低溶解度、以及目前配方的限制，含水溶液並不能提供可 遞送助孕酮及/或***之有效的治療劑量的配方給病患。然而，助孕酮及/或***具充分的親脂性，其可以具治療效果的濃度製備於疏水性溶劑中，例如以三酸甘油酯為基底的溶劑。 The most effective route of administration of progestogens (e.g., progesterone) and/or estrogens (e.g., estradiol) is the mode of administration that is not administered orally (e.g., intravenously). However, due to the hydrophobic nature of progesterone and/or estradiol molecules, their low solubility in water, and the limitations of current formulations, aqueous solutions do not provide A formulation that delivers an effective therapeutic dose of progesterone and/or estradiol to the patient. However, progesterone and/or estradiol are sufficiently lipophilic, which can be prepared in a hydrophobic solvent at a therapeutically effective concentration, such as a triglyceride-based solvent.

本領域已知經水包油型乳劑靜脈注射的疏水性藥物遞送。於Wright等人的文獻(Ann.Emerg.Med.2007,49：391-402)中，利用了一個雙組分系統(two component system)，其中，先將助孕酮溶解於酒精溶液(第一組分)中，而後，再將此酒精助孕酮溶液注入一市售可得的油脂型乳劑Intralipid^® 20%(Fresenius Kabi，Sweden)(第二組分)中，並於該酒精溶液/乳劑混合液經由靜脈投與之前，短暫地手動將其混合(例如搖動)。此製備方法有以下幾項缺點： Hydrophobic drug delivery by intravenous injection of an oil-in-water emulsion is known in the art. In the literature of Wright et al. ( Ann. Emerg. Med. 2007, 49: 391-402), a two component system is utilized in which progesterone is first dissolved in an alcohol solution (first In the component), the alcohol progesterone solution is then injected into a commercially available oil-based emulsion Intralipid ^® 20% (Fresenius Kabi, Sweden) (second component), and in the alcohol solution/emulsion The mixture is briefly mixed (eg, shaken) manually before being administered via the vein. This preparation method has the following disadvantages:

第一，將酒精溶液投與TBI病患並不理想；第二，儘管酒精的存在增加了助孕酮及/或***的溶解度，但低切(low shear)的手動混合並不能使全部的助孕酮/***都進入油相(oil phase)中。因此，此種乳劑僅可溶解有限含量的助孕酮或***，故必須採用大量的油脂以達到理想的血清中助孕酮及/或***的量。然而，將大體積的乳劑，及/或大量的油脂投與病患，會造成相當嚴重的後果，例如誘發高血脂症(hyperlipidemia)或水腫(oedema)。結果，該病患會暴露在一個不良的油脂及/或液體的負荷，以及副作用的風險中。 First, it is not ideal to administer alcoholic solutions to patients with TBI. Second, although the presence of alcohol increases the solubility of progesterone and/or estradiol, low shear manual mixing does not Progesterone/estradiol enters the oil phase. Therefore, such an emulsion can only dissolve a limited amount of progesterone or estradiol, so a large amount of oil must be used to achieve the desired amount of progesterone and/or estradiol in the serum. However, the administration of large volumes of emulsion, and/or large amounts of oil, to a patient can have quite serious consequences, such as the induction of hyperlipidemia or oedema. As a result, the patient is exposed to a poor load of fats and/or fluids, as well as the risk of side effects.

此外，未溶解的助孕激素及/或***會結晶化(crystallization)，接著在含水相(aqueous phase)中發生氧化作 用，因此不僅會造成組合物中微粒物質量增加而聚積，也造成高量的有效成分降解產物。已確實顯示，當一助孕酮的酒精溶液注入一市售的油脂型乳劑組合物(例如Intralipid^® 20%)中，一部分的荷爾蒙會處於結晶形式，而非溶解於乳劑中。已有報告指出此未溶解的助孕酮會吸附於該注射液袋以及輸送導管的表面，且觀察到並非全部助孕酮都進到這些雙組分乳劑的油相中，導致無法確定最終組合物中助孕酮所達到的濃度及該荷爾蒙的生物利用率。 In addition, undissolved progestogens and/or estrogens crystallize and then oxidize in the aqueous phase, thereby not only causing an increase in the mass of the particulate matter in the composition but also causing high The amount of active ingredient degradation products. It has been shown that when a progesterone alcohol solution is injected into a commercially available greasy emulsion composition (e.g., Intralipid ^® 20%), a portion of the hormone will be in crystalline form rather than being dissolved in the emulsion. It has been reported that this undissolved progesterone is adsorbed on the surface of the injection bag and the delivery catheter, and it is observed that not all progesterone enters the oil phase of these two-component emulsions, resulting in the inability to determine the final combination. The concentration achieved by the progesterone and the bioavailability of the hormone.

最後，是關於安定性的問題。雙組分系統中的助孕酮-油脂混合物必須於投藥前幾小時方可製備(意即，在使用前幾小時，將第一組分加入第二組分中，並混合)，因為所得之混合物不能於室溫中儲存。製備這樣要求的混合物，對於開業醫師來說既耗時且不方便，尤其不能滿足TBI的治療(立即治療對病患結果是重要的)。 Finally, it is about stability. The progesterone-fat mixture in the two-component system must be prepared a few hours before administration (ie, the first component is added to the second component a few hours before use and mixed) because of the The mixture cannot be stored at room temperature. The preparation of such a desired mixture is time consuming and inconvenient for the practitioner, and in particular does not satisfy the treatment of TBI (immediate treatment is important for patient outcome).

製造含有荷爾蒙之乳劑的替代方法，係於製造油脂型乳劑時，直接將荷爾蒙併入油中(WO 2004/110402)。 An alternative method of making a hormone-containing emulsion is to incorporate the hormone directly into the oil when making the oil-based emulsion (WO 2004/110402).

CN 101152186記載使用界面活性劑Solutol S15或poloxamer 188於製備可注射的助孕酮配方。儘管使用這些界面活性劑可達到助孕酮高溶解度，但是這些高濃度的界面活性劑經由靜脈投與，會伴隨著非所欲的副作用，包括中度組織胺釋放、蒙麻疹、以及過敏性反應(搔癢性皮炎、紅斑)。 CN 101152186 describes the use of the surfactant Solutol S15 or poloxamer 188 for the preparation of injectable progesterone formulations. Although the use of these surfactants can achieve high solubility of progesterone, these high concentrations of surfactants are administered intravenously with undesired side effects including moderate histamine release, measles, and allergic reactions. (pruritic dermatitis, erythema).

於本領域中，已知使用有機溶劑係一增加助孕酮及/ 或***於油脂型乳劑中之溶解度的一種方法。助孕酮可高度溶解於苯甲酸或其衍生物中。舉例而言，JP 60-258110記載使用苯甲酸苯甲酯以增加助孕酮於油脂型乳劑中的溶解度。然而，因為苯甲醇及苯甲酸苯甲酯一般係有毒且已知會引起過敏，所以在非經口投與之組合物中併含該等物質被認為是非常危險的。 It is known in the art to use an organic solvent to increase progesterone and/or Or a method of solubility of estradiol in a grease emulsion. Progesterone is highly soluble in benzoic acid or its derivatives. For example, JP 60-258110 describes the use of benzyl benzoate to increase the solubility of progesterone in oil emulsions. However, since benzyl alcohol and benzyl benzoate are generally toxic and are known to cause allergies, the inclusion of such materials in compositions for parenteral administration is considered to be very dangerous.

撇開乳劑溶解度與安定性的問題不談，仍有改善荷爾蒙於治療或預防神經傷害之有效性的問題。 Regardless of the solubility and stability of the emulsion, there are still problems in improving the effectiveness of hormones in treating or preventing nerve damage.

已意外地發現，可藉由一種非經口投與之含有荷爾蒙的水包油型乳劑來解決先前技術的問題，其係包含助孕激素及/或***；以及富含ω-3脂肪酸之魚油及/或包含一或多種ω-3脂肪酸部分的磷脂質。 Surprisingly, it has been found that prior art problems can be solved by a non-orally administered hormone-containing oil-in-water emulsion comprising progestogen and/or estrogen; and omega -3 fatty acids. Fish oil and/or phospholipids containing one or more omega -3 fatty acid moieties.

本文所用之用語「油」係可與「油脂」及「脂肪」輕易互換，係指於體溫下(即，約37℃)為液體的親脂性高沸點有機化合物，且於可注射配方中係醫藥可接受的。本發明之油係包含甘油酯、部分甘油酯、脂肪酸殘基以及非甘油酯二者，及其混合物。除非文中有另外說明，本文所用的用語「油」不包含磷脂質。 As used herein, the term "oil" is used interchangeably with "fat" and "fat" and refers to a lipophilic, high-boiling organic compound that is liquid at body temperature (ie, about 37 ° C) and is a pharmaceutical ingredient in an injectable formulation. Acceptable. The oils of the present invention comprise both glycerides, partial glycerides, fatty acid residues, and non-glycerides, and mixtures thereof. The term "oil" as used herein does not include phospholipids unless otherwise stated herein.

本文所用之用語「水包油型乳劑」係指一膠體分散系統，其中，液態油係分散於一含水介質(連續相)中呈小液滴(離散相)。 As used herein, the term "oil-in-water emulsion" refers to a colloidal dispersion system in which a liquid oil is dispersed in an aqueous medium (continuous phase) in the form of small droplets (discrete phase).

本文所用之用語「磷脂質」係指一具有一或二種脂 肪酸與一個磷酸根基團之甘油酯。除了甘油-衍生的磷脂質，本文所用之用語「磷脂質」亦包含神經鞘磷脂(sphingomyelin)。 As used herein, the term "phospholipid" means having one or two lipids. A fatty acid with a glyceride of a phosphate group. In addition to glycerol-derived phospholipids, the term "phospholipid" as used herein also encompasses sphingomyelin.

本文所用之用語「含水介質(aqueous medium)」係指一含有水的液體。 As used herein, the term "aqueous medium" means a liquid containing water.

本文所用之單數形式「一」、「該」及類似用語係代表單數及複數，除非表明為僅代表單數。 The singular forms "a", "the" and "the"

本文所用之用語「治療有效量」係指將一藥物投與一需要治療之個體時，可提供一特定藥用反應之藥物劑量。並強調，藥物之治療有效量或治療程度並非僅限於可有效治療本文中所述之病情/疾病，即便於此技術領域中具有通常知識者認為此劑量為治療有效量。為方便起見，以下所提供的例示性劑量、藥物遞送量、治療有效量、以及治療程度皆以成人個體為參考。本領域中具通常知識者可依據治療一特定個體及/或病情/疾病所需之標準實務而調整此用量。 As used herein, the term "therapeutically effective amount" refers to a dose of a drug that provides a particular medicinal response when a drug is administered to an individual in need of treatment. It is also emphasized that the therapeutically effective amount or degree of treatment of the drug is not limited to the effective treatment of the conditions/diseases described herein, even if one of ordinary skill in the art recognizes that the dose is a therapeutically effective amount. For convenience, the exemplary dosages, drug delivery amounts, therapeutically effective amounts, and therapeutic levels provided below are all referenced to adult individuals. Those of ordinary skill in the art can adjust this amount based on the standard practice required to treat a particular individual and/or condition/disease.

除非文中有另外說明，用語「每單位體積之重量百分比」或「%重量/體積」係描述以「公克」表示每100毫升組合物中所包含的某一成分的質量。除非文中有另外說明，用語「每單位重量之重量百分比」或「%重量/重量」係代表一成分的質量為組合物(包含該成分)質量的百分比。 Unless otherwise stated herein, the terms "percent by weight per unit volume" or "% weight/volume" are used to describe the mass of a component contained in every 100 milliliters of composition expressed in grams. Unless otherwise stated herein, the phrase "percent by weight per unit weight" or "% by weight/weight" means that the mass of a component is a percentage of the mass of the composition (including the component).

本文所用之「光子雙關頻譜法(Photon Correlation Spectroscopy，PCS)」係指根據美國藥典《United States Pharmacopoeia，USP》第729章方法1所述之利用Zetasizer 1000 HAS (Malvern儀器)之方法所測得的PCS。 As used herein, "Photon Correlation Spectroscopy (PCS)" refers to the use of Zetasizer 1000 HAS as described in Method 1 of Chapter 729 of the United States Pharmacopoeia United States Pharmacopoeia, USP. PCS measured by the method of (Malvern Instruments).

本文所用之「d(0,5)以體積為基礎的平均直徑(volume-based mean diameter)」係指根據美國藥典第429章《Light diffraction measurement of particle size》所述之利用具有Hydro S分散單元之Mastersizer 2000(Malvern儀器)所測得的d(0,5)。 As used herein, "d(0,5) volume-based mean diameter" means the use of a Hydro S dispersing unit as described in U.S. Pharmacopoeia Chapter 429, "Light diffraction measurement of particle size". d(0,5) measured by Mastersizer 2000 (Malvern Instruments).

本文所用之「Zeta電位(zeta-potential)」係指於一膠體系統中經實驗使用Zetasizer 1000 HAS(Malvern儀器)測得之電動電位(electrokinetic potential)。 As used herein, "zeta-potential" refers to the electrokinetic potential measured experimentally using a Zetasizer 1000 HAS (Malvern instrument) in a colloidal system.

本文所用之用語「不含晶形固體」係指本發明乳劑符合微粒大小以及注射液體計數之標準(美國藥典第788章，方法2-微觀顆粒計數檢定)。 As used herein, the phrase "free of crystalline solids" means that the emulsion of the present invention meets the criteria for particle size and injected liquid count (US Pharmacopoeia Chapter 788, Method 2 - Microparticle Count Verification).

第1圖所示為治療對大腦皮質梗塞體積的影響。 Figure 1 shows the effect of treatment on the volume of cerebral cortical infarction.

第2圖所示為治療對行為評等(Behavioral scoring)的影響。 Figure 2 shows the effect of treatment on behavioral scoring.

本發明之第一具體實施態樣係一種非經口投與之含有荷爾蒙的水包油型乳劑，其係包含：a)助孕激素及/或***；以及b)魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%的二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)。 A first embodiment of the present invention is a non-orally administered hormone-containing oil-in-water emulsion comprising: a) a progestogen and/or an estrogen; and b) a fish oil triglyceride, Wherein the fish oil triglyceride is composed of fatty acid esterified glycerol, wherein the fatty acid comprises eicosapentaenoic acid (EPA) and 22% in an amount of at least 45% by weight of the fatty acid. Carbahexaenoic acid (DHA).

本發明之水包油型乳劑係包含一油相以及一含水相。 The oil-in-water emulsion of the present invention comprises an oil phase and an aqueous phase.

本發明之水包油型乳劑係包含一助孕酮及/或***作為活性醫藥組分(active pharmaceutical ingredient，API)。 The oil-in-water emulsion of the present invention comprises a progesterone and/or an estrogen as an active pharmaceutical ingredient (API).

本文所用之「助孕激素」包括天然的助孕激素與合成的助孕激素二種。一般而言，助孕激素係具有通式I，其中X1及X2係獨立地選自-COCH₃、-OCOC₅H₁₁、-OH、乙炔基、-OCOCH₃、-H、-CH₂CN；其中X3係選自-H、-CH₃、或Cl；其中X4係選自-H、-OH、或-CH₃；以及其中X5係選自CH₃或CH₂CH₃。該助孕激素可含有具有一個或多個雙鍵的環狀結構，舉例來說，在3號碳與4號碳、4號碳與5號碳、5號碳與6號碳、6號碳與7號碳、5號碳與10號碳、10號碳與9號碳、及/或15號碳與16號碳之間。 As used herein, "progestin" includes both natural progestogens and synthetic progestogens. In general, the progestogen has the general formula I, wherein X1 and X2 are independently selected from -COCH ₃ , -OCOC ₅ H ₁₁ , -OH, ethynyl, -OCOCH ₃ , -H, -CH ₂ CN; wherein X3 is selected from -H, -CH _3, or Cl; wherein X4 is selected from -H, -OH, or -CH _3; and wherein X5 is selected from CH ₃ or CH ₂ CH _3. The progestogen may contain a cyclic structure having one or more double bonds, for example, carbons No. 3 and No. 4, No. 4 carbons and No. 5 carbons, No. 5 carbons, No. 6 carbons, No. 6 carbons With No. 7 carbon, No. 5 carbon and No. 10 carbon, No. 10 carbon and No. 9 carbon, and / or No. 15 carbon and No. 16 carbon.

該助孕激素包括，例如助孕激素的衍生物，如5-α-二氫助孕酮(5-α-dihydroprogesterone)、6-去氫-逆助孕酮(6-dehydro-retroprogesterone，又稱去氫孕酮(dydrogesterone))、 羥助孕酮己酯(hydroxyprogesterone caproate)、左炔諾孕酮(levonorgestrel)、炔諾酮(norethindrone)、炔諾酮乙酸酯(norethindrone acetate)、羥炔諾酮(norethynodrel)、甲基炔諾酮(norgestrel)、甲羥助孕酮(medroxyprogesterone)、氯地孕酮(chlormadinone)、以及甲地孕酮(megestrol)。「助孕激素」亦包括，但不限於經修飾作用產生之助孕酮的17α-OH酯，以及經修飾作用將6-α-甲基(6-α-methyl)、6-甲基(6-methyl)、6-烯基(6-ene)、以及6-氯基(6-chloro)取代基引至助孕酮及/或19-去甲助孕酮(19-nor-progesterones)上。另外，合成助孕酮的非限制性例子包括，炔諾酮(Micronor^®)、甲基炔諾酮(Ovrette^®)、左炔諾孕酮(Norplant^®，含有乙烯***(ethinyl estradiol)，Alesse^®、Nordette^®)、乙基羥基二降孕二烯炔酮(gestodene)、乙酸甲羥黃體酮(medroxyprogesterone acetate，Provera^®)、丙甲雌烯酮(promegestone)、諾美孕酮乙酸酯(nomegestrol acetate)、利奈孕酮(lynestrenol)以及地諾孕素(dienogest)。 The progestogen includes, for example, a progestogen derivative such as 5-α-dihydroprogesterone, 6-dehydro-retroprogesterone (6-dehydro-retroprogesterone, also known as 6-dehydro-retroprogesterone) Dedrogesterone, hydroxyprogesterone caproate, levonorgestrel, norethindrone, norethindrone acetate, hydroxyalkane Norethynodrel, norgestrel, medroxyprogesterone, chlormadinone, and megestrol. "Progestin" also includes, but is not limited to, 17α-OH esters of progesterone produced by modification, and modified 6-α-methyl (6-α-methyl), 6-methyl (6) -methyl), 6-alkenyl (6-ene), and 6-chloro (6-chloro) substituents are introduced to progesterone and/or 19-nor-progesterones. Further, non-limiting examples include synthetic progesterone, norethindrone (Micronor ^®), norgestrel (Ovrette ^®), levonorgestrel (Norplant ^®, containing ethylene estradiol (ethinyl estradiol), Alesse ^® , Nordette ^® ), gestodene, medroxyprogesterone acetate (Provera ^® ), promegestone, and norgestimate acetate (nomegestrol acetate), lynestrenol and dienogest.

於一具體實施態樣中，該助孕激素係選自以下群組：助孕酮、羥炔諾酮、炔諾酮乙酸酯、甲羥助孕酮、甲羥助孕酮-17-乙酸酯(medroxyprogesteron 17-acetate)、左炔諾孕酮、去氫孕酮(dydrogesterone)、羥助孕酮己酯、炔諾酮、乙基羥基二降孕二烯炔酮、諾美孕酮乙酸酯、丙甲雌烯酮、地諾孕素、氯地孕酮、甲地孕酮、甲地孕酮乙酸酯、及/或前述之混合物。 In a specific embodiment, the progestogen is selected from the group consisting of progesterone, norethisterone, norethisterone acetate, medroxyprogesterone, and medroxyprogesterone-17-B. Acid ester (medroxyprogesteron 17-acetate), levonorgestrel, dydrogesterone, hydroxyprogesterone hexyl ester, norethisterone, ethyl hydroxydigestrel, norgestrel B An acid ester, propyl ketene, dienogest, chlorgestrel, megestrol acetate, megestrol acetate, and/or a mixture thereof.

於特定具體實施態樣中，該助孕激素係選自以下群 組：5-α-二氫助孕酮、甲羥助孕酮、去氫孕酮、以及助孕酮及/或前述之混合物。 In a specific embodiment, the progestogen is selected from the group consisting of Group: 5-alpha-dihydroprogesterone, medroxyprogesterone, dehydroprogesterone, and progesterone and/or a mixture of the foregoing.

於另一具體實施態樣中，該助孕激素係選自以下群組：孕烯醇酮(pregnelonone)、助孕酮、甲羥助孕酮及其醫藥可接受之衍生物。 In another embodiment, the progestogen is selected from the group consisting of pregnelonone, progesterone, medroxyprogesterone, and pharmaceutically acceptable derivatives thereof.

於特定具體實施態樣中，該助孕激素係助孕酮。本文所用之用語「助孕激素」係指具有下式II結構之助孕激素家族。 In a specific embodiment, the progestin is a progesterone. As used herein, the term "progesterone" refers to a family of progestogens having the structure of Formula II below.

助孕酮又被稱作D4-孕烯-3,20-二酮(D4-pregnene-3,20-dione)、δ-4-孕烯-3,20-二酮(delta-4-pregnene-3,20-dione)、或孕-4-烯基-3,20-二酮(pregn-4-ene-3,20-dione)。於非常特定具體實施態樣中，助孕酮係經微粉化(micronized)，Proquina(墨西哥)即一微粉化助孕酮的供應者。 Progesterone is also known as D4-pregnene-3,20-dione, delta-4-pregnene-3,20-dione (delta-4-pregnene- 3,20-dione), or pregn-4-ene-3,20-dione (pregn-4-ene-3, 20-dione). In a very specific embodiment, the progesterone is micronized and Proquina (Mexico) is a supplier of micronized progesterone.

助孕激素(例如任何助孕激素，包括助孕酮)可以其醫藥可接受鹽之形式適用於本發明。 Progestogens (e.g., any progestin, including progestin) can be used in the present invention in the form of their pharmaceutically acceptable salts.

本發明之水包油型乳劑可包含其含量為至少0.1公克/公升，較佳為至少0.15公克/公升，更佳為0.15至12公克/公升，甚佳為0.8至4公克/公升，特別為1至2.5公克/公升之助孕激素。 The oil-in-water emulsion of the present invention may comprise a content of at least 0.1 g/liter, preferably at least 0.15 g/l, more preferably from 0.15 to 12 g/l, very preferably from 0.8 to 4 g/l, especially Progesterone from 1 to 2.5 g/L.

於一較佳具體實施態樣中，該水包油型乳劑係包含其含量為0.15至12公克/公升之助孕激素。 In a preferred embodiment, the oil-in-water emulsion comprises a progestogen at a level of from 0.15 to 12 grams per liter.

本發明之水包油型乳劑可包含其含量為至少0.3公克/公升、至少0.5公克/公升、至少1公克/公升之助孕激素。根據任一具體實施態樣，該乳劑可包含其含量為少於或等於3公克/公升、少於或等於2.5公克/公升、或少於或等於2公克/公升之助孕激素(例如助孕酮)。於一特定具體實施態樣中，本發明之水包油型乳劑可包含約1至2公克/公升，尤其約1.5公克/公升之助孕酮。 The oil-in-water emulsion of the present invention may comprise a progestin having a content of at least 0.3 grams per liter, at least 0.5 grams per liter, and at least 1 gram per liter. According to any embodiment, the emulsion may comprise a progestin having a content of less than or equal to 3 grams per liter, less than or equal to 2.5 grams per liter, or less than or equal to 2 grams per liter (eg, progesterone ketone). In a particular embodiment, the oil-in-water emulsion of the present invention may comprise from about 1 to 2 grams per liter, especially about 1.5 grams per liter of progesterone.

根據本發明之一替代具體實施態樣，該水包油型乳劑係包含一或多種***。 According to an alternative embodiment of the invention, the oil-in-water emulsion comprises one or more estrogens.

於一較佳具體實施態樣中，該乳劑係包含下式III所示之雌三醇(1,3,5(10)-estratriene-3,16α,17β-triol)： In a preferred embodiment, the emulsion comprises estriol (1,3,5(10)-estratriene-3,16α,17β-triol) of the following formula III:

於另一具體實施態樣中，該乳劑係包含下式IV所示之***(1,3,5(10)-estratriene-3,17β-diol)： In another embodiment, the emulsion comprises estradiol (1,3,5(10)-estratriene-3,17β-diol) of the following formula IV:

於另一具體實施態樣中，該乳劑係包含下式V所示之雌一醇(estrone)： In another embodiment, the emulsion comprises an estrone of the following formula V:

根據本發明之一較佳具體實施態樣，該水包油型乳劑係包含選自以下群組的***：***、雌一醇、雌三醇、以及其衍生物及混合物。 According to a preferred embodiment of the present invention, the oil-in-water emulsion comprises an estrogen selected from the group consisting of estradiol, estradiol, estriol, and derivatives and mixtures thereof.

特別佳為***。 Particularly preferred is estradiol.

該***於該水包油型乳劑中，以該乳劑計，較佳以0.015至5公克/公升，更佳為0.015至1.5公克/公升，以及最佳為0.05至0.3公克/公升(每公升克數)的含量存在。 The estrogen is in the oil-in-water emulsion, preferably from 0.015 to 5 g/liter, more preferably from 0.015 to 1.5 g/liter, and most preferably from 0.05 to 0.3 g/liter (liter per liter, based on the emulsion). The content of grams is present.

於一較佳具體實施態樣中，該乳劑係包含其含量為0.015至1.5公克/公升，較佳為0.05至1公克/公升，更佳為0.08至0.5 公克/公升，尤其為0.1至0.3公克/公升之***。 In a preferred embodiment, the emulsion comprises a content of from 0.015 to 1.5 grams per liter, preferably from 0.05 to 1 gram per liter, more preferably from 0.08 to 0.5. In grams per liter, especially 0.1 to 0.3 grams per liter of estradiol.

根據本發明之另一具體實施態樣，該水包油型乳劑包含一助孕激素與***的組合。該乳劑中助孕激素及***之重量比為2：1至500：1，較佳為2：1至200：1，更佳為5：1至50：1，以及甚佳為10：1至20：1。 According to another embodiment of the invention, the oil-in-water emulsion comprises a combination of a progestin and an estrogen. The weight ratio of progestogen to estrogen in the emulsion is from 2:1 to 500:1, preferably from 2:1 to 200:1, more preferably from 5:1 to 50:1, and even better at 10:1. Until 20:1.

較佳地，該水包油型乳劑係包含***及/或助孕酮。 Preferably, the oil-in-water emulsion comprises estradiol and/or progesterone.

本發明之一具體實施態樣係關於***與孕烯醇酮及/或助孕醇的組合，另關於雌三醇與孕烯醇酮及/或助孕醇的組合。一替代的特別較佳具體實施態樣係關於***及/或孕烯醇酮及/或助孕醇，尤其是與助孕醇的組合。於二替代方案，可額外包含甲羥助孕酮，或可由甲羥助孕酮取***烯醇酮及/或助孕醇。因此，根據本發明，可組合二種以上的荷爾蒙。 One embodiment of the invention relates to the combination of estrogen and pregnenolone and/or progestin, and in combination with estriol and pregnenolone and/or progesterone. An especially preferred embodiment of the invention relates to the combination of estradiol and/or pregnenolone and/or progesterone, especially with a progestin. In the alternative, the hydroxyprogesterone may be additionally included, or the pregnenolone and/or the progesterone may be replaced by the hydroxyprogesterone. Therefore, according to the present invention, two or more kinds of hormones can be combined.

為達一較佳的水包油型乳劑的劑量，若需要，可以適量的水稀釋上代(parent)乳劑，較佳係使用最多達四倍水量。 To achieve a preferred oil-in-water emulsion dosage, if desired, the parent emulsion can be diluted with an appropriate amount of water, preferably up to four times the amount of water.

該水包油型乳劑之油相係包含魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%的二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)；而且ω-3脂肪酸的總含量較佳為該脂肪酸的至少50重量%，更佳為至少55重量%，甚佳為至少60重量%，以及最佳為至少65重量%。 The oil phase of the oil-in-water emulsion comprises fish oil triglyceride, wherein the fish oil triglyceride is composed of fatty acid esterified glycerol, wherein the fatty acid comprises a content of the fatty acid. At least 45% of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and the total content of omega-3 fatty acids is preferably at least 50% by weight of the fatty acid, more preferably at least 55 weight %, very preferably at least 60% by weight, and most preferably at least 65% by weight.

於歐洲藥典(European Pharmacopeia，EP)中，有 二個關於可接受用於非經口型乳劑的魚油的專論EP1352及EP1912，題目分別為「ω-3酸三酸甘油酯」與「魚油，富含ω-3酸」(EP1352，EP 1912，2008)。專論EP 1352實質上與EP 1912不同，EP 1352中生物活性ω-3脂肪酸(n3-FAs)的組成及要求比EP 1912的要高很多(EP 1352：EPA+DHA45%；n3-FAs總量60%，相較於EP 1912：EPA：13%；DHA9%；n3-FAs總量28%)。EP 1912中n3-FAs的量與自然界中發現的一致。相較之下，EP 1352中的n3-FAs濃度實質上較高，並且可藉由如分子蒸餾法之增量製程而獲得，藉此移除那些伴隨著出現的非所欲的脂肪酸，例如肉豆蔻酸(myristic acid)、棕櫚酸(palmitic acid)、以及硬脂酸(stearic acid)。這樣做，所有存在脂肪酸的濃度，尤其是ω-3脂肪酸的濃度，成比例的增加。於一例示性具體實施態樣中，以魚油三酸甘油酯的脂肪酸總重量計，該魚油三酸甘油酯係包含其含量為至少60重量%，較佳為至少65重量%之ω-3脂肪酸。以魚油三酸甘油酯的脂肪酸總重量計，該魚油三酸甘油酯係包含總含量為至少45重量%，較佳為至少50重量%之二十碳五烯酸(EPA)以及二十二碳六烯酸(DHA)。舉例而言，根據EP 1352，其所討論的脂肪酸以及ω-3脂肪酸(例如EPA及DHA)係指魚油三酸甘油酯中這些酸的組成部分。舉例而言，所討論的脂肪酸以及ω-3脂肪酸(例如EPA及DHA)當存在於魚油三酸甘油酯中時係呈其酯化形式。 In the European Pharmacopeia (EP), there are two monographs EP1352 and EP1912 on fish oil that can be used in non-oral emulsions, titled "omega-3 acid triglyceride" and "fish oil," Rich in omega-3 acid" (EP 1352, EP 1912, 2008). Monograph EP 1352 is essentially different from EP 1912. The composition and requirements of bioactive omega-3 fatty acids (n3-FAs) in EP 1352 are much higher than those of EP 1912 (EP 1352: EPA + DHA). 45%; total amount of n3-FAs 60% compared to EP 1912: EPA: 13%; DHA 9%; total amount of n3-FAs 28%). The amount of n3-FAs in EP 1912 is consistent with that found in nature. In contrast, the concentration of n3-FAs in EP 1352 is substantially higher and can be obtained by an incremental process such as molecular distillation, thereby removing those undesired fatty acids that accompany the appearance, such as meat. Myristic acid, palmitic acid, and stearic acid. In doing so, all concentrations of fatty acids present, especially omega-3 fatty acids, increase proportionally. In an exemplary embodiment, the fish oil triglyceride comprises an omega-3 fatty acid having a content of at least 60% by weight, preferably at least 65% by weight, based on the total weight of the fatty acid of the fish oil triglyceride. . The fish oil triglyceride comprises at least 45% by weight, preferably at least 50% by weight, of eicosapentaenoic acid (EPA) and twenty-two carbon, based on the total weight of the fatty acid of the fish oil triglyceride. Hexenoic acid (DHA). For example, according to EP 1352, the fatty acids and omega-3 fatty acids (eg EPA and DHA) discussed are part of these acids in fish oil triglycerides. For example, the fatty acids in question as well as omega-3 fatty acids (eg, EPA and DHA) are in their esterified form when present in fish oil triglycerides.

根據本發明，以全部ω-3脂肪酸含量的重量計，該魚油三酸甘油酯係包含由其含量為30%或更多之二十碳五烯酸、其含 量為30%或更少之二十二碳六烯酸、以及其含量為40%或更少之二十二碳五烯酸(docosapentaenoic acid，DPA)所組成的ω-3脂肪酸。 According to the present invention, the fish oil triglyceride comprises eicosapentaenoic acid having a content of 30% or more, based on the total omega-3 fatty acid content, An amount of 30% or less of docosahexaenoic acid, and an omega-3 fatty acid composed of docosapentaenoic acid (DPA) in an amount of 40% or less.

該魚油三酸甘油酯可含有至少一種ω-6脂肪酸，例如多種ω-6脂肪酸。該至少一種ω-6脂肪酸可包含例如花生油酸(arachidonic acid，AA，20：4n6)、亞麻仁油酸(linoleic acid，LA，18：2n6)、γ-次亞麻油酸(gamma linolenic acid，ALA，18：3n6)或前述之組合。舉例而言，脂肪酸與甘油進行酯化而形成魚油三酸甘油酯，以該脂肪酸的重量計，該至少一種ω-6脂肪酸之總量可為約0.1%至約1.0%，或約0.2%至約0.9%，或約0.3%至約0.8%，或約0.4%至約0.7%，或約0.5%至約0.6%。 The fish oil triglyceride may contain at least one omega-6 fatty acid, such as a plurality of omega-6 fatty acids. The at least one omega-6 fatty acid may comprise, for example, arachidonic acid (AA, 20:4n6), linoleic acid (LA, 18:2n6), gamma-linolenic acid (ALA). , 18:3n6) or a combination of the foregoing. For example, the fatty acid is esterified with glycerol to form a fish oil triglyceride, and the total amount of the at least one omega-6 fatty acid may be from about 0.1% to about 1.0%, or about 0.2%, by weight of the fatty acid. About 0.9%, or about 0.3% to about 0.8%, or about 0.4% to about 0.7%, or about 0.5% to about 0.6%.

可由歐洲藥典所載之「魚油，富含ω-3酸」，測定n3-FAs的含量。n3-FA的內容可為任何單一n3-FA，或其任何組合。於一例示性具體實施態樣中，該組合物可含有EPA、DHA、DPA或前述之組合，舉例而言，EPA、DHA、DPA各一種。個別的劑量，例如二十碳五烯酸(EPA)的每日總劑量，以體重計，可為配方的0至300毫克/公斤，例如50至250毫克/公斤，例如100至200毫克/公斤。個別的劑量，例如二十二碳六烯酸(DHA)的每日總劑量，以體重計，可為配方的0至300毫克/公斤，例如50至250毫克/公斤，例如100至200毫克/公斤。個別的劑量，例如二十二碳五烯酸(DPA)的每日總劑量，以體重計，可為配方的0至300毫克/公斤，例如50至250毫克/公斤，例如100至200毫克/公斤。舉例而言，EPA、DHA、及/或DPA可以一提供生命器官(vital organ)之神經保護的有效量 存在。 The content of n3-FAs can be determined by the "fish oil, rich in omega-3 acid" contained in the European Pharmacopoeia. The content of n3-FA can be any single n3-FA, or any combination thereof. In an exemplary embodiment, the composition may contain EPA, DHA, DPA, or a combination of the foregoing, for example, one each of EPA, DHA, and DPA. Individual doses, such as the total daily dose of eicosapentaenoic acid (EPA), may range from 0 to 300 mg/kg of formula, for example 50 to 250 mg/kg, for example 100 to 200 mg/kg, by weight. . Individual doses, such as the total daily dose of docosahexaenoic acid (DHA), may range from 0 to 300 mg/kg of formula, for example 50 to 250 mg/kg, for example 100 to 200 mg/kg. kg. The individual doses, such as the total daily dose of docosapentaenoic acid (DPA), may range from 0 to 300 mg/kg of formula, for example 50 to 250 mg/kg, for example 100 to 200 mg/kg. kg. For example, EPA, DHA, and/or DPA can provide an effective amount of neuroprotection for a vital organ. presence.

各自以油成分的總重量計，該魚油三酸甘油酯係以至少25重量%，較佳為至少35重量%，更佳為至少50重量%，尤其為至少75重量%，以及特別為至少85重量%的含量存在。 Each of the fish oil triglycerides is at least 25% by weight, preferably at least 35% by weight, more preferably at least 50% by weight, especially at least 75% by weight, and especially at least 85, based on the total weight of the oil component. The content of % by weight is present.

根據一較佳具體實施態樣，以油成分的總重量計，該魚油三酸甘油酯係以55至95重量%，更佳為60至92重量%，尤其為70至90重量%的含量存在。 According to a preferred embodiment, the fish oil triglyceride is present in an amount of from 55 to 95% by weight, more preferably from 60 to 92% by weight, especially from 70 to 90% by weight, based on the total weight of the oil component. .

根據本發明之一較佳具體實施態樣，該水包油型乳劑係額外包含中鏈三酸甘油酯(MCT)。 According to a preferred embodiment of the invention, the oil-in-water emulsion additionally comprises medium chain triglycerides (MCT).

乳劑之油成分的例示性第二成分可包含至少一種中鏈三酸甘油酯(MCT)，例如多個MCT。舉例而言，以該乳劑之油成分的總重量計，該至少一種MCT係以約10%至約69%，或約10%至約40%，或約10%至約30%，或約10%至約20%，或約10%至約15%，或約20%至約60%，或約30%至約50%，或約40%至約45%的含量存在。例如使用例示範圍之MCT，可增加酯化的ω-3脂肪酸傳送至人體的量。例如使用例示之MCT範圍，使用一相對少量的MCT，可增加酯化的ω-3脂肪酸傳送至人體的量，卻仍然達到有益的代謝性清除以及乳劑之物理化學的穩定性特徵。 An exemplary second component of the oil component of the emulsion can comprise at least one medium chain triglyceride (MCT), such as a plurality of MCTs. For example, the at least one MCT is from about 10% to about 69%, or from about 10% to about 40%, or from about 10% to about 30%, or about 10, based on the total weight of the oil component of the emulsion. % to about 20%, or from about 10% to about 15%, or from about 20% to about 60%, or from about 30% to about 50%, or from about 40% to about 45%. For example, using an exemplary range of MCT, the amount of esterified omega-3 fatty acid delivered to the human body can be increased. For example, using an exemplary MCT range, a relatively small amount of MCT can be used to increase the amount of esterified omega-3 fatty acid delivered to the body while still achieving beneficial metabolic clearance and physicochemical stability characteristics of the emulsion.

舉例而言，該MCT可包含一飽和中鏈脂肪酸，例如多個飽和中鏈脂肪酸。於一例示性具體實施態樣中，該MCT係一具有6至12個碳原子之脂肪酸的三酸甘油酯。該MCT係衍生自一如蔬菜之植物，例如多個植物。該MCT可含有一8個碳的飽和脂肪酸 (8：0)，辛酸(caprylic acid)(例如為MCT重量的約50%至約80%的含量)。該MCT可含一10個碳的飽和脂肪酸(10：0)，癸酸(capric acid)(例如為MCT重量的約20%至約50%的含量)。舉例而言，該MCT可含有其含量為MCT重量之至少90%的辛酸及癸酸的三酸甘油酯。本揭露所用MCT的描述可例如符合歐洲藥典專論0868，題目為「三酸甘油酯，中鏈」(Triglycerida saturate media)的要求(EP 0868，2008)。 For example, the MCT can comprise a saturated medium chain fatty acid, such as a plurality of saturated medium chain fatty acids. In an exemplary embodiment, the MCT is a triglyceride of a fatty acid having from 6 to 12 carbon atoms. The MCT is derived from a plant such as a vegetable, such as a plurality of plants. The MCT can contain a saturated fatty acid of 8 carbons (8:0), caprylic acid (for example, a content of from about 50% to about 80% by weight of MCT). The MCT may contain a 10 carbon saturated fatty acid (10:0), capric acid (e.g., a content of from about 20% to about 50% by weight of the MCT). For example, the MCT can contain a triglyceride of caprylic acid and capric acid in an amount of at least 90% by weight of the MCT. The description of the MCT used in the present disclosure may, for example, comply with the requirements of the European Pharmacopoeia monograph 0868, entitled "Triglycerida saturate media" (EP 0868, 2008).

於此所述的水包油型乳劑組合物的油可額外包含中鏈三酸甘油酯。「中鏈三酸甘油酯(MCT)」係可自然地衍生而來或經合成之另一類的三酸甘油酯油。MCT由長度為6至14個碳，較佳係6至12個碳，尤其是8至10個碳之脂肪酸所形成。與水包油型乳劑一併投與之中鏈三酸甘油酯(MCT)主要係作為一能量來源。MCT係如Miglyol 812(沙索德國有限責任公司)或CRODAMOL GTCC-PN(新澤西禾大公司)等市售取得。 The oil of the oil-in-water emulsion composition described herein may additionally comprise a medium chain triglyceride. "Medium chain triglyceride (MCT)" is a triglyceride oil which can be naturally derived or synthesized. MCT is formed from fatty acids having a length of from 6 to 14 carbons, preferably from 6 to 12 carbons, especially from 8 to 10 carbons. The medium chain triglyceride (MCT) is mainly used as an energy source together with the oil-in-water emulsion. MCT is commercially available, such as Miglyol 812 (Sasol Germany LLC) or CRODAMOL GTCC-PN (New Jersey Heda).

根據本發明之一較佳具體實施態樣，該乳劑係包含一由經脂肪酸酯化後之甘油所組成的MCT，包含至少50重量%之脂肪酸，選自具有7、9以及11個碳原子之脂肪酸所組成之群組。 According to a preferred embodiment of the present invention, the emulsion comprises an MCT composed of fatty acid esterified glycerol, comprising at least 50% by weight of a fatty acid selected from the group consisting of 7, 9, and 11 carbon atoms. a group of fatty acids.

前述定義之MCT與魚油三酸甘油酯之組合乃本發明之水包油型乳劑之優勢。 The combination of MCT and fish oil triglyceride as defined above is an advantage of the oil-in-water emulsion of the present invention.

根據本發明之一較佳具體實施態樣，各自以油成分之總重量計，該水包油型乳劑係包含其含量為5至75重量%，較佳為10至55重量%，尤其為15至45重量%之中鏈三酸甘油酯。 According to a preferred embodiment of the present invention, the oil-in-water emulsion is contained in an amount of from 5 to 75% by weight, preferably from 10 to 55% by weight, especially 15 based on the total weight of the oil component. Up to 45% by weight of medium chain triglyceride.

於本發明之一較佳具體實施態樣中，該水包油型乳劑係包含重量比範圍為1：1至9：1，較佳為1.5：1至8：1，尤其為2：1至7：1之魚油以及中鏈三酸甘油酯。 In a preferred embodiment of the present invention, the oil-in-water emulsion comprises a weight ratio ranging from 1:1 to 9:1, preferably from 1.5:1 to 8:1, especially from 2:1 to 7:1 fish oil and medium chain triglyceride.

根據一尤其較佳之具體實施態樣，以油成分之總重量計，該油相中之魚油三酸甘油酯與MCT的含量係至少90重量%，較佳為至少95重量%，更佳為至少98重量%，尤其為至少99重量%。 According to a particularly preferred embodiment, the fish oil triglyceride and MCT content in the oil phase is at least 90% by weight, preferably at least 95% by weight, more preferably at least, based on the total weight of the oil component. 98% by weight, in particular at least 99% by weight.

該油成分可額外包含其他油，該油之熔點較佳為小於30℃，更特別為小於20℃，亦包括小於10℃。 The oil component may additionally comprise other oils, preferably having a melting point of less than 30 ° C, more particularly less than 20 ° C, and also less than 10 ° C.

以油成分之總重量計，該油成分較佳係包含含有至少75重量%之三酸甘油酯，或至少85重量%之三酸甘油酯的油。於一特定之具體實施態樣中，該油成分係包含至少90重量%，或至少95重量%之三酸甘油酯。 Preferably, the oil component comprises an oil comprising at least 75% by weight of triglyceride, or at least 85% by weight of triglyceride, based on the total weight of the oil component. In a particular embodiment, the oil component comprises at least 90% by weight, or at least 95% by weight, of triglyceride.

於一更特定之具體實施態樣中，該油相係額外包含長鏈三酸甘油酯(long-chain triglycerides，LCT)。 In a more specific embodiment, the oil phase additionally comprises long-chain triglycerides (LCT).

於某些具體實施態樣中，該油可包含一植物油。「植物油」係指衍生自植物種子或堅果仁的油。植物油係典型的「長鏈三酸甘油酯(LCT)」，於三個脂肪酸(長度通常為14至22個碳，且取決於油的來源，帶有不同數目及位置的不飽合鍵)與甘油上的三個羥基形成酯鍵(ester bond)而形成的。於某些具體實施態樣中，高純度等級(亦稱作「超精製」)的植物油係用來確保該水包油型乳劑的安全性以及穩定性。於某些具體實施態樣中，可能 會使用由經控制的植物油氫化作用所產生的氫化植物油。 In certain embodiments, the oil can comprise a vegetable oil. "Vegetable oil" means an oil derived from plant seeds or nuts. Vegetable oils are typically "long-chain triglycerides (LCT)" in three fatty acids (typically 14 to 22 carbons in length, depending on the source of the oil, with different numbers and positions of unsaturated bonds) and glycerol The upper three hydroxyl groups form an ester bond. In some embodiments, a high purity grade (also referred to as "super-refining") vegetable oil is used to ensure the safety and stability of the oil-in-water emulsion. In some specific implementations, it is possible Hydrogenated vegetable oils produced by the hydrogenation of controlled vegetable oils will be used.

例示性植物油包含但不限於杏仁油、巴西棕櫚果油、黑醋粟籽油、琉璃苣油、芥花籽油、蓖麻油、椰子油、玉米油、棉籽油、橄欖油、花生油、棕櫚油、棕櫚仁油、菜籽油、紅花籽油、大豆油、葵花油以及芝麻油。亦可使用這些油的氫化及/或部分氫化形式。於特定具體實施態樣中，該油係額外包含紅花籽油、芝麻油、玉米油、橄欖油及/或大豆油。於更特定之具體實施態樣中，該油係額外包含紅花籽油及/或大豆油。 Exemplary vegetable oils include, but are not limited to, almond oil, carnauba oil, black vinegar seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, palm oil, Palm kernel oil, rapeseed oil, safflower oil, soybean oil, sunflower oil and sesame oil. Hydrogenated and/or partially hydrogenated forms of these oils can also be used. In a particular embodiment, the oil system additionally comprises safflower seed oil, sesame oil, corn oil, olive oil, and/or soybean oil. In a more specific embodiment, the oil system additionally comprises safflower seed oil and/or soybean oil.

於特定具體實施態樣中，該油係額外包含大豆油，該大豆油可具有一9%至13%之棕櫚酸含量(重量/重量)、一2.5%至5%之硬脂酸含量、一17%至30%之油酸(oleic acid)含量、一48%至58%之亞麻仁油酸含量、以及一5%至11%之次亞麻油酸含量。 In a specific embodiment, the oil system additionally comprises soybean oil, which may have a palmitic acid content (weight/weight) of from 9% to 13%, a stearic acid content of from 2.5% to 5%, and a 17% to 30% oleic acid content, a 48% to 58% linoleic acid content, and a 5% to 11% linoleic acid content.

另外，於一特定具體實施態樣中，該水包油型乳劑組合物可包含結構三酸甘油酯。本文所用之「結構三酸甘油酯」係一三酸甘油酯，包含具有至少一個具有6至12個碳原子碳鏈長度之脂肪酸基團以及至少一個具有大於12個碳單元碳鏈長度之脂肪酸基團之三酸甘油酯或三酸甘油酯之混合物。 Additionally, in a particular embodiment, the oil-in-water emulsion composition can comprise a structural triglyceride. As used herein, "structural triglyceride" is a triglyceride comprising a fatty acid group having at least one carbon chain length of 6 to 12 carbon atoms and at least one fatty acid group having a carbon chain length greater than 12 carbon units. a mixture of triglycerides or triglycerides.

已發現高含量的ω-3脂肪酸殘基會增進荷爾蒙治療病患的效果。因此，根據本發明之特定具體實施態樣，該水包油型乳劑基本上不含植物油及/或除了魚油以及MCT之外的油。本發明所指基本上不含的意思是，以該乳劑之總重量計，其含量少於 10重量%，較佳少於5重量%，更佳少於2重量%，尤其少於1重量%，例如少於0.1重量%。 High levels of omega-3 fatty acid residues have been found to enhance the efficacy of hormone-treated patients. Thus, in accordance with certain embodiments of the present invention, the oil-in-water emulsion is substantially free of vegetable oil and/or oil other than fish oil and MCT. The term "substantially free" as used herein means that the amount of the emulsion is less than the total weight of the emulsion. 10% by weight, preferably less than 5% by weight, more preferably less than 2% by weight, especially less than 1% by weight, for example less than 0.1% by weight.

於一特定具體實施態樣中，該乳劑係含有不超過0.9%(重量/重量)，包括不超過0.8%(重量/重量)，或不超過0.5%(重量/重量)之極性改質劑，其係選自以下所組成之群組：單酸甘油脂(monoglycerides)、雙甘油酯(diglycerides)、乙醯化單酸甘油脂、乙醯化雙甘油酯、及/或前述之混合物。於另一特定具體實施態樣中，該乳劑係含有不超過0.9%(重量/重量)，包括不超過0.8%(重量/重量)，例如不超過0.5%(重量/重量)之單酸甘油脂。 In a specific embodiment, the emulsion contains no more than 0.9% (w/w), including no more than 0.8% (w/w), or no more than 0.5% (w/w) of polar modifier. It is selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides, and/or mixtures thereof. In another specific embodiment, the emulsion contains no more than 0.9% (weight/weight), including no more than 0.8% (weight/weight), such as no more than 0.5% (weight/weight) of monoglyceride. .

不同地表現，於一特定具體實施態樣中，該乳劑係含有不超過30重量%，包括不超過20重量%，不超過10重量%，或不超過5重量%之磷脂質，極性改質劑，其係選自以下所組成之群組：單酸甘油脂、雙甘油酯、乙醯化單酸甘油脂、乙醯化雙甘油酯、及/或前述之混合物。使用相對於乳劑中磷脂質含量為顯著濃度的極性改質劑對於磷脂質的穩定特性可能會有副作用。 Differently manifested, in a specific embodiment, the emulsion contains no more than 30% by weight, including no more than 20% by weight, no more than 10% by weight, or no more than 5% by weight of phospholipid, polar modifier It is selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides, and/or mixtures thereof. The use of a polar modifier having a significant concentration relative to the phospholipid content of the emulsion may have side effects on the stability properties of the phospholipid.

於特定之具體實施態樣中，該水包油型乳劑係包含100至300公克/公升，較佳為120至280公克/公升，尤其為150至250公克/公升，例如200公克/公升的油。 In a particular embodiment, the oil-in-water emulsion comprises from 100 to 300 grams per liter, preferably from 120 to 280 grams per liter, especially from 150 to 250 grams per liter, for example 200 grams per liter of oil. .

於某些具體實施態樣中，一相當大比例的助孕激素及/或***係包含於該水包油型乳劑之油滴中。於某些具體實施態樣中，超過80%的助孕激素及/或***溶解並保持於該油 滴中。於某些具體實施態樣中，多於85%、90%、92%、94%、95%、96%、97%、98%、99%或99.5%的助孕激素及/或***溶解於油相中(於20℃下測定)。 In certain embodiments, a substantial proportion of progestogen and/or estrogen is included in the oil droplets of the oil-in-water emulsion. In some embodiments, more than 80% of progestogens and/or estrogens are dissolved and retained in the oil. Drop in. In some embodiments, more than 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% of progestogen and/or estrogen is dissolved. In the oil phase (measured at 20 ° C).

本發明之水包油型乳劑較佳係包含乳化劑，其係以至多50公克/公升或至多20公克/公升，較佳為2至15公克/公升的含量存在。 The oil-in-water emulsion of the present invention preferably comprises an emulsifier which is present in an amount of up to 50 g/liter or up to 20 g/l, preferably from 2 to 15 g/l.

本發明之水包油型乳劑可進一步包含一或多種乳化劑/界面活性劑，包括磷脂質。於某些具體實施態樣中，該乳化劑係源自天然。天然存在的乳化劑包括大豆卵磷脂、蛋卵磷脂、葵花油卵磷脂、神經胺醇(sphingosine)、神經節苷脂(ganglioside)、植物鞘胺醇(phytosphingosine)、及其組合。氫化卵磷脂(即，經控制卵磷脂之氫化作用的產物)亦可額外用於本發明中。 The oil-in-water emulsion of the present invention may further comprise one or more emulsifiers/surfactants, including phospholipids. In certain embodiments, the emulsifier is derived from nature. Naturally occurring emulsifiers include soy lecithin, egg lecithin, sunflower oil lecithin, sphingosine, ganglioside, phytosphingosine, and combinations thereof. Hydrogenated lecithin (i.e., a product of controlled hydrogenation of lecithin) may also be additionally used in the present invention.

於特定之具體實施態樣中，本發明組合物係包含作為一界面活性劑的磷脂質。可用於本發明之例示性磷脂質包括，但不限於磷脂醯膽鹼(phosphatidyl choline)、磷脂醯乙醇胺(phosphatidylethanolamine)、磷脂醯甘油(phosphatidylglycerol)、磷脂酸(phosphatidic acid)、溶血磷脂醯膽鹼(lyso-phosphtidylcholine)及其混合物。這些磷脂質通常具有4至22個碳原子，例如10至18個碳原子，以及不同程度的飽和。該組合物的磷脂質成分可為一單一磷脂質或一數個磷脂質之混合物。所用的磷脂質可以是天然的或是合成的，但用於非經口投與，尤其是靜脈注射應是可接受的。 In a particular embodiment, the compositions of the present invention comprise a phospholipid as a surfactant. Exemplary phospholipids useful in the present invention include, but are not limited to, phosphatidyl choline, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine ( Lyso-phosphtidylcholine) and mixtures thereof. These phospholipids typically have from 4 to 22 carbon atoms, such as from 10 to 18 carbon atoms, and varying degrees of saturation. The phospholipid component of the composition can be a single phospholipid or a mixture of a plurality of phospholipids. The phospholipids used may be natural or synthetic, but for parenteral administration, especially intravenous injections should be acceptable.

合適之磷脂質的非完全列舉的清單如下：磷脂酸，包括二肉豆蔻磷脂酸鈉鹽(1,2-Dimyristoyl-sn-glycero-3-phosphatidic acid，sodium salt，DMPA-Na)、二棕櫚醯磷脂酸鈉鹽(1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid，sodium salt，DPPA-Na)、二硬脂醯磷脂酸鈉鹽(1,2-Distearoyl-sn-glycero-3-phosphatidic acid，sodium salt，DSPA-Na)；磷脂醯膽鹼，包括二月桂醯磷脂醯膽鹼(1,2-Dilauroyl-sn-glycero-3-phosphocholine，DLPC)、二肉豆蔻磷脂醯膽鹼(1,2-Dimyristoyl-sn-glycero-3-phosphocholine，DMPC)、二棕櫚醯磷脂醯膽鹼(1,2-Dipalmitoyl-sn-glycero-3-phosphocholine，DPPC)、二硬脂醯磷脂醯膽鹼(1,2-Distearoyl-sn-glycero-3-phosphocholine，DSPC)；磷脂醯乙醇胺，包括二月桂醯磷脂醯乙醇胺(1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine，DLPE)、二肉豆蔻磷脂醯乙醇胺(1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine，DMPE)、二棕櫚醯磷脂醯乙醇胺(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine，DPPE)、二硬脂醯磷脂醯乙醇胺(1,2-Distearoyl-sn-glycero-3-phosphoethanolamine，DSPE)；磷甘油(phosphoglycerol)：包括二月桂醯磷甘油鈉鹽(1,2-Dilauroyl-sn-glycero-3-phosphoglycerol，sodium salt，DLPG-Na)、二肉豆蔻磷甘油鈉鹽(1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol，sodium salt，DMPG-Na)、二肉豆蔻磷甘油銨鹽(1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol，ammonium salt，DMP-sn-1-G,NH4)、二棕櫚醯磷甘油鈉鹽(1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol，sodium salt，DPPG-Na)、二硬脂醯磷脂醯甘油鈉鹽(1,2-Distearoyl-sn-glycero-3-phosphoglycerol，sodium salt，DSPG-Na)、二硬脂醯磷-SN-1-甘油鈉鹽(1,2-Distearoyl-sn-glycero-3-phospho-sn-1-glycerol，sodium salt，DSP-sn-1G-Na)；磷絲胺酸(phosphoserine)，包括二棕櫚醯磷絲胺酸鈉鹽(1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine，sodium salt，DPPS-Na)；混合鏈磷脂質，包括棕櫚醯油醯磷脂醯膽鹼(1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine，POPC)、棕櫚醯油醯磷甘油鈉鹽(1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol，sodium salt，POPG-Na)、棕櫚醯油醯磷甘油銨鹽(1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol，ammonium salt，POPG-NH4)；溶血磷脂質(lysophospholipid)，包括棕櫚醯溶血磷脂醯膽鹼(1-Palmitoyl-2-lyso-sn-glycero-3-phosphocholine，P-lyso-PC)、硬脂醯溶血磷脂醯膽鹼(1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine，S-lyso-PC)；聚乙二醇磷脂質(pegylated phospholipid)，包括硝基-(羰基-甲氧基聚乙二醇2000)-MPEG-2000-DPPE鈉鹽(N-(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DPPE，sodium salt)、硝基-(羰基-甲氧基聚乙二醇5000)-MPEG-5000-DSPE鈉鹽 (N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DSPE，sodium salt)、硝基-(羰基-甲氧基聚乙二醇5000)-MPEG-5000-DPPE鈉鹽(N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DPPE，sodium salt)、硝基-(羰基-甲氧基聚乙二醇750)-MPEG-750-DSPE鈉鹽(N-(Carbonyl-methoxypolyethyleneglycol 750)-MPEG-750-DSPE，sodium salt)、硝基-(羰基-甲氧基聚乙二醇2000)-MPEG-2000-DSPE鈉鹽(N-(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DSPE，sodium salt)。 A not-to-be-listed list of suitable phospholipids is as follows: phosphatidic acid , including 1,2-Dimyristoyl-sn-glycero-3-phosphatidic acid, sodium salt, DMPA-Na, dipalmitine 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid, sodium salt, DPPA-Na, distearoyl-sn-glycero-3-phosphatidic Acid, sodium salt, DSPA-Na); phospholipid choline , including 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC), dimylopectin phosphocholine (1) , 2-Dimyristoyl-sn-glycero-3-phosphocholine, DMPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), distearyl phospholipid choline ( 1,2-Distearoyl-sn-glycero-3-phosphocholine, DSPC); phospholipids, ethanolamines , including 1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE), dimylopectin 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), dipalmitoside phospholipid, ethanolamine (1,2-Dipalmitoyl-sn-glycero-3-phosphoet hanolamine, DPPE), distearyl acyl acyl phosphatidyl ethanolamine (-Distearoyl-sn 1,2-glycero -3-phosphoethanolamine, DSPE); glycerol phosphate (phosphoglycerol): comprising dilauryl phosphate acyl glycerol sodium salt (1,2-Dilauroyl -sn-glycero-3-phosphoglycerol, sodium salt, DLPG-Na), 1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt, DMPG-Na, dimucous 1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonium salt, DMP-sn-1-G, NH4, dipalmitosyl phosphate sodium salt (1, 2 -Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt, DPPG-Na), 1,2-Distearoyl-sn-glycero-3-phosphoglycerol, sodium salt, DSPG-Na , distearyl phosphate acyl glycerol sodium salt -SN-1- (1,2-distearoyl-sn-glycero -3-phospho-sn-1-glycerol, sodium salt, DSP-sn-1G-Na); phosphorus wire amine acid (phosphoserine), comprising dipalmitoyl phosphorus acyl serine sodium salt (1,2-dipalmitoyl-sn-glycero -3-phospho-L-serine, sodium salt, DPPS-Na); mixed chain phospholipids, comprising palmitic acyl Oil phosphatidylcholine (1-Palmitoyl-2-oleoyl-sn -glycero-3-phosphocholine, POPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (sodium salt, POPG-Na), palm ruthenium oil, phospholammonium phosphate salt (1-palmitoyl-2-oleoyl -sn-glycero-3-phosphoglycerol, ammonium salt, POPG-NH4); lysophospholipids (lysophospholipid), comprising palmitic acyl hemolytic phosphatidylcholine (1-palmitoyl-2-lyso- Sn-glycero-3-phosphocholine, P-lyso-PC), stearin lysophosphatidylcholine (1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine, S-lyso-PC); polyethylene alcohol phospholipid (pegylated phospholipid), a nitro group comprising - (carbonyl - methoxypolyethylene glycol 2000) -MPEG-2000-DPPE sodium salt (N- (carbonyl-methoxypolyethyleneglycol 2000) -MPEG-2000-DPPE, sodium salt , nitro-(carbonyl-methoxypolyethylene glycol 5000)-MPEG-5000-DSPE sodium salt (N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DSPE, sodium salt), nitro-(carbonyl) -Methoxy polyethylene glycol 5000)-MPEG-5000-DPPE sodium salt (N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DPPE, sodium salt), nitro-(carbonyl-methoxy polyethylene) Alcohol 750)-MPEG-7 50-DSPE sodium salt (N-(Carbonyl-methoxypolyethyleneglycol 750)-MPEG-750-DSPE, sodium salt), nitro-(carbonyl-methoxy polyethylene glycol 2000)-MPEG-2000-DSPE sodium salt (N - (Carbonyl-methoxypolyethyleneglycol 2000) - MPEG-2000-DSPE, sodium salt).

於一具體實施態樣中，根據本發明之組合物，以組合物的總體積之重量計，磷脂質的含量範圍係0.5至20公克/公升。於某些具體實施態樣中，磷脂質係以0.7至20公克/公升，包括0.8至18公克/公升，例如1至15公克/公升的含量存在。 In one embodiment, the composition according to the invention has a phospholipid content ranging from 0.5 to 20 grams per liter by weight of the total volume of the composition. In certain embodiments, the phospholipid system is present at a level of from 0.7 to 20 grams per liter, including from 0.8 to 18 grams per liter, such as from 1 to 15 grams per liter.

於一其他特定具體實施態樣中，磷脂質乳化劑的來源為卵磷脂，例如蛋卵磷脂。根據美國藥典(USP)，卵磷脂係一非所有權名稱，其係描述一主要由磷脂醯膽鹼、磷脂醯乙醇胺、磷脂醯絲胺酸(phosphatidylserine)、及磷脂醯肌醇(phosphatidylinositol)與不同含量之例如三酸甘油酯、脂肪酸以及碳水化合物等其他物質結合後所組成的丙酮不溶性(acetone-insoluble)磷脂質的錯合混合物。 In a further specific embodiment, the source of the phospholipid emulsifier is lecithin, such as egg lecithin. According to the United States Pharmacopoeia (USP), lecithin is a non-ownership name, which is described mainly by phospholipid choline, phospholipid, ethanolamine, phospholipidylserine, and phospholipidinositol. For example, a mixture of acetone-insoluble phospholipids composed of a combination of triglycerides, fatty acids, and other substances such as carbohydrates.

大豆卵磷脂以及蛋卵磷脂(包括這些化合物的氫化型)於生物系統安全性中具有一長遠的歷程，其表現乳化作用與溶解作用結合的性質，而且於體內比大部分的合成的界面活性劑 傾向更快地被代謝為無害物質。市售可得的大豆磷脂質/卵磷脂係為申特弗(Centrophase)以及申特力產品(Centrolex products)(中央索亞公司)、磷脂(Phospholipon)(磷脂質德國有限責任公司)、類脂(Lipoid)(類脂德國有限責任公司)、大豆卵磷脂(EPIKURON)(德固薩公司)，以及PL90(瑞典費森尤斯卡比公司)。於特定之具體實施態樣中，磷脂質的來源為蛋卵磷脂。 Soy lecithin and egg lecithin (including the hydrogenated form of these compounds) have a long history in the safety of biological systems, which exhibits the combination of emulsification and dissolution, and is more in vivo than most synthetic surfactants. It tends to be metabolized to harmless substances more quickly. Commercially available soy lecithin/lecithin is Centrifase and Centrolex products (Central Soya), Phospholipon (phospholipid German limited liability company), lipid ( Lipoid) (Leaf Germany GmbH), Soy Lecithin (EPIKURON) (Degussa), and PL90 (Fresten Ukrainian, Sweden). In a particular embodiment, the source of the phospholipid is egg lecithin.

於某些具體實施態樣中，以組合物的總體積之重量計，乳化劑(包括磷脂質)於該組合物中的總含量為0.5至48公克/公升，尤其為0.8至42公克/公升。於某些具體實施態樣中，其中該乳化劑係為蛋卵磷脂，其含量範圍為1至39公克/公升，例如3至29公克/公升，包括3.5至27公克/公升，包括4至26公克/公升，尤其為10至20公克/公升，例如11至15公克/公升。 In certain embodiments, the total amount of emulsifier (including phospholipids) in the composition is from 0.5 to 48 grams per liter, especially from 0.8 to 42 grams per liter, based on the total volume of the composition. . In certain embodiments, wherein the emulsifier is egg lecithin in an amount ranging from 1 to 39 grams per liter, such as from 3 to 29 grams per liter, including from 3.5 to 27 grams per liter, including from 4 to 26 In grams per liter, especially 10 to 20 grams per liter, for example 11 to 15 grams per liter.

較佳地，該乳劑係包含磷脂質，該磷脂質係包含ω-3脂肪酸部分，較佳為自磷蝦(磷蝦目(Euphausiacea))獲得之磷脂質。 Preferably, the emulsion comprises a phospholipid comprising an omega-3 fatty acid moiety, preferably a phospholipid obtained from krill (Euphausiacea).

於一具體實施態樣中，該乳劑係蛋卵磷脂，該蛋卵磷脂係包含60%至80%重量/重量，例如67%重量/重量之磷脂醯膽鹼；10%至20%重量/重量，例如15%重量/重量之磷脂醯乙醇胺；小於等於3%重量/重量，例如2%重量/重量之神經鞘磷脂；以及小於等於3%重量/重量，例如1%重量/重量之溶血磷脂醯膽鹼。 In one embodiment, the emulsion is egg lecithin, and the egg lecithin comprises 60% to 80% by weight, such as 67% by weight of phospholipid choline; 10% to 20% by weight/weight. , for example, 15% by weight/weight phospholipid oxime ethanolamine; 3% by weight/weight, for example, 2% by weight/weight of sphingomyelin; and 3% by weight/weight, for example, 1% by weight/weight of lysophospholipid 醯choline.

「蛋卵磷脂PL90」(Fresenius Kabi AB)係一具有該磷脂質含量之蛋卵磷脂的例子。 "Fresenius Kabi AB" is an example of an egg lecithin having the phospholipid content.

已發現ω-3脂肪酸殘基可改善荷爾蒙於治療及預防期間的效果。因此，根據一特別較佳之具體實施態樣，該水包油型乳劑包含一具有ω-3脂肪酸部分之磷脂質，較佳為自磷蝦(磷蝦目)獲得之磷脂質。 Omega-3 fatty acid residues have been found to improve the effects of hormones during treatment and prevention. Thus, according to a particularly preferred embodiment, the oil-in-water emulsion comprises a phospholipid having an omega-3 fatty acid moiety, preferably a phospholipid obtained from krill (Krill).

可自磷蝦獲得包含ω-3脂肪酸殘基之磷脂質。舉例而言，以磷蝦油的重量計，該磷蝦油可含有其含量為約20%至約60%，例如約30%至約50%之含有ω-3脂肪酸的磷脂質。於一例示性具體實施態樣中，以磷蝦油的重量計，該磷蝦油可含有其含量為少於約30%，例如少於約5%之含有ω-3脂肪酸的三酸甘油酯。於一例示性具體實施態樣中，磷蝦油可實質上不含含有ω-3脂肪酸的三酸甘油酯。舉例而言，磷脂質(PLs)與三酸甘油酯(TGs)二者都具有3碳的骨架(三酸甘油酯)，特定官能基分別與標註為sn-1、sn-2及sn-3的位置為1、2及3上的碳相接。PLs與TGs的sn-1與sn-2位置上可含有長鏈脂肪酸，例如18個碳的化合物(例如亞麻仁油酸、α-次亞麻油酸、油酸及硬脂酸)及/或含有20或更多個碳的極長鏈脂肪酸(例如花生油酸、二十碳五烯酸、二十二碳六烯酸及二十二碳五烯酸)。TGs的sn-3位置上亦由上述之長鏈脂肪酸佔據，例如已知為中性脂肪的化合物。然而，PLs的sn-3位置上係由磷酸連結至醇類(例如膽鹼、乙醇胺、絲胺酸、肌醇等)佔據，如此會顯著地改變分子，賦予它親水性及疏水性二種特性，並被稱作兩親(amphiphilic)化合物。作為修飾生物膜結構的一部分，且表現兩親特性，PLs在許多代謝過程中扮演著不可或缺的角色。 Phospholipids containing omega-3 fatty acid residues can be obtained from krill. For example, the krill oil may contain from about 20% to about 60%, for example from about 30% to about 50%, by weight of the krill oil, of a phospholipid containing an omega-3 fatty acid. In an exemplary embodiment, the krill oil may contain less than about 30%, such as less than about 5%, of triglyceride containing omega-3 fatty acids, based on the weight of the krill oil. . In an exemplary embodiment, the krill oil may be substantially free of triglycerides containing omega-3 fatty acids. For example, both phospholipids (PLs) and triglycerides (TGs) have a 3-carbon backbone (triglycerides) with specific functional groups labeled as sn-1, sn-2, and sn-3, respectively. The position is the carbon on 1, 2 and 3. The sn-1 and sn-2 positions of PLs and TGs may contain long-chain fatty acids, such as 18 carbon compounds (eg, linoleic acid, alpha-linolenic acid, oleic acid, and stearic acid) and/or Very long chain fatty acids of 20 or more carbons (eg, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid). The sn-3 position of TGs is also occupied by the above-mentioned long-chain fatty acids, such as compounds known as neutral fats. However, the sn-3 position of PLs is occupied by phosphate linked to alcohols (such as choline, ethanolamine, serine, inositol, etc.), which significantly changes the molecule, giving it two properties of hydrophilicity and hydrophobicity. And is called an amphiphilic compound. As part of a modified biofilm structure and exhibiting amphiphilic properties, PLs play an integral role in many metabolic processes.

於一例示性具體實施態樣中，一預定量之含有ω-3脂肪酸的磷脂質包含與磷脂質的第一及第二位置相接，但不與其第三位置相接的ω-3脂肪酸。此即，一預定量之含有ω-3脂肪酸的磷脂質可包含一位於磷脂質的第二位置(即，中間位置)的ω-3脂肪酸。舉例而言，以含有ω-3脂肪酸的磷脂質之總重量計，該包含與磷脂質的第一及第二位置相接，但不與其第三位置相接的ω-3脂肪酸之含有ω-3脂肪酸的磷脂質，其可以約70%至約80%，例如為約80%至約95%的含量存在。 In an exemplary embodiment, a predetermined amount of the phospholipid comprising the omega-3 fatty acid comprises an omega-3 fatty acid that is in contact with the first and second positions of the phospholipid, but not in contact with its third position. That is, a predetermined amount of the phospholipid containing the omega-3 fatty acid may comprise an omega-3 fatty acid at a second position (ie, an intermediate position) of the phospholipid. For example, the omega-3 fatty acid containing the first and second positions of the phospholipid, but not the third position of the phospholipid, is contained in the total weight of the phospholipid containing the omega-3 fatty acid. The phospholipid of the fatty acid, which may be present at a level of from about 70% to about 80%, for example from about 80% to about 95%.

根據另一例示性態樣，其提供一種非經口投與該水包油型乳劑的方法，該方法包含以一非經口之水包油型乳劑將一含有自海洋甲殼類動物獲得之磷脂質之組合物非經口投與一人體，該水包油型乳劑含有具保護性濃度的自然界存在的抗氧化劑、蝦紅素(astaxanthin)，以對抗存在不飽和ω-3脂肪酸的化學崩解或氧化作用。多不飽和ω-3脂肪酸的氧化作用會導致反應性含氧物種(reactive oxygen species)的形成，此可能會在靜脈管內投與時造成傷害。因此，一特定之富含ω-3脂肪酸的水包油型乳劑需要可對抗化學崩解之保護作用。於磷蝦油中發現的蝦紅素可能提供獨特之保護作用，以對抗ω-3脂肪酸的氧化作用，這就好比大豆油中的α-生育酚(alpha-tocopherol)，其可保護對抗ω-6脂肪酸的氧化作用。因此，就如同在磷蝦油中發現之以水產為基礎(marine-based)的磷脂質係包含一高濃度的n3-FAs，其可獨特地增強該乳劑的物理安定性，因此，存在磷蝦油中的蝦紅素亦可獨 特地增強該水包油型乳劑之化學安定性。有如以磷蝦油作為主界面活性劑或與卵磷脂(egg phospholipids)之共界面活性劑的例示態樣，蝦紅素可能是主要抗氧化劑或是與α-生育酚的共抗氧化劑。 According to another exemplary aspect, there is provided a method for parenterally administering the oil-in-water emulsion, the method comprising: a phospholipid obtained from a marine crustacean as an inseparable oil-in-water emulsion The composition of the quality is administered orally to a human body. The oil-in-water emulsion contains a protective concentration of a naturally occurring antioxidant, astaxanthin, against chemical disintegration of unsaturated omega-3 fatty acids. Or oxidation. Oxidation of polyunsaturated omega-3 fatty acids can lead to the formation of reactive oxygen species, which can cause damage when administered in a venous tube. Therefore, a specific oil-in-water emulsion rich in omega-3 fatty acids needs to be protected against chemical disintegration. The astaxanthin found in krill oil may provide a unique protective effect against the oxidation of omega-3 fatty acids, which is like alpha-tocopherol in soybean oil, which protects against ω- 6 oxidation of fatty acids. Thus, just as the marine-based phospholipid system found in krill oil contains a high concentration of n3-FAs, it uniquely enhances the physical stability of the emulsion, and therefore, the presence of krill Astaxanthin in oil can also be used alone The chemical stability of the oil-in-water emulsion is specifically enhanced. As exemplified by the use of krill oil as the primary surfactant or co-surfactant with egg phospholipids, astaxanthin may be the primary antioxidant or a co-antioxidant with alpha-tocopherol.

本發明之另一替代性具體實施態樣係一非經口投與之含有荷爾蒙的水包油型乳劑，其係包含：a)如前定義之助孕激素及/或***；以及b)一如前定義之自海洋甲殼類動物獲得之磷脂質。 Another alternative embodiment of the present invention is a hormone-containing oil-in-water emulsion for parenteral administration comprising: a) a progestogen and/or an estrogen as defined above; and b) Phospholipids obtained from marine crustaceans as previously defined.

於一具體實施態樣中，該乳劑包含不超過1.5%(重量/重量)、不超過1.2%(重量/重量)、或不超過0.8%(重量/重量)，包括不超過0.4%(重量/重量)之聚乙二醇-十五羥基硬脂酸脂(polyethylene glycol 15-hydroxystearate)。於另一具體實施態樣中，該組合物包含不超過1.5%(重量/重量)、不超過1.2%(重量/重量)、或不超過0.8%(重量/重量)，包括不超過0.4%(重量/重量)之聚乙二醇酯(polyethylene glycol ester)及/或聚乙烯-丙二醇(polyethylene-propylene glycol)。 In one embodiment, the emulsion comprises no more than 1.5% (weight/weight), no more than 1.2% (weight/weight), or no more than 0.8% (weight/weight), including no more than 0.4% (weight/weight). Weight) of polyethylene glycol 15-hydroxystearate (polyethylene glycol 15-hydroxystearate). In another embodiment, the composition comprises no more than 1.5% (weight/weight), no more than 1.2% (weight/weight), or no more than 0.8% (weight/weight), including no more than 0.4% ( Weight/weight) of polyethylene glycol ester and/or polyethylene-propylene glycol.

根據若干具體實施態樣，本發明提供包含助孕激素及/或***之醫藥組合物，其中，該組合物以包含一含水相、一油相、以及一界面活性劑之乳劑的型式存在。 According to several embodiments, the present invention provides a pharmaceutical composition comprising a progestogen and/or an estrogen, wherein the composition is in a form comprising an aqueous phase, an oil phase, and an emulsion of a surfactant.

含水介質Aqueous medium

如前述，本發明之水包油型乳劑進一步包含一含水介質。「含水介質」或「含水相」係指一含有水的液體。於若干具體實施態樣中，該含水介質為水及/或含水的緩衝溶液。 As stated above, the oil-in-water emulsion of the present invention further comprises an aqueous medium. "Aqueous medium" or "aqueous phase" means a liquid containing water. In some embodiments, the aqueous medium is a water and/or aqueous buffer solution.

本發明之水包油型乳劑可包含70至98重量%，較佳係70至90重量%。 The oil-in-water emulsion of the present invention may comprise from 70 to 98% by weight, preferably from 70 to 90% by weight.

於若干具體實施態樣中，該乳劑可包含0至4毫莫耳濃度之生理可相容的緩衝劑。 In several embodiments, the emulsion may comprise a physiologically compatible buffer at a concentration of from 0 to 4 millimolar.

於若干具體實施態樣中，根據本發明之水包油型乳劑可視需要包含一共界面活性劑。適用於本發明乳劑之共界面活性劑為可防止油脂型乳劑的絮凝作用(flocculation)及/或聚結作用(coalescence)者。例示性的共界面活性劑包括，但不限於膽固醇、油酸、油酸酯(oleate)、Tween 80(聚乙二醇-山梨醇油酸酯，PEG-sorbitan monooleate)、HCO-60、Solutol H15(聚氧乙烯-660-羥基硬脂酸酯)、PEG-400(聚乙二醇)、Pluronic F68(BASF)、Cremophor EL(聚氧乙烯-35-蓖麻醇酸酯，polyoxyethylene-35-ricinoleate)、或膽酸的鹽，例如去氧膽酸。於其他具體實施態樣中，該共界面活性劑選自以下群組：C12-C22脂肪酸、其鹽、及/或其混合物，例如C16-C20脂肪酸、其鹽、及/或其混合物，或C18脂肪酸、其鹽、及/或其混合物。於特定具體實施態樣中，該脂肪酸係單不飽和的。 In several embodiments, the oil-in-water emulsions according to the present invention may optionally comprise a total of surfactants. The co-surfactant suitable for use in the emulsion of the present invention is one which prevents flocculation and/or coalescence of the oil-and-fat emulsion. Exemplary co-surfactants include, but are not limited to, cholesterol, oleic acid, oleate, Tween 80 (PEG-sorbitan monooleate), HCO-60, Solutol H15 (polyoxyethylene-660-hydroxystearate), PEG-400 (polyethylene glycol), Pluronic F68 (BASF), Cremophor EL (polyoxyethylene-35-ricinoleate, polyoxyethylene-35-ricinoleate Or a salt of bile acid, such as deoxycholic acid. In other embodiments, the co-surfactant is selected from the group consisting of C12-C22 fatty acids, salts thereof, and/or mixtures thereof, such as C16-C20 fatty acids, salts thereof, and/or mixtures thereof, or C18 Fatty acids, salts thereof, and/or mixtures thereof. In a particular embodiment, the fatty acid is monounsaturated.

於若干具體實施態樣中，該組合物中之該共界面活性劑可以大於或等於0.005%、大於或等於0.01%、或者大於或等於0.02%的含量(重量/體積)存在。根據任一這些具體實施態樣，該共界面活性劑可以小於或等於4%、小於或等於1%、或者小於或等於0.04%的含量(重量/體積)存在。 In several embodiments, the co-surfactant in the composition can be present at a level (weight/volume) greater than or equal to 0.005%, greater than or equal to 0.01%, or greater than or equal to 0.02%. According to any of these specific embodiments, the co-surfactant may be present in a content (weight/volume) of less than or equal to 4%, less than or equal to 1%, or less than or equal to 0.04%.

於特定具體實施態樣中，該共界面活性劑係選自以下群組：長鏈脂肪酸，例如棕櫚酸、油酸、或硬脂酸、或其鹼金屬鹽。油酸酯及/或油酸，特別是油酸鈉(sodium oleate)係特別適合之共界面活性劑。 In a particular embodiment, the co-surfactant is selected from the group consisting of long chain fatty acids such as palmitic acid, oleic acid, or stearic acid, or an alkali metal salt thereof. Oleic acid esters and/or oleic acid, especially sodium oleate, are particularly suitable co-surfactants.

於某些具體實施態樣中，該共界面活性劑係油酸酯及/或油酸，該共界面活性劑可以等於或大於0.005%、等於或大於0.01%、或者等於或大於0.02%的含量(重量/體積)存在。根據任一這些具體實施態樣，該共界面活性劑可以小於或等於0.5%、小於或等於0.2%、小於或等於0.1%、或者小於或等於0.05%的含量(重量/體積)存在。於特定具體實施態樣中，該共界面活性劑係油酸鈉，並且以0.03%(0.3公克/公升)的含量(重量/體積)存在。於此所述之乳劑可適用於非經口，例如靜脈注射或靜脈輸入。典型之治療時間可持續如3至7天。於特定具體實施態樣中，特定共界面活性劑的濃度因此必須維持於最小值，以避免產生例如刺激性、抑制細胞色素p450等副作用。於特定具體實施態樣中，Pluronic F68(聚(乙二醇)-13-聚(丙二醇-共丙二醇))係以小於0.7%(重量/體積)、或小於0.5%(重量/體積)的含量存在。於其他特定具體實施態樣中，Solutol-HS(Macrogol-15-羥基硬脂酸酯)係以小於1.2%(重量/體積)、或小於15%(重量/體積)的含量存在。 In some embodiments, the co-surfactant is oleate and/or oleic acid, and the co-surfactant may be equal to or greater than 0.005%, equal to or greater than 0.01%, or equal to or greater than 0.02%. (weight/volume) is present. According to any of these embodiments, the co-surfactant may be present in an amount (weight/volume) of less than or equal to 0.5%, less than or equal to 0.2%, less than or equal to 0.1%, or less than or equal to 0.05%. In a particular embodiment, the co-surfactant is sodium oleate and is present at a level (weight/volume) of 0.03% (0.3 grams per liter). The emulsions described herein are suitable for parenteral administration, such as intravenous or intravenous administration. Typical treatment times can last as long as 3 to 7 days. In a particular embodiment, the concentration of the particular co-surfactant must therefore be maintained at a minimum to avoid side effects such as irritation and inhibition of cytochrome p450. In a specific embodiment, Pluronic F68 (poly(ethylene glycol)-13-poly(propylene glycol-co-propylene glycol)) is present in an amount of less than 0.7% (weight/volume) or less than 0.5% (weight/volume). presence. In other specific embodiments, Solutol-HS (Macrogol-15-hydroxystearate) is present at a level of less than 1.2% (weight/volume), or less than 15% (weight/volume).

滲透劑Penetrant

根據本發明之水包油型乳劑可包含一滲透劑及/或一液體滲性調節物(tonicity modulator)。該組合物可具有200至 1000毫滲莫耳/公斤(mOsm/Kg)範圍之滲透壓(osmolality)。 The oil-in-water emulsion according to the present invention may comprise a penetrant and/or a tonicity modulator. The composition can have 200 to Osmolality in the range of 1000 milliosmoles per kilogram (mOsm/Kg).

根據本發明之特定具體實施態樣，該乳劑可為等滲透壓的(isotonic及iso-osmatic)。該組合物可具有220至600毫滲莫耳/公斤，或230至360毫滲莫耳/公斤之滲透壓。 According to a particular embodiment of the invention, the emulsion can be isotonic and iso-osmatic. The composition may have an osmotic pressure of from 220 to 600 milliosmoles per kilogram, or from 230 to 360 milliosmoles per kilogram.

適合之滲透及/或液體滲性調節物的試劑包括氯化鉀或氯化鈉、海藻糖、蔗糖、山梨醇、甘油、葡萄糖、木糖醇、甘露醇、聚乙二醇、丙二醇、白蛋白、胺基酸、及其混合物。於某些具體實施態樣中，係使用例如甘油、右旋葡萄糖、乳糖、山梨醇或蔗糖等可增加滲透壓的試劑，而達到270至330毫滲莫耳/公斤，例如280至300毫滲莫耳/公斤之滲透壓。 Suitable agents for penetration and/or liquid permeability modifiers include potassium chloride or sodium chloride, trehalose, sucrose, sorbitol, glycerol, glucose, xylitol, mannitol, polyethylene glycol, propylene glycol, albumin , amino acids, and mixtures thereof. In certain embodiments, agents that increase osmotic pressure, such as glycerol, dextrose, lactose, sorbitol, or sucrose, are used to achieve 270 to 330 milliosmoles per kilogram, such as 280 to 300 milliosmoles. Mohr / kg osmotic pressure.

於一具體實施態樣中，該滲透劑係一生理可接受的多元醇，例如甘油、山梨醇或木糖醇。於一特定具體實施態樣中，該滲透劑係甘油。 In one embodiment, the penetrant is a physiologically acceptable polyol such as glycerol, sorbitol or xylitol. In a particular embodiment, the penetrant is glycerin.

滲透劑及/或液體滲性調節物的試劑，一般係於一不造成不良生物效應但足以提供等滲透壓(isosmotic及/或isotonic)之組合物的濃度下使用。當使用甘油作為滲透劑，甘油可以2%至5%(重量/體積)，例如2.1%至2.9%(重量/體積)，包括2.3%至2.7%之範圍的含量存在。於特定具體實施態樣中，本發明之乳劑係包含2.5%甘油(25公克/公升)。 The agents of the penetrant and/or liquid osmotic modifier are generally employed at a concentration that does not cause undesirable biological effects but is sufficient to provide an isostomotic and/or isotonic composition. When glycerin is used as the penetrating agent, the glycerin may be present in an amount ranging from 2% to 5% (weight/volume), for example from 2.1% to 2.9% (weight/volume), including from 2.3% to 2.7%. In a particular embodiment, the emulsion of the invention comprises 2.5% glycerol (25 grams per liter).

pH值調節劑pH regulator

於若干具體實施態樣中，根據本發明之乳劑的pH值為pH6.0至pH9.0，例如pH6.5至pH8.5，包括pH7.0至pH8.0之範圍。 該組合物之pH值可以本領域所悉知的方法作調整，例如透過使用一適當的鹼中和脂肪酸上的負電荷、透過使用一適當的緩衝液、或其組合。有多種不同的鹼以及緩衝液適合與本發明之乳劑一起使用。本領域中具有通常知識者會認同於乳劑中添加緩衝液，不僅會影響最終之pH值，也會影響該乳劑的離子強度。高離子強度緩衝液會對乳劑之zeta電位產生負面影響，故高離子強度是非所欲的。於一特定具體實施態樣中，係透過1N的氫氧化鈉將pH值調整至所需值。 In several embodiments, the pH of the emulsion according to the invention is from pH 6.0 to pH 9.0, such as from pH 6.5 to pH 8.5, including pH 7.0 to pH 8.0. The pH of the composition can be adjusted by methods known in the art, such as by neutralizing the negative charge on the fatty acid with a suitable base, by using a suitable buffer, or a combination thereof. A wide variety of bases and buffers are suitable for use with the emulsions of the present invention. Those of ordinary skill in the art would recognize that the addition of a buffer to the emulsion not only affects the final pH but also the ionic strength of the emulsion. High ionic strength buffers can have a negative effect on the zeta potential of the emulsion, so high ionic strength is undesirable. In a specific embodiment, the pH is adjusted to the desired value by means of 1 N sodium hydroxide.

視需要之添加物Additives as needed

根據本發明之乳劑，其可視需要包含一或多種醫藥可接受之添加物，例如連結劑、螯合劑、錯合劑、防腐劑(包含抗菌劑及抗氧化劑)、黏度改良劑、及其他生物可相容之材料或治療試劑。 An emulsion according to the present invention may optionally contain one or more pharmaceutically acceptable additives such as binding agents, chelating agents, complexing agents, preservatives (including antibacterial agents and antioxidants), viscosity modifiers, and other biocompatible phases. Contains materials or therapeutic agents.

組合物成分之比例Proportion of composition ingredients

雖然前面已說明本發明之組合物可包含之不同成分的例示性含量，但如下所討論的，本發明的其他方面係關於特定成分之比例。 While the foregoing has exemplified exemplary amounts of different ingredients that may be included in the compositions of the present invention, as discussed below, other aspects of the invention pertain to ratios of particular ingredients.

乳化劑(磷脂質)：油Emulsifier (phospholipid): oil

已發現水包油型乳劑中過量的磷脂質會導致磷脂質降解物在高壓蒸氣滅菌及/或存放之後增加，並使得pH值下降，然後對乳劑安定性造成負面影響。 Excess phospholipids in oil-in-water emulsions have been found to cause phospholipid degradation products to increase after autoclaving and/or storage, and to lower the pH, which then negatively impacts emulsion stability.

於一較佳具體實施態樣中，例如其中該乳化劑係磷 脂質，以全部油成分之%(重量/重量)表示，該乳劑係包含6.8%至43%，例如8.4%至42.5%，包括12%至26%，例如14%至25%，包括15%至22%的含量範圍之乳化劑。於一特定具體實施態樣中，乳化劑係磷脂質，且其係以該油之16至18%(重量/重量)的含量存在。 In a preferred embodiment, for example, wherein the emulsifier is phosphorus Lipid, expressed as % (w/w) of total oil component, the emulsion comprising 6.8% to 43%, such as 8.4% to 42.5%, including 12% to 26%, such as 14% to 25%, including 15% to 22% content range of emulsifiers. In a particular embodiment, the emulsifier is a phospholipid and is present at a level of from 16 to 18% (weight/weight) of the oil.

於更佳具體實施態樣中，以油的%(重量/重量)表示，該水包油型乳劑係包含其含量為大於或等於6.8%、大於或等於8.4%、大於或等於12%、大於或等於14%、或者大於或等於15%的磷脂質。於若干具體實施態樣中，以油的%(重量/重量)表示，該組合物係包含其含量為小於或等於43%、小於或等於42.5%、小於或等於26%、小於或等於25%、或者小於或等於22%的磷脂質。 In a more preferred embodiment, the oil-in-water emulsion comprises a content of greater than or equal to 6.8%, greater than or equal to 8.4%, greater than or equal to 12%, greater than % by weight of oil (weight/weight). Or 14%, or greater than or equal to 15% phospholipid. In several embodiments, expressed as % (weight/weight) of oil, the composition comprises a content of less than or equal to 43%, less than or equal to 42.5%, less than or equal to 26%, less than or equal to 25%. , or less than or equal to 22% of phospholipids.

於本發明之另一較佳具體實施態樣中，例如其中磷脂質的來源係卵磷脂，該組合物係包含其含量範圍為油的3%至20%(重量/重量)，例如油的4%至18%(重量/重量)，包括油的6%至16%(重量/重量)，例如油的8%至14%(重量/重量)的該卵磷脂。於一特定具體實施態樣中，乳化劑係一蛋卵磷脂，且其係以油的19%至21%(重量/重量)的含量存在。 In another preferred embodiment of the present invention, for example, wherein the source of the phospholipid is lecithin, the composition comprises 3% to 20% (weight/weight) in an amount ranging from oil to oil, for example, 4 % to 18% (weight/weight), including 6% to 16% (w/w) of oil, such as 8% to 14% (w/w) of the lecithin of the oil. In a particular embodiment, the emulsifier is an egg lecithin and is present at a level of from 19% to 21% (weight/weight) of the oil.

於若干具體實施態樣中，以油的%(重量/重量)表示，本發明之乳劑係包含其含量為大於或等於8%、大於或等於10%、大於或等於13%、大於或等於15%、或者大於或等於18%的卵磷脂，例如蛋卵磷脂。於若干具體實施態樣中，以油的%(重量/重量)表示，該組合物係包含其含量小於或等於50%、小於或等 於48%、小於或等於40%、小於或等於33%、或者小於或等於31%的卵磷脂。 In several embodiments, the emulsion of the present invention comprises an amount of greater than or equal to 8%, greater than or equal to 10%, greater than or equal to 13%, greater than or equal to 15 in terms of % (weight/weight) of oil. %, or greater than or equal to 18% lecithin, such as egg lecithin. In several embodiments, expressed as % (weight/weight) of oil, the composition comprises a content of less than or equal to 50%, less than or equal to Lecithin at 48%, less than or equal to 40%, less than or equal to 33%, or less than or equal to 31%.

共界面活性劑：油Common interfacial active agent: oil

如上提，於本發明之某些具體實施態樣中，該組合物包含一共界面活性劑，例如油酸酯或油酸。於特定具體實施態樣中，以油成分的%重量/重量表示，該共界面活性劑係可以0.08%至2%，例如0.1%至0.9%、包括0.3%至0.7%的含量範圍存在。於另一具體實施態樣中，共界面活性劑係以大於該油的0.02%(重量/重量)的含量存在。於一特定具體實施態樣中，共界面活性劑係油酸酯或油酸，且其係以該油的0.5%(重量/重量)的含量存在。 As mentioned above, in certain embodiments of the invention, the composition comprises a co-surfactant such as oleate or oleic acid. In a particular embodiment, the co-surfactant may be present in a range of from 0.08% to 2%, such as from 0.1% to 0.9%, including from 0.3% to 0.7%, expressed as % by weight of the oil component. In another embodiment, the co-surfactant is present at a level greater than 0.02% (weight/weight) of the oil. In a particular embodiment, the co-surfactant is oleate or oleic acid and is present at a level of 0.5% (weight/weight) of the oil.

於若干具體實施態樣中，以油的%(重量/重量)表示，共界面活性劑係以大於0.02、大於或等於0.08%、大於或等於0.1%、或者大於或等於0.3%的含量存在。於其他具體實施態樣中，以油的%(重量/重量)表示，共界面活性劑的濃度係小於或等於0.2%、小於或等於0.9%、或者小於或等於0.7%。 In several embodiments, the co-surfactant is present in an amount greater than 0.02, greater than or equal to 0.08%, greater than or equal to 0.1%, or greater than or equal to 0.3%, expressed as % oil (weight/weight). In other specific embodiments, the concentration of the co-surfactant is less than or equal to 0.2%, less than or equal to 0.9%, or less than or equal to 0.7%, expressed as % of oil (weight/weight).

共界面活性劑：乳化劑(磷脂質)Common interfacial surfactant: emulsifier (phospholipid)

於本發明之一較佳具體實施態樣中，該組合物係包含作為一乳化劑之磷脂質，以及一共界面活性劑，例如油酸酯。於這些具體實施態樣之特定方面，共界面活性劑與乳化劑可以1：85至1：12，例如1：82至1：17，包括1：68至1：20，例如1：51至1：26，包括2：85至1：34(重量/重量)的比例(共界面活性劑：磷脂質)範圍存在。 In a preferred embodiment of the invention, the composition comprises a phospholipid as an emulsifier and a co-surfactant such as an oleate. In particular aspects of these embodiments, the co-surfactant and emulsifier can be from 1:85 to 1:12, such as from 1:82 to 1:17, including from 1:68 to 1:20, such as 1:51 to 1 :26, including a ratio of 2:85 to 1:34 (weight/weight) (co-surfactant: phospholipid) is present.

於一較佳具體實施態樣中，共界面活性劑與磷脂質係以大於或等於1：85、大於或等於1：82、大於或等於1：68、大於或等於1：51，或者大於或等於2：85(重量/重量)的比例(共界面活性劑：磷脂質)存在。於若干具體實施態樣中，共界面活性劑與磷脂質係以小於或等於1：12、小於或等於1：17、小於或等於1：20、小於或等於1：26、或者小於或等於1：34(重量/重量)的比例(共界面活性劑：磷脂質)存在。 In a preferred embodiment, the co-surfactant and the phospholipid system are greater than or equal to 1:85, greater than or equal to 1:82, greater than or equal to 1:68, greater than or equal to 1:51, or greater than or A ratio equal to 2:85 (weight/weight) (co-surfactant: phospholipid) is present. In several embodiments, the co-surfactant and the phospholipid system are less than or equal to 1:12, less than or equal to 1:17, less than or equal to 1:20, less than or equal to 1:26, or less than or equal to 1 A ratio of 34 (weight/weight) (co-surfactant: phospholipid) is present.

於本發明之另一較佳具體實施態樣中，該組合物係包含作為乳化劑之蛋卵磷脂，以及一共界面活性劑，例如油酸酯。於這些具體實施態樣之特定方面，共界面活性劑與乳化劑可以1：100至1：15，例如1：80至1：20，包括1：70至3：70，例如1：60至1：30；包括1：50至1：40(重量/重量)的比例(共界面活性劑：卵磷脂)範圍存在。 In another preferred embodiment of the invention, the composition comprises egg lecithin as an emulsifier, and a co-surfactant such as an oleate. In particular aspects of these embodiments, the co-surfactant and emulsifier can be from 1:100 to 1:15, such as from 1:80 to 1:20, including from 1:70 to 3:70, such as 1:60 to 1 : 30; includes a ratio ranging from 1:50 to 1:40 (weight/weight) (co-surfactant: lecithin).

於特定具體實施態樣中，共界面活性劑與卵磷脂係以大於或等於1：100、大於或等於1：80、大於或等於1：70、大於或等於1：60、或者大於或等於1：50(重量/重量)的比例(輔界面活性劑：卵磷脂)存在。於若干具體實施態樣中，共界面活性劑與卵磷脂係以小於或等於1：15、小於或等於1：20、小於或等於3：70、小於或等於1：30、或者小於或等於1：40(重量/重量)的比例存在。 In a specific embodiment, the co-surfactant and lecithin are greater than or equal to 1:100, greater than or equal to 1:80, greater than or equal to 1:70, greater than or equal to 1:60, or greater than or equal to 1 A ratio of 50 (weight/weight) (auxiliary surfactant: lecithin) is present. In several embodiments, the co-surfactant and lecithin are less than or equal to 1:15, less than or equal to 1:20, less than or equal to 3:70, less than or equal to 1:30, or less than or equal to 1 : 40 (weight / weight) ratio exists.

於一特定具體實施態樣中，其中，該共界面活性劑係油酸酯，而該乳化劑係蛋卵磷脂，共界面活性劑與乳化劑的比 例範圍係1：45至1：20(重量/重量)，例如1：40至1：25(重量/重量)。 In a specific embodiment, wherein the co-surfactant is an oleate, and the emulsifier is egg lecithin, a ratio of a co-surfactant to an emulsifier. Examples range from 1:45 to 1:20 (weight/weight), for example from 1:40 to 1:25 (weight/weight).

包裝package

本發明之水包油型乳劑可以可立即使用(ready-to-use)組合物的形式提供。「可立即使用」的意思係不需要其他調配，例如稀釋或與多種成分混合在一起。 The oil-in-water emulsion of the present invention can be provided in the form of a ready-to-use composition. "Ready to use" means no additional formulation, such as dilution or mixing with multiple ingredients.

本發明之水包油型乳劑可以密封包裝(sealed packaging)的型式提供。該包裝可適用於液體配方以及助孕激素及/或***。較不適合用來包裝油質配方的材料的例子包括PVC以及DEHP。可適用於油質配方的包裝包括，但不限於以聚丙烯為基質的袋子以及玻璃瓶。傳統的玻璃係適合用來包裝本發明組合物的材料。於特定具體實施態樣中，該乳劑係包裝於一密封容器中。可於該容器加上外包裝，以提供對物理環境的保護作用。於一具體實施態樣中，該組合物係包裝於一容量為250毫升的密封的容器中。於一具體實施態樣中，該水包油型乳劑係包裝於一上部空間具有惰性氣體的密封的容器中。 The oil-in-water emulsion of the present invention can be provided in the form of a sealed packaging. The package is suitable for use in liquid formulations as well as progestogens and/or estrogens. Examples of materials that are less suitable for packaging oily formulations include PVC and DEHP. Packages that are suitable for use in oily formulations include, but are not limited to, polypropylene-based bags and glass bottles. Conventional glass systems are suitable for packaging the materials of the compositions of the present invention. In a particular embodiment, the emulsion is packaged in a sealed container. An outer packaging can be added to the container to provide protection to the physical environment. In one embodiment, the composition is packaged in a sealed container having a capacity of 250 ml. In one embodiment, the oil-in-water emulsion is packaged in a sealed container having an inert gas in an upper space.

於若干具體實施態樣中，該組合物係包裝於惰性容器中。於若干具體實施態樣中，惰性容器會吸收光。於其他具體實施態樣中，該容器係包含雙層瓶壁；並且，於更特定具體實施態樣中，二層間的空間係充滿惰性氣體，以防止氧化作用。為延長儲存時間，包裝材料係有助於防止大氣環境中的氧氣擴散到本發明之組合物中，以防止在組合物中形成氧降解物質(oxygen degradant)。 In several embodiments, the composition is packaged in an inert container. In some embodiments, the inert container absorbs light. In other embodiments, the container comprises a double wall of water; and, in a more specific embodiment, the space between the two layers is filled with an inert gas to prevent oxidation. In order to extend the storage time, the packaging material helps to prevent oxygen in the atmosphere from diffusing into the composition of the present invention to prevent the formation of oxygen-degrading substances in the composition (oxygen) Degradant).

於若干具體實施態樣中，該組合物係以單位劑量包裝。一單位劑量係可提供足夠組合物，供投與助孕激素及/或***之單次劑量(bolus dose)於一個體，或於一預定時間投與該組合物，例如治療的第一個小時、前二個小時、前四個小時等。緊急情況下，單位劑量使得可快速且方便地投與該組合物，舉例而言，給救護車上的醫務輔助人員或傷害事件發生地點的第一線救護人員使用。單位劑量形式的非限制例子為注射劑、預裝好的注射器、玻璃藥瓶、及/或密封的袋子。 In several embodiments, the composition is packaged in unit doses. A unit dose system provides a sufficient composition for administering a bolus dose of progestogen and/or estrogen to a subject, or administering the composition for a predetermined period of time, such as the first treatment Hours, first two hours, first four hours, etc. In an emergency, the unit dose allows for rapid and convenient administration of the composition, for example, to a paramedical ambulance on the ambulance or a first line ambulance crew at the location of the injury event. Non-limiting examples of unit dosage forms are injections, pre-filled syringes, glass vials, and/or sealed bags.

於若干具體實施態樣中，該組合物係包裝於一類似用於實施連續注入治療之胰島素幫浦裝置的裝置中，或包裝於設計來與該裝置一起使用的筒件中。例示性胰島素幫浦係由MiniMed以及Disetronic銷售。該幫捕可包含例如一套管、一儲存該組合物之幫浦儲存器或筒件、一可以電池操作的幫浦、以及一讓使用者可控制所遞送之有效物的精確量的工具，例如電腦晶片。 In several embodiments, the composition is packaged in a device similar to an insulin pump device for performing continuous infusion therapy, or packaged in a cartridge designed for use with the device. An exemplary insulin pumping system is marketed by MiniMed and Disetronic. The tap can include, for example, a cannula, a pump reservoir or cartridge for storing the composition, a battery operable pump, and a tool that allows the user to control the precise amount of active delivered. For example, a computer chip.

特定實施例Specific embodiment

於一特定具體實施態樣中，本發明之乳劑係包含：a)其含量範圍為1.0至2.0公克/公升之助孕酮；b)以水包油型乳劑計，100至300克/公升的油成分，其係包含：i)以該油成分之總重量計，至少50重量%之魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至 少45%之二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)；以及較佳ω-3脂肪酸的總含量為該脂肪酸重量的至少50%；以及ii)以該油成分之總重量計，10至50重量%之MCT；c)4至20公克/公升之磷脂質，較佳為8至20公克/公升之磷脂質；以及d)10至50公克/公升之甘油。 In a specific embodiment, the emulsion of the present invention comprises: a) progesterone in an amount ranging from 1.0 to 2.0 g/l; b) in an oil-in-water emulsion, from 100 to 300 g/liter An oil component comprising: i) at least 50% by weight, based on the total weight of the oil component, of fish oil triglyceride, wherein the fish oil triglyceride is composed of fatty acid esterified glycerol, wherein The fatty acid is contained in an amount of up to the weight of the fatty acid 45% less eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and preferably the total content of omega-3 fatty acids is at least 50% by weight of the fatty acid; and ii) the oil 10 to 50% by weight of MCT; c) 4 to 20 grams per liter of phospholipid, preferably 8 to 20 grams per liter of phospholipid; and d) 10 to 50 grams per liter of glycerol, based on the total weight of the ingredients; .

於一特定具體實施態樣中，本發明之乳劑係包含：a)其含量範圍為0.05至1.0公克/公升之***以及其含量範圍為1.0至2.0公克/公升之助孕酮以及；b)以水包油型乳劑計，100至300克/公升的油成分，其係包含：i)以該油成分之總重量計，至少50重量%之魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%之二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)；且較佳ω-3脂肪酸的總含量為該脂肪酸重量的至少50%；以及ii)以該油成分之總重量計，10至50重量%之MCT；c)4至20公克/公升之磷脂質，較佳為8至20公克/公升之磷脂質；以及d)10至50公克/公升之甘油。 In a specific embodiment, the emulsion of the present invention comprises: a) estradiol in an amount ranging from 0.05 to 1.0 g/l and progesterone in an amount ranging from 1.0 to 2.0 g/l; and b; An oil component of 100 to 300 g/liter, based on the oil-in-water emulsion, comprising: i) at least 50% by weight of fish oil triglyceride based on the total weight of the oil component, wherein the fish oil three The glyceride is composed of a fatty acid esterified glycerol, wherein the fatty acid comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid in an amount of at least 45% by weight of the fatty acid ( DHA); and preferably the total content of omega-3 fatty acids is at least 50% by weight of the fatty acid; and ii) 10 to 50% by weight of MCT based on the total weight of the oil component; c) 4 to 20 g/l Phospholipids, preferably from 8 to 20 grams per liter of phospholipid; and d) from 10 to 50 grams per liter of glycerol.

於一特定具體實施態樣中，本發明之乳劑係包含：a)其含量範圍為0.05至1.0公克/公升之***； b)以水包油型乳劑計，100至300克/公升的油成分，其係包含：i)以該油成分之總重量計，至少50重量%之魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%之二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)；以及較佳ω-3脂肪酸的總含量為該脂肪酸重量的至少50%；以及ii)以該油成分之總重量計，10至50重量%之MCT；c)4至20公克/公升之磷脂質，較佳為8至20公克/公升之磷脂質；以及d)10至50公克/公升之甘油。 In a specific embodiment, the emulsion of the present invention comprises: a) estradiol in an amount ranging from 0.05 to 1.0 g/l; b) an oil component of from 100 to 300 g/liter, based on the oil-in-water emulsion, comprising: i) at least 50% by weight, based on the total weight of the oil component, of fish oil triglyceride, wherein the fish oil The triglyceride is composed of a fatty acid esterified glycerol, wherein the fatty acid comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid in an amount of at least 45% by weight of the fatty acid. (DHA); and preferably the total content of omega-3 fatty acids is at least 50% by weight of the fatty acid; and ii) 10 to 50% by weight of MCT based on the total weight of the oil component; c) 4 to 20 g/ Liters of phospholipids, preferably 8 to 20 g/L of phospholipid; and d) 10 to 50 g/L of glycerol.

乳劑的性質The nature of the emulsion

本發明之組合物的外觀通常是乳白色，且視覺上是均質的乳劑。 The compositions of the present invention are typically milky white in appearance and are visually homogeneous emulsions.

乳劑液滴顆粒大小分佈(Emulsion Droplet Particle Size Distribution)Emulsion Droplet Particle Size Distribution PFAT5值PFAT5 value

美國藥典(USP)設定油脂可注射乳劑中球滴大小分佈的限制(USP 729-Pharm.Forum.2005；3：1448-1453)。該可注射乳劑中脂肪球滴之直徑大於5微米的限制，係表示為大於5微米的脂肪的體積/重量百分比不超過0.05%，或表示為PFAT5不超過0.05%(USP 729-Pharm.Forum.2005；3：1448-1453)。組合物的PFAT5值若超過0.05%，對靜脈注射而言是不安全的。乳劑的PFAT5 值受許多因素的影響，包括乳劑中的總油含量、磷脂質的類型與含量、共界面活性劑的選擇、共界面活性劑與油的比例、以及乳劑液滴對於聚結作用及/或絮凝作用的安定性。 The United States Pharmacopoeia (USP) sets limits on the size distribution of ball droplets in oil-injectable emulsions (USP 729-Pharm.Forum. 2005; 3:1448-1453). The limit of the diameter of the fat globules in the injectable emulsion greater than 5 microns is expressed as a volume/weight percentage of fat greater than 5 microns not exceeding 0.05%, or expressed as PFAT5 not exceeding 0.05% (USP 729-Pharm.Forum. 2005; 3: 1448-1453). A composition having a PFAT5 value of more than 0.05% is not safe for intravenous injection. Emulsion PFAT5 Values are affected by a number of factors, including total oil content in the emulsion, type and amount of phospholipids, choice of co-surfactant, ratio of co-activator to oil, and emulsion droplets for coalescence and/or flocculation. The stability of the action.

於特定之具體實施態樣中，本發明之組合物的PFAT5值係小於或等於0.05%，例如小於或等於0.04%，包括小於或等於0.02%，例如小於或等於0.01%。 In a particular embodiment, the composition of the invention has a PFAT5 value of less than or equal to 0.05%, such as less than or equal to 0.04%, including less than or equal to 0.02%, such as less than or equal to 0.01%.

於一具體實施態樣中，本發明之組合物的100%乳劑液滴的直徑係小於或等於5微米，並且至少98%的液滴，包括99%的液滴的直徑係小於或等於1.5微米。係以庫爾特粒度分析儀(Coulter Multisizer III)測定直徑大於1微米的液滴的顆粒大小分佈。 In one embodiment, the 100% emulsion droplets of the composition of the present invention have a diameter of less than or equal to 5 microns, and at least 98% of the droplets, including 99% of the droplets, have a diameter less than or equal to 1.5 microns. . The particle size distribution of droplets having a diameter greater than 1 micron was measured using a Coulter Multisizer III.

光子相關法(PCS)Photon correlation method (PCS)

於一具體實施態樣中，直徑小於或等於1微米的液滴具有350奈米之PCS z-average最大值，及/或不超過0.25的PCS多分散性數值。於一特定具體實施態樣中，直徑小於或等於1微米的液滴具有250奈米之z-average最大值及/或不超過0.20的多分散性數值。於一更特定具體實施態樣中，尺寸小於或等於1微米的液滴具有220奈米之z-average最大值及/或不超過0.15的多分散性數值。 In one embodiment, a droplet having a diameter of less than or equal to 1 micrometer has a PCS z-average maximum of 350 nanometers, and/or a PCS polydispersity value of no more than 0.25. In a particular embodiment, a droplet having a diameter of less than or equal to 1 micron has a z-average maximum of 250 nanometers and/or a polydispersity value of no more than 0.20. In a more specific embodiment, droplets having a size less than or equal to 1 micron have a z-average maximum of 220 nm and/or a polydispersity value of no more than 0.15.

液滴大小中間值(Median Droplet Size)Median Droplet Size

由於液滴大小係直接影響各現象的速率，例如聚結作用、乳油分離(creaming)、絮凝作用、奧斯華粗化(ostwald ripening)、以及最後的相分離(phase separation)，故乳劑的液滴 大小係決定乳劑不安定化的反應動力學的關鍵參數。因此，乳劑的液滴大小係表示乳劑的安定性。有多種參數會影響乳劑的液滴大小，包括如油的類型、界面活性劑以及共界面活性劑的類型、活性組分的存在、油的含量、油與界面活性劑的比例、以及油與共界面活性劑的比例。 Since the droplet size directly affects the rate of each phenomenon, such as coalescence, creaming, flocculation, ostwald ripening, and finally phase separation, the emulsion liquid drop The size determines the key parameters of the reaction kinetics of emulsion instability. Therefore, the droplet size of the emulsion indicates the stability of the emulsion. There are a number of parameters that affect the droplet size of the emulsion, including, for example, the type of oil, the type of surfactant and co-surfactant, the presence of the active component, the oil content, the ratio of oil to surfactant, and the total The proportion of surfactant.

於一特定具體實施態樣中，本發明之組合物之以體積為基礎的直徑中間值(或稱D[4,3])，係維持在小於或等於300奈米，例如小於或等於230奈米，包括小於或等於約200奈米，例如小於或等於185奈米，包括小於或等於約180奈米。接著，於121℃下高壓蒸氣滅菌15分鐘，及/或於60℃下存放至少3週，包括4週。 In a particular embodiment, the volume-based diameter intermediate value (or D[4,3]) of the composition of the invention is maintained at less than or equal to 300 nanometers, such as less than or equal to 230 nanometers. Meters, including less than or equal to about 200 nanometers, such as less than or equal to 185 nanometers, including less than or equal to about 180 nanometers. Next, autoclave at 121 ° C for 15 minutes, and / or store at 60 ° C for at least 3 weeks, including 4 weeks.

液滴大小平均值(Mean Droplet Size)Mean Droplet Size

於一具體實施態樣中，本發明之組合物之乳劑液滴顆粒之以體積為基礎的直徑平均值(或稱d(0,5))，係維持在小於或等於320奈米，例如小於或等於250奈米，包括小於或等於200奈米，例如小於或等於185奈米，包括小於或等於180奈米。較佳地，該液滴顆粒係240至320奈米。 In one embodiment, the volume-based diameter average (or d(0,5)) of the emulsion droplet particles of the composition of the present invention is maintained at less than or equal to 320 nanometers, such as less than Or equal to 250 nanometers, including less than or equal to 200 nanometers, such as less than or equal to 185 nanometers, including less than or equal to 180 nanometers. Preferably, the droplet particles are from 240 to 320 nm.

於一特定具體實施態樣中，本發明之組合物之以體積為基礎的直徑平均值(或稱d(0,5))，係維持在小於或等於300奈米，例如小於或等於250奈米，包括小於或等於200奈米，例如小於或等於185奈米，包括小於或等於180奈米。接著，於121℃下高壓蒸氣滅菌15分鐘，及/或於60℃下存放至少3週，包括4週。 In a particular embodiment, the volume-based diameter average (or d(0,5)) of the composition of the invention is maintained at less than or equal to 300 nanometers, such as less than or equal to 250 nanometers. Meters, including less than or equal to 200 nanometers, such as less than or equal to 185 nanometers, including less than or equal to 180 nanometers. Next, autoclave at 121 ° C for 15 minutes, and / or store at 60 ° C for at least 3 weeks, including 4 weeks.

Zeta電位(zeta-potential)Zeta potential (zeta-potential)

Zeta電位係與乳劑的安定性有關。具有高Zeta電位的乳劑係為電安定的，而具有低Zeta電位的乳劑容易凝結或絮凝。例如界面活性劑以及共界面活性劑的選擇及含量、乳劑的pH值、以及含水溶液的離子強度會影響乳劑的Zeta電位。 The Zeta potential is related to the stability of the emulsion. Emulsions with a high zeta potential are electrically stable, while emulsions with a low zeta potential tend to coagulate or flocculate. For example, the choice and amount of surfactant and co-surfactant, the pH of the emulsion, and the ionic strength of the aqueous solution can affect the zeta potential of the emulsion.

於一具體實施態樣中，本發明之組合物之Zeta電位係於-30毫伏至-70毫伏，例如-40毫伏至-65毫伏，包括-51毫伏至-60毫伏之範圍。此外，本發明之乳劑組合物的Zeta電位可為-30毫伏、-35毫伏、-40毫伏、-45毫伏、-50毫伏、-55毫伏、-60毫伏、-65毫伏、或-70毫伏、或者更高。 In one embodiment, the composition of the present invention has a Zeta potential of from -30 millivolts to -70 millivolts, such as from -40 millivolts to -65 millivolts, including from -51 millivolts to -60 millivolts. range. Further, the emulsion composition of the present invention may have a zeta potential of -30 mV, -35 mV, -40 mV, -45 mV, -50 mV, -55 mV, -60 mV, -65 Millivolts, or -70 millivolts, or higher.

微粒物質Particulate matter

於某些具體實施態樣中，本發明之乳劑於環境溫度(即一個或多個選自4℃、2℃至8℃、或20℃至25℃的溫度)下係不含晶形固體。於一特定具體實施態樣中，本發明之乳劑組合物符合注射液體中微粒大小與計數的標準(美國藥典第788章，方法2-微觀顆粒計數檢定)。舉例而言，該組合物每毫升可含有0至12個等於或大於10微米的顆粒以及0至2個等於或大於25微米的顆粒。 In certain embodiments, the emulsions of the present invention are free of crystalline solids at ambient temperature (i.e., one or more temperatures selected from 4 ° C, 2 ° C to 8 ° C, or 20 ° C to 25 ° C). In a particular embodiment, the emulsion compositions of the present invention meet the criteria for particle size and count in the injectable liquid (US Pharmacopoeia Chapter 788, Method 2 - Microparticle Count Verification). For example, the composition may contain from 0 to 12 particles equal to or greater than 10 microns and from 0 to 2 particles equal to or greater than 25 microns per milliliter.

乳劑的安定性Emulsion stability 無菌(Sterility)Sterility

於特定具體實施態樣中，本發明之乳劑係無菌的。本文所用之「無菌」係指該組合物符合美國藥典第71章的要求。於特定具體實施態樣中，該組合物係符合美國藥典第85章(細菌 內毒素試驗)的要求，並視需要額外地符合美國藥典第151章(熱原試驗)的要求。 In a particular embodiment, the emulsion of the invention is sterile. As used herein, "sterile" means that the composition meets the requirements of Chapter 71 of the United States Pharmacopoeia. In a specific embodiment, the composition is in accordance with the United States Pharmacopoeia Chapter 85 (Bacteria) Endotoxin test) requirements and additional compliance with the requirements of the United States Pharmacopoeia Chapter 151 (pyrogenic test).

於特定具體實施態樣中，本發明之乳劑係達到改良的助孕激素及/或***的溶解度，並同時達到維持或改善該乳劑的化學安定性及/或物理安定性。於特定具體實施態樣中，該組合物可於121℃下以高壓蒸氣滅菌法進行加熱殺菌15分鐘，且不會危及乳劑的物理或化學完整性。以高壓蒸氣滅菌進行殺菌，與過濾滅菌比較，不僅就微生物安全是有益的，並且更具經濟效益。 In a particular embodiment, the emulsion of the present invention achieves improved solubility of progestogen and/or estrogen while at the same time maintaining or improving the chemical stability and/or physical stability of the emulsion. In a particular embodiment, the composition can be heat sterilized by autoclaving at 121 °C for 15 minutes without compromising the physical or chemical integrity of the emulsion. Sterilization by autoclaving is not only beneficial to microbiological safety, but also more economical than filter sterilization.

此外，於特定具體實施態樣中，該乳劑展現了較先前技術優異之安全性，舉例而言，(a)該組合物符合注射液體中顆粒大小及計數的標準(美國藥典第788章，方法2)，及/或包含較少的助孕激素及/或***的結晶；(b)該組合物具有較低的PFAT5值(如前所詳細討論)；(c)該組合物含有較低的化學性雜質；(d)為達微生物安全，該組合物可以黃金標準方法進行高壓滅菌；及/或(e)該組合物不含酒精或潛在的有毒有機溶劑。 Moreover, in certain embodiments, the emulsion exhibits superior safety over the prior art, for example, (a) the composition meets the criteria for particle size and count in the injected liquid (US Pharmacopoeia Chapter 788, Method) 2), and/or contain less progesterone and/or estrogen crystals; (b) the composition has a lower PFAT5 value (as discussed in detail above); (c) the composition contains lower Chemical impurities; (d) for microbiological safety, the composition can be autoclaved by gold standard methods; and/or (e) the composition is free of alcohol or potentially toxic organic solvents.

與先前技術的組合物相較，上述之一或多個該組合物的優點中，該乳劑係提供改良的其所含之助孕激素可利用性(例如良好的藥物動力學以及生物可利用性，例如可反應在血清荷爾蒙量及/或血漿濃度)，並且該乳劑的投與係提供改良的病患劑量恆定性。 Among the advantages of one or more of the above compositions, the emulsion provides improved progestogen availability (e.g., good pharmacokinetics and bioavailability) as compared to prior art compositions. For example, it can be reacted in serum hormone and/or plasma concentration), and the administration of the emulsion provides improved patient dose constancy.

最後，本發明之乳劑組合物除可方便且安全的使用外，且因為具有無菌的可立即使用的形式且於室溫下具有1或2年 儲藏期限，因而具有優勢。 Finally, the emulsion composition of the present invention can be conveniently and safely used, and because it has a sterile ready-to-use form and has 1 or 2 years at room temperature. The shelf life is therefore advantageous.

製造程序Manufacturing process

本發明之另一具體實施態樣係製備本發明之水包油型乳劑的方法。 Another embodiment of the invention is a method of preparing an oil-in-water emulsion of the invention.

該方法包含以下步驟：a)溶解助孕激素及/或***於一包含魚油三酸甘油酯的油相中，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%之二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)；以及較佳ω-3脂肪酸的總含量為該脂肪酸重量之至少60%；以及b)較佳係於乳化劑存在下，於含水相中乳化該油相。 The method comprises the steps of: a) dissolving a progestogen and/or an estrogen in an oil phase comprising fish oil triglyceride, wherein the fish oil triglyceride is composed of fatty acid esterified glycerol, Wherein the fatty acid comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in an amount of at least 45% by weight of the fatty acid; and preferably the total content of the omega -3 fatty acid is At least 60% by weight of the fatty acid; and b) preferably in the presence of an emulsifier, emulsifying the oil phase in the aqueous phase.

另一方面，本發明係關於一種製造如前定義之水包油型乳劑組合物的方法，該方法係包含以下步驟： In another aspect, the invention relates to a method of making an oil-in-water emulsion composition as defined above, the method comprising the steps of:

a)合併水與磷脂質以及一視需要之滲透劑，以製造一含水組合物。 a) combining water with phospholipids and, if desired, penetrants to produce an aqueous composition.

b)合併助孕激素及/或***與油，以製造一油質組合物；以及c)合併該含水組合物與該油質組合物，接著進行均質作用以形成一均質的水包油型乳劑。 b) combining progestogen and/or estrogen and oil to produce an oleaginous composition; and c) combining the aqueous composition with the oleaginous composition, followed by homogenization to form a homogeneous oil-in-water type Emulsion.

根據一特定具體實施態樣，於合併該含水組合物與該油質組合物之前，先將該含水組合物均質化以製造一均質的懸浮液。於另一有助益的具體實施態樣中，添加助孕激素及/或雌性 激素至溫度至少為40℃的油中，以促進助孕激素及/或***的稀釋。於另一特定具體實施態樣中，於該油質組合物與該含水組合物合併之前，先過濾該油質組合物。 According to a particular embodiment, the aqueous composition is homogenized prior to combining the aqueous composition with the oleaginous composition to produce a homogeneous suspension. In another specific embodiment, add progestogen and/or female Hormone to oil at a temperature of at least 40 ° C to promote the dilution of progesterone and / or estrogen. In another specific embodiment, the oleaginous composition is filtered prior to combining the oleaginous composition with the aqueous composition.

於若干非常特定之具體實施態樣中，該製造方法係包含以下步驟：A)溶解一視需要的滲透劑於一含水介質中，並攪拌；B)加入乳化劑，例如蛋卵磷脂，並攪拌；C)視需要加入一共界面活性劑以及一pH值調節劑，並混合；D)溶解助孕激素及/或***於油中以形成一油相；E)過濾該油相，接著添加已過濾的該油相至該含水相中，並混合；F)進行均質作用以形成一均質的乳劑G)視需要加入水；H)視需要加入足量的1N的氫氧化鈉(NaOH)，以調整pH值到pH8.0至pH8.8；I)視需要加入足量的含水介質以達到最終體積。 In a number of very specific embodiments, the method of manufacture comprises the steps of: A) dissolving a desired penetrant in an aqueous medium and stirring; B) adding an emulsifier, such as egg lecithin, and stirring. ; C) if necessary, add a total of surfactant and a pH adjuster, and mix; D) dissolve progesterone and / or estrogen in oil to form an oil phase; E) filter the oil phase, then add Filtering the oil phase into the aqueous phase and mixing; F) homogenizing to form a homogeneous emulsion G) adding water as needed; H) adding a sufficient amount of 1N sodium hydroxide (NaOH) as needed Adjust the pH to pH 8.0 to pH 8.8; I) Add sufficient amount of aqueous medium as needed to reach the final volume.

於一特定具體實施態樣中，該均質作用係於大於或等於350巴(bar)，或者大於或等於370巴下進行。 In a particular embodiment, the homogenization is carried out at greater than or equal to 350 bar, or greater than or equal to 370 bar.

於特定具體實施態樣中，製造該乳劑的方法係涉及溶解蛋卵磷脂於含水介質中(而不是溶解於油中)、添加該油相至該含水相中(而不是添加該含水相至該油相中)、以及於大於或等於350巴下進行均質作用等步驟。這些步驟被認為可以產生就顆粒大小以及乳劑安定性等性質而言具有優勢的乳劑。 In a specific embodiment, the method of making the emulsion involves dissolving egg lecithin in an aqueous medium (rather than dissolving in oil), adding the oil phase to the aqueous phase (rather than adding the aqueous phase to the In the oil phase), and at a temperature greater than or equal to 350 bar, the steps of homogenization are carried out. These steps are believed to produce emulsions that are advantageous in terms of particle size and emulsion stability.

於另一特定具體實施態樣中，該乳劑係包裝於密封的容器中並殺菌，例如加熱到至少121℃(即，121℃至123℃)並保持最少15分鐘。該高壓蒸氣滅菌程序係可循環。 In another specific embodiment, the emulsion is packaged in a sealed container and sterilized, for example, to at least 121 ° C (ie, 121 ° C to 123 ° C) and held for a minimum of 15 minutes. The autoclave sterilization process is cyclable.

於其它非常特定之具體實施態樣中，該製造方法係包含以下步驟：A)溶解一滲透劑於一含水介質中，並攪拌；B)加入磷脂質，尤其係蛋卵磷脂，並攪拌；C)視需要加入一共界面活性劑以及一pH值調節劑，並混合；D)溶解助孕激素及/或***於魚油三酸甘油酯中以形成一油相；E)過濾該油相，接著添加該已過濾的油相至該含水相中，並混合；F)進行均質作用以形成一均質的乳劑G)視需要加入水；H)視需要加入足量的1N氫氧化鈉，以調整pH值到pH8.0至pH8.8；I)視需要加入足量的含水介質以達到最終體積。 In other very specific embodiments, the method of manufacture comprises the steps of: A) dissolving a penetrant in an aqueous medium and stirring; B) adding a phospholipid, especially egg lecithin, and stirring; Adding a total of a surfactant and a pH adjuster as needed, and mixing; D) dissolving the progestogen and/or estrogen in fish oil triglyceride to form an oil phase; E) filtering the oil phase, followed by Adding the filtered oil phase to the aqueous phase and mixing; F) homogenizing to form a homogeneous emulsion G) adding water as needed; H) adding sufficient 1N sodium hydroxide as needed to adjust the pH Values to pH 8.0 to pH 8.8; I) Add sufficient amount of aqueous medium as needed to reach the final volume.

以下將提供詳細的製造方法之實施例。本領域之技藝人士可輕易了解各種不同的可進行且仍不悖離本發明之範疇的修飾及變化。 Detailed embodiments of the manufacturing method will be provided below. Modifications and variations that can be made without departing from the scope of the invention are readily apparent to those skilled in the art.

治療方法treatment method

本發明之另一具體實施態樣係一醫藥組合物，其係包含本發明之水包油型乳劑，或由本發明之水包油型乳劑所組成。 Another embodiment of the present invention is a pharmaceutical composition comprising the oil-in-water emulsion of the present invention or consisting of the oil-in-water emulsion of the present invention.

較佳地，本發明之醫藥組合物係用於治療或預防中風及/或創傷後之神經傷害。 Preferably, the pharmaceutical composition of the present invention is for the treatment or prevention of nerve damage after stroke and/or trauma.

根據本發明之另一較佳之具體實施態樣，本發明之醫藥組合物係用於治療或預防腦震盪後之神經傷害，或用於治療或預防創傷性事件。 According to another preferred embodiment of the present invention, the pharmaceutical composition of the present invention is for treating or preventing nerve damage after a concussion, or for treating or preventing a traumatic event.

本文所述之乳劑可為非經口投與，例如以靜脈或動脈內的方式投與至個體作治療或預防之用。於特定具體實施態樣中，該個體係指哺乳類動物，例如人類。 The emulsions described herein can be administered parenterally, for example, by intravenous or intraarterial administration to an individual for treatment or prevention. In a particular embodiment, the system refers to a mammal, such as a human.

本文所述之乳劑具有神經保護及/或神經再生的性質。因此，該組合物係有用於治療或預防神經系統失調或疾病。例示性的失調或疾病包括，但不限於中樞神經系統(CNS)失調或疾病、脊髓(spinal cord)傷害、創傷性的腦部傷害、輕度頭部傷害、包括暫時失去腦部功能的腦震盪、兒童的頭部傷害、CNS的退化性疾病，例如帕金森氏症(Parkinson's disease)、失智(dementia)，包括阿茲海默症(Alzheimer's disease)、髓鞘脫失病(demyelinating conditions)，例如多發性硬化症(multiple sclerosis)以及慢性的糖尿性周邊神經病理學。 The emulsions described herein have neuroprotective and/or neuroregenerative properties. Thus, the composition is useful for treating or preventing a nervous system disorder or disease. Exemplary disorders or diseases include, but are not limited to, central nervous system (CNS) disorders or diseases, spinal cord injuries, traumatic brain injuries, mild head injuries, concussions including temporary loss of brain function. , children's head injuries, degenerative diseases of the CNS, such as Parkinson's disease, dementia, including Alzheimer's disease, demyelinating conditions, For example, multiple sclerosis and chronic diabetic peripheral neuropathology.

其它例示性的失調或疾病包括缺血性神經疾病，例如缺血性CNS傷害、中風(包括缺血性中風、出血性中風、以及短暫性腦缺血發作)、以及歸因於心臟手術期間的心肺繞道手術(cardiopulmonary bypass)的神經認知缺損(neurocognitive impairment)，例如灌流後症狀(post-perfusion syndrome)。其它實 例包括失語症(aphasia)、睡眠障礙、以及焦慮症(anxiety disorders)，例如創傷後壓力症候群(post-traumatic stress disorder)。 Other exemplary disorders or diseases include ischemic neurological diseases such as ischemic CNS injury, stroke (including ischemic stroke, hemorrhagic stroke, and transient ischemic attack), and during cardiac surgery Neurocognitive impairment of cardiopulmonary bypass, such as post-perfusion syndrome. Other real Examples include aphasia, sleep disorders, and anxiety disorders, such as post-traumatic stress disorders.

該組合物亦有用於緩和與上所列疾病有關的症狀，例如修復認知功能、修復睡眠模式、正常化情感性精神病等。該醫藥組合物亦有用於治療創傷後壓力症候群。 The composition is also useful for alleviating symptoms associated with the diseases listed above, such as repairing cognitive function, repairing sleep patterns, normalizing affective psychosis, and the like. The pharmaceutical composition is also useful for treating post-traumatic stress syndrome.

根據一具體實施態樣，本發明係提供一種治療一患有創傷性CNS傷害(例如創傷性腦部傷害)的哺乳類動物個體的方法。例示性的方法包含治療哺乳類動物個體之創傷性腦部損傷(TBI)，其係將根據本發明之醫藥組合物投與至有需要的哺乳類動物個體，以遞送治療有效濃度的助孕激素及/或***。於一特定具體實施態樣中，該哺乳動物個體係指人類。舉例而言，本發明之方法可包含以非經口的方式，將本發明之包含助孕激素及/或***之醫藥組合物投與至一具有創傷性CNS傷害(例如TBI)的個體。根據本發明方法，該醫藥組合物係用於促進關於創傷性中樞神經系統傷害的正面治療反應。 According to a specific embodiment, the present invention provides a method of treating a mammalian individual suffering from a traumatic CNS injury, such as a traumatic brain injury. An exemplary method comprises treating a traumatic brain injury (TBI) in a mammalian individual by administering a pharmaceutical composition according to the present invention to a mammalian in need thereof to deliver a therapeutically effective concentration of a progestogen and/or Or estrogen. In a particular embodiment, the mammalian system is a human. For example, the method of the present invention may comprise administering a pharmaceutical composition comprising a progestogen and/or estradiol of the present invention to a subject having a traumatic CNS injury (eg, TBI) in a non-oral manner. . According to the method of the invention, the pharmaceutical composition is for promoting a positive therapeutic response to traumatic central nervous system injury.

創傷性腦部損傷係指暫時或永久地損害大腦功能的腦部組織物理傷害。臨床上被懷疑有可能的診斷，可再以影像(主要為CT)確認。臨床顯示係顯著地隨嚴重性與後果改變。損傷一般被分為開放性以及封閉性。開放性損傷涉及頭及頭骨的穿透。封閉性損傷一般係發生於頭部被敲擊、頭部撞到物體、或是頭部被激烈的震動而造成腦部迅速加速與減速。 Traumatic brain injury refers to physical damage to the brain tissue that temporarily or permanently impairs brain function. Clinically suspected possible diagnosis can be confirmed by imaging (mainly CT). Clinical manifestations vary significantly with severity and consequences. Damage is generally divided into openness and closure. Open injuries involve the penetration of the head and skull. Closed injury usually occurs when the head is struck, the head hits the object, or the head is subjected to intense vibrations, causing rapid acceleration and deceleration of the brain.

本發明之醫藥組合物可用於治療TBI，包括鈍傷(例如，封閉性損傷)，以及穿透性傷害。「治療」係指任何對於具有創傷性CNS傷害的個體所作的改善，包括改善的形態復原(即，提高的組織存活率)及/或行為復原二者。該改善的特徵可在於增加於創傷性CNS傷害後之行為及結構復原的速度及/或程度。因此，「正面治療反應」係包括一完全反應以及一部分反應。專利申請案WO2006/102644、WO2006/102596、以及WO2008/039898已詳細論述決定已發生之完全或部分治療反應的多種方法。 The pharmaceutical compositions of the invention are useful in the treatment of TBI, including blunt trauma (e.g., occlusive injury), as well as penetrating injury. "Treatment" refers to any improvement in an individual with traumatic CNS injury, including improved morphological recovery (ie, increased tissue survival) and/or behavioral recovery. This improvement may be characterized by an increase in the behavior and structural recovery rate and/or extent of traumatic CNS injury. Therefore, "positive treatment response" includes a complete reaction as well as a part of the reaction. Various methods for determining the complete or partial therapeutic response that has occurred have been discussed in detail in the patent applications WO2006/102644, WO2006/102596, and WO2008/039898.

「治療有效量」意即一足以引起一治療效果之助孕激素及/或***的含量。因此，於若干具體實施態樣中，根據本發明，助孕激素及/或***於投與的劑量單位中的含量，係有效於治療或預防CNS之創傷性傷害後的神經傷害，因而引起一神經保護作用。神經退化係指中樞神經系統喪失神經元的進程。本文所用之「神經保護作用」係指於一創傷性CNS傷害後，停止及/或回復神經退化的進程。該治療有效量係取決於多種因素，包括如助孕激素及/或***的特定活性(specific activity)、創傷性傷害嚴重度以及形態、造成的神經傷害、病患的反應性、病患的體重、其他個人內部因素、投與的型式及/或方法、以及所使用的醫藥組合物。 By "therapeutically effective amount" is meant a level of progestin and/or estrogen sufficient to cause a therapeutic effect. Therefore, in several embodiments, according to the present invention, the content of the progestogen and/or estrogen in the administered dosage unit is effective for treating or preventing nerve damage after traumatic injury of the CNS, thereby causing A neuroprotective effect. Neurodegeneration refers to the process by which the central nervous system loses neurons. As used herein, "neuroprotective" refers to the process of stopping and/or restoring neurodegeneration after a traumatic CNS injury. The therapeutically effective amount depends on a variety of factors including, for example, the specific activity of the progestin and/or estrogen, the severity of the traumatic injury and the morphology, the resulting nerve damage, the patient's reactivity, the patient's Body weight, other personal internal factors, the type and/or method of administration, and the pharmaceutical composition used.

本發明之醫藥組合物可以本領域中已知任何可接受的方法投與，包括靜脈注射(IV)、肌內注射(IM)、或皮下注射(SC)。於特定具體實施態樣中，該組合物係以靜脈的方式投與， 例如IV注射。當以靜脈的方式投與，該組合物可於1至144小時的期間以注入液投與。 The pharmaceutical compositions of this invention may be administered by any acceptable method known in the art, including intravenous (IV), intramuscular (IM), or subcutaneous (SC). In a specific embodiment, the composition is administered intravenously, For example IV injection. When administered intravenously, the composition can be administered as an infusion solution over a period of from 1 to 144 hours.

助孕激素及/或***可於一天內投與一或數次。治療的期間可為1、2、3、4、5、6、7或更多天，每天一次。每日劑量可以個人劑量單位的形式或數個較小之劑量單位的形式投與單一劑量(single dosage)，或者於一特定期間內，多次的投與分次劑量(subdivided dosage)。後續的劑量單位可於第一次投與後的任何時間點投與，以達到治療效果。例如可投與額外的劑量單位，以保護該個體免於遭受第一次傷害數日後的第二波水腫。於一特定具體實施態樣中，該第一劑量單位係不晚於發生傷害的8小時後投與。 Progesterone and/or estrogen can be administered one or several times a day. The duration of treatment can be 1, 2, 3, 4, 5, 6, 7, or more days, once a day. The daily dose can be administered as a single dosage form in the form of a personal dosage unit or as a plurality of smaller dosage units, or multiple subdivided dosages over a specified period of time. Subsequent dosage units can be administered at any point after the first administration to achieve a therapeutic effect. For example, an additional dosage unit can be administered to protect the individual from the second wave of edema after a few days of the first injury. In a particular embodiment, the first dosage unit is administered no later than 8 hours after the injury has occurred.

於本發明之特定具體實施態樣中，助孕激素及/或***係以一連續給藥方案投與。該「連續給藥方案」，係指於一療程中，助孕激素及/或***可連續每小時地以助孕激素及/或***的注入劑量投與。 In a particular embodiment of the invention, the progestogen and/or estrogen are administered in a continuous dosing regimen. The "continuous dosing regimen" means that progestogen and/or estrogen can be administered continuously in an hourly dose of progestogen and/or estrogen during a course of treatment.

於本發明之另一具體實施態樣中，至少一種額外的神經保護性試劑可與該助孕激素及/或***合併投與(亦可作為同一組合物的一部分或是一分開的組合物)，以增強創傷性CNS傷害後的神經保護作用。 In another embodiment of the invention, at least one additional neuroprotective agent can be administered in combination with the progestin and/or estrogen (either as part of the same composition or as a separate composition) ) to enhance neuroprotection after traumatic CNS injury.

以上係本發明之蓋括敘述，以下所載之特定實施例可使本發明更容易被理解，且實施例係僅用於闡明本發明之目的，並非用以限制本發明。 The present invention is to be understood as being limited by the scope of the present invention.

實施例Example

製備含有荷爾蒙之油型乳劑的一般程序 General procedure for preparing oil-containing emulsions containing hormones

將甘油與部分的水混合後，以細胞均質機(Ultra Turrax^®)將乳化劑(卵磷脂)以及共乳化劑油酸鈉分散(溶液I)。平行製備油相，視需要使用生育酚，並於70℃以及氮惰性大氣下，將***以及助孕酮溶解於其中(溶液II)。將溶液II加入溶液I中，使用Ultra Turrax細胞均質機，接著於一高壓均質機中、至少400巴至800巴、30℃至70℃下，進行4至5個均質作用循環。之後，加入剩餘的水，並以氫氧化鈉作為溶液，調整所得之水包油型乳劑的pH值到7.5至9.0。 After mixing glycerin with a portion of the water, the emulsifier (lecithin) and the co-emulsifier sodium oleate (dispersion I) were dispersed by a cell homogenizer (Ultra Turrax ^® ). The oil phase was prepared in parallel, tocopherol was used as needed, and estradiol and progesterone were dissolved therein at 70 ° C under a nitrogen atmosphere (solution II). Solution II is added to Solution I, and an Ultra Turrax cell homogenizer is used, followed by 4 to 5 homogenization cycles in a high pressure homogenizer at at least 400 to 800 bar, 30 to 70 °C. Thereafter, the remaining water was added, and the pH of the resulting oil-in-water emulsion was adjusted to 7.5 to 9.0 using sodium hydroxide as a solution.

待乳劑裝填於一適當品質的容器中，以已知方法加熱滅菌該乳劑，得到一無菌且穩定的水包油型乳劑，含有平均油滴大小為小於0.5微米及具有至少18個月之儲藏穩定性的油脂液滴。 The emulsion is filled in a suitable quality container, and the emulsion is heat-sterilized by a known method to obtain a sterile and stable oil-in-water emulsion containing an average oil droplet size of less than 0.5 μm and a storage stability of at least 18 months. Sexual grease droplets.

¹⁾以魚油三酸甘油酯中脂肪酸的總重量計，EPA以及DHA的含量係55.5重量%。EPA與DHA的重量比為3：2。 ¹⁾ The content of EPA and DHA is 55.5 wt% based on the total weight of the fatty acid in fish oil triglyceride. The weight ratio of EPA to DHA is 3:2.

¹⁾以魚油三酸甘油酯中脂肪酸的總重量計，EPA以及DHA的含量係55.5重量%。EPA與DHA的重量比為3：2。 ¹⁾ The content of EPA and DHA is 55.5 wt% based on the total weight of the fatty acid in fish oil triglyceride. The weight ratio of EPA to DHA is 3:2.

¹⁾以魚油三酸甘油酯中脂肪酸的總重量計，EPA以及DHA的含量係55.5重量%。EPA與DHA的重量比為3：2。 ¹⁾ The content of EPA and DHA is 55.5 wt% based on the total weight of the fatty acid in fish oil triglyceride. The weight ratio of EPA to DHA is 3:2.

以一中風模式進行實驗 Experiment with a stroke mode

為確定本發明之乳劑於治療中風後之神經傷害的效果，係分析表4中所表現的乳劑。 To determine the effect of the emulsion of the present invention on the treatment of nerve damage following stroke, the emulsions presented in Table 4 were analyzed.

表4 ¹⁾中鏈三酸甘油酯 ²⁾以魚油三酸甘油酯中脂肪酸的總重量計，EPA以及DHA的含量係55.5重量%。EPA與DHA的重量比為3：2。 Table 4 ¹⁾ Medium chain triglyceride ²⁾ The content of EPA and DHA is 55.5% by weight based on the total weight of the fatty acid in fish oil triglyceride. The weight ratio of EPA to DHA is 3:2.

用以確定本發明之乳劑之效果的中風模式係描述於J.Dong等人的文獻(Brain,Behavior,And Immunity.2011,25：715-726)中。 The stroke pattern used to determine the effect of the emulsion of the present invention is described in J. Dong et al. ( Brain, Behavior, And Immunity. 2011, 25: 715-726).

方法method 動物以及一般雄性威斯達大鼠(Wistar rat)中的實驗性暫時性大腦中動脈阻塞(transient middle cerebral artery Experimental transient middle cerebral artery in animals and in general male Wistar rats (transient middle cerebral artery) occlusion，tMCAO)程序Occlusion, tMCAO) program

雄性威斯達大鼠(將近300公克，3個月大，德國查理斯河公司)係於一無病原的環境下維持。根據歐盟實驗動物學會(Federation of European Laboratory Animal Science Association)的建議，動物每週接受一次例行性鼠籠維護以及微生物的監測。 Male Wistar rats (nearly 300 grams, 3 months old, Charles River, Germany) were maintained in a pathogen free environment. According to the recommendations of the Federation of European Laboratory Animal Science Association, animals receive weekly routine cage maintenance and microbiological monitoring.

食物以及水係任意採食。研究以及動物照料程序係經地方政府動物照料中心評審委員會(德國北萊茵-威斯特法倫)認可。以5%麻醉劑麻醉動物(德國路德維希港亞培公司)，並以面罩維持麻醉劑於1.5至2.5%(依照個別的動物及操作步驟)。左總頸動脈(common carotid artery，CCA)、內頸動脈(internal carotid artery，ICA)、以及外頸動脈(external carotid artery，ECA)係於頸中部切開後暴露出來。接著，將最接近的ECA與CCA連接起來，盡可能小心地維持迷走神經(vagus nerve)。其後，由氣管分枝部(bifurcation)前的CCA內腔，將一市售的導管(朝日經皮冠狀動脈血管成形術導引管柔軟型，德國亞培血管醫療器材部)置入末端ICA中，直到用手感受到阻力。因此，以導管的頂端阻塞大腦中動脈(middle cerebral artery，MCA)的原點，以獲得一滴與基準值相較，係大於50%的大腦血流量(Cerebral blood flow，CBF)(參見下方)。於整個手術的程序中，以加熱墊以及加熱燈將體溫維持在37至37.5℃。1小時後，將導管抽出，並開始再灌流期間。接著，將暴露的血管小心地連接起來以防止流血，切口無菌地癒合，並將動物放回牠們的籠子中。23小時後，以5%麻醉劑將大鼠深度麻醉，並進行組織染色、 分子分析、以及動物行為測試。 Food and water are eaten at will. Research and animal care procedures are accredited by the Local Government Animal Care Center Review Board (North Rhine-Westphalia, Germany). The animals were anesthetized with 5% anesthesia (Abbott, Ludwigshafen, Germany) and the anesthetic was maintained at 1.5 to 2.5% with a mask (according to individual animals and procedures). The left common carotid artery (CCA), the internal carotid artery (ICA), and the external carotid artery (ECA) are exposed after the mid-neck section is incision. Next, connect the closest ECA to CCA and maintain the vagus nerve as carefully as possible. Thereafter, a commercially available catheter (softening type of the aorta percutaneous coronary angioplasty catheter, German Abbott Vascular Medical Device Department) was placed at the end ICA by the CCA lumen before the bifurcation. In the middle, until the resistance is felt by hand. Therefore, the origin of the middle cerebral artery (MCA) is blocked by the tip of the catheter to obtain a drop of Cerebral blood flow (CBF) greater than 50% compared to the baseline value (see below). The body temperature was maintained at 37 to 37.5 ° C with a heating pad and a heat lamp throughout the procedure. After 1 hour, the catheter was withdrawn and reperfusion was started. The exposed blood vessels are then carefully joined to prevent bleeding, the incisions are aseptically healed, and the animals are returned to their cages. After 23 hours, the rats were deeply anesthetized with 5% anesthesia and tissue staining was performed. Molecular analysis, and animal behavior testing.

荷爾蒙以及油型乳劑之製備及其應用Preparation of hormones and oil emulsions and their applications

乳劑之應用以及採血 Application of emulsion and blood collection

如表4所述之乳劑，係於tMCAO開始12小時後，透過永久型頸靜脈導管1而應用。 The emulsion as described in Table 4 was applied through the permanent jugular vein catheter 1 12 hours after the start of tMCAO.

為靜脈採血以及乳劑的應用，係由總結締組織以及腹側頸區的肌膜製備而將右頸外靜脈外部化。 For venous blood collection and application of the emulsion, the right external jugular vein is externalized by summarizing the sarcolemmal preparation of the tissue and the ventral neck region.

由小切口進入靜脈後，該頸導管(美國加州庫比蒂諾Alzet公司，大鼠頸導管)的頂端係遠側進入約1至1.5毫米。將2毫米的靜脈吻部與導管切口旁邊的鬆散末端永久地連接起來。該導管係保持在位置上，直到實驗結束(24小時後犧牲)。 After entering the vein from a small incision, the apex of the neck catheter (Alzet, Calif., Rat, USA) has a distal apex of about 1 to 1.5 mm. The 2 mm venous snout is permanently connected to the loose end next to the catheter incision. The catheter was held in position until the end of the experiment (sacrificed after 24 hours).

所有的注射係以一微幫浦系統(德國Aesculap公司)緩慢地進行500微升體積的注射3分鐘。為避免頸靜脈中導管頂部的凝聚作用(coagulation)，該導管係經高倍稀釋的肝抗凝血素(以生理氯化鈉稀釋1000倍)浸灌。 All injections were slowly injected in a 500 microliter volume for 3 minutes using a micro pump system (Aesculap, Germany). To avoid coagulation of the top of the catheter in the jugular vein, the catheter was infused with a high-dilution of hepatic anticoagulant (diluted 1000 times with physiological sodium chloride).

所有使用的溶液係於應用之前加熱至體溫(38℃)。 All solutions used were heated to body temperature (38 ° C) prior to application.

荷爾蒙(17-β***以及助孕酮)係製備溶解於100%酒精中作為儲備原液(stock solution)，並進一步稀釋於提供的乳劑(實施例1至3)中。 The hormone (17-beta estradiol and progesterone) was prepared to be dissolved in 100% alcohol as a stock solution and further diluted in the provided emulsion (Examples 1 to 3).

每個應用的類固醇結果劑量係：助孕酮(德國，Sigma-Aldrich)：10毫克/公斤體重；17-β***(德國，Sigma-Aldrich)25微克/公斤體重。 The steroidal dose range for each application: progesterone (Sigma, Sigma-Aldrich): 10 mg/kg body weight; 17-beta estradiol (Germany, Sigma-Aldrich) 25 μg/kg body weight.

具有或不具有荷爾蒙的乳劑係於tMCAO開始1小時以及12小時後應用。 Emulsions with or without hormones were applied 1 hour and 12 hours after the start of tMCAO.

除乳劑之外，製備一不含脂質之含有荷爾蒙之氯化鈉/酒精溶液(氯化鈉/酒精***/助孕激素，NaCl/EtOHEstrogen/Progestogen(NaCl/EtOH E/P))。再一次，將荷爾蒙溶解於酒精中以製備一儲備溶液。進一步將該儲備溶液稀釋於鹽水(氯化鈉)中，以達成如上所示乳劑相同之應用體積(500微升)以及劑量規範。 In addition to the emulsion, a lipid-free sodium chloride/alcohol solution containing a hormone (sodium chloride/alcoholic estrogen/progestin, NaCl/EtOHEstrogen/Progestogen (NaCl/EtOH E/P)) was prepared. Again, the hormone is dissolved in alcohol to prepare a stock solution. The stock solution was further diluted in saline (sodium chloride) to achieve the same applied volume (500 microliters) of emulsion as indicated above and the dosage specification.

局部大腦血流量(regional cerebral blood flow，rCBF)的估計Estimation of regional cerebral blood flow (rCBF)

為確保一適當的MCAO，於大腦局部缺氧期間，使用一雷射多普勒微流儀(Laser-Doppler flowmetry，LDF)，測定MCA的局部腦灌流(regional cerebral perfusion)。 To ensure a proper MCAO, regional cerebral perfusion of MCA was measured using a laser-Doppler flowmetry (LDF) during partial hypoxia of the brain.

因此，每一動物均接受開顱手術，以於接近後囪門3至5毫米以及中部側面4毫米的完整硬腦膜(dura mater)上，放置一2毫米的雷射多普勒探針(瑞典Perimed公司，PeriFlux System 5000，Type PF 5001)。將導管***ICA之前，直接進行基準線測定，每10分鐘紀錄一次MCA的rCBF，並計算其平均值。只有rCBF減少至少50%(平均值)的動物將進一步進行研究，因為沒有可被肯定的適當的氧氣供應不足/梗塞，必須將其餘動物排除在研究之外。 Therefore, each animal undergoes a craniotomy to place a 2 mm laser Doppler probe on a complete dura mater close to the posterior canal 3 to 5 mm and the central side 4 mm (Sweden) Perimed, PeriFlux System 5000, Type PF 5001). Before inserting the catheter into the ICA, perform a baseline measurement directly, record the rCBF of the MCA every 10 minutes, and calculate the average value. Animals with a reduction in rCBF of at least 50% (average) will be further studied because there is no adequate oxygen supply/infarction that can be affirmed and the remaining animals must be excluded from the study.

動物分析Animal analysis

一般而言，所有分析皆於單盲方式下進行。於此「單 盲」意即，進行應用的乳劑之製備、tMCAO手術、以及所有乳劑應用的第一實驗者知道所測試的藥物，該第一實驗者係將動物編號。操作行為測試、心搏排血量分析的第二實驗者則完全不知道編號，僅操作以加密的數字標定的動物。該第二實驗者進行分析以及數學/統計評估，並回覆數據給的第一實驗者，第一實驗者會分配數據所對應的動物/治療。 In general, all analyses were performed in a single-blind manner. Here "Blind" means that the first experimenter who applied the applied emulsion preparation, tMCAO surgery, and all emulsion applications knew the drug being tested, and the first experimenter numbered the animals. The second experimenter who performed the behavioral test and the cardiac output analysis did not know the number at all, and only operated the animals calibrated with the encrypted number. The second experimenter performs an analysis and a mathematical/statistical evaluation, and replies to the first experimenter of the data, and the first experimenter assigns the animal/treatment corresponding to the data.

測定梗塞體積(infarct volume)Infarct volume

相對於設置為100%之未經保護之tMCAO動物的總梗塞體積，該梗塞體積的數據係以百分比改變表示，這提供一目了然之較佳保護程度。 The infarct volume data is expressed as a percentage change relative to the total infarct volume of 100% unprotected tMCAO animals, which provides a better level of protection at a glance.

為精確計算該梗塞體積，係採用TTC染色法(2,3,5-triphenyltetrazolium chloride staining method)。以大鼠腦定位儀(奧圖腦定位儀，不鏽鋼1毫米大鼠冠狀300-600 GM，哈佛儀器)快速的將大腦切割成厚度為2毫米的冠狀薄片。於37℃下，將薄片置於2%TTC溶液中15分鐘。活組織染成紅色，該梗塞組織則未染色並保持灰白色。該薄片係於TTC染色後冷凍保存。TTC染色薄片的影像係由Canon數位相機IXUS 9015存取。加入各薄片的平均面積並乘上2毫米(薄片的厚度)以計算總皮質梗塞體積。以方程式：校正體積(皮質梗塞體積×完整的對側體積)/完整的同側體積，進行梗塞體積的水腫校正。自損傷的對側腦半球減去同側體積，以計算該水種體積(Garcia等人的文獻，Stroke.1995,26：627-634)。以無存取軟體的裝置(美國ImageJ 1.41)進行測定。 To accurately calculate the infarct volume, a 2,3,5-triphenyltetrazolium chloride staining method was used. The rat brain aligner (Otto brain locator, stainless steel 1 mm rat crown 300-600 GM, Harvard instrument) was used to rapidly cut the brain into a 2 mm thick coronal slice. The flakes were placed in a 2% TTC solution for 15 minutes at 37 °C. The living tissue was stained red and the infarcted tissue was unstained and remained grayish white. The sheet was cryopreserved after TTC staining. The image of the TTC stained sheet was accessed by the Canon digital camera IXUS 9015. The average area of each sheet was added and multiplied by 2 mm (thickness of the sheet) to calculate the total cortical infarct volume. The edema correction of the infarct volume was performed by equation: corrected volume (cortical infarct volume x intact contralateral volume) / intact ipsilateral volume. The ipsilateral volume is subtracted from the injured contralateral hemisphere to calculate the water species volume (Garcia et al., Stroke. 1995, 26: 627-634). The measurement was carried out in a device without access software (ImageJ 1.41, USA).

行為測試Behavioral test

犧牲動物以前，根據並稍作修飾Garcia等人的文獻(Stroke.1995,26：627-634)，對研究中所有大鼠進行簡單的行為測試(Garcia Neuroscoring)。進行六個獨立的行為測試，以1至3分評等，最高18分。評估該等下列行為：自發活性、前腳伸展、以及攀爬的能力、對鈍棒的本體感覺、本體感覺(觸鬚觸碰)、自發走動。一般而言，為損傷的操作組或偽操作組的動物係為18分，相較之下，tMCAO組的動物為平均大約6分。 Prior to sacrificing animals, a simple behavioral test (Garcia Neuroscoring) was performed on all rats in the study according to and slightly modified the literature of Garcia et al. ( Stroke . 1995, 26: 627-634). Conduct six independent behavioral tests, rating 1 to 3 points, up to 18 points. Evaluate these behaviors: spontaneous activity, forefoot extension, and the ability to climb, the proprioception of the blunt stick, the proprioception (touch of the touch), spontaneous movement. In general, the animal system for the injured or pseudo-operational group was 18 points, compared to an average of about 6 points for the animals in the tMCAO group.

該中風模式的測試結果係表現於第1圖及第2圖。 The test results of this stroke mode are shown in Figures 1 and 2.

於該等圖式中使用下列縮寫： The following abbreviations are used in these figures:

氯化鈉/酒精 ***/助孕激素 靜脈注射(NaCl/EtOH E/P i.v.)：係如上述之含有荷爾蒙的氯化鈉/酒精溶液，經靜脈注射投與。 Sodium chloride/alcoholic estrogen/progesterone intravenously (NaCl/EtOH E/P iv) : is administered as a calcium chloride/alcohol solution containing hormone as described above and administered intravenously.

力保肪寧 MCT ***/助孕激素 靜脈注射(Lipofundun MCT E/P i.v.)：係根據如上述之表4中實例1之含有荷爾蒙的乳劑，並經靜脈注射投與。 Li Bao Ning MCT estrogen/progestin-drug intravenous (Lipofundun MCT E/P iv) : according to the hormone-containing emulsion of Example 1 in Table 4 above, and administered intravenously.

5/5 乳劑 靜脈注射(5/5 emulsion i.v.)：係根據實例2之不含荷爾蒙的乳劑，並經靜脈注射投與。 5/5 Intravenous emulsion (5/5 emulsion iv) : A hormone-free emulsion according to Example 2, administered intravenously.

5：5 乳劑 ***/助孕激素 靜脈注射(5：5 emulsion E/P i.v.)：係根據如上述之表4中實例2之含有荷爾蒙的乳劑，並經靜脈注射投與。 5:5 Emulsion estrogen/progesterone intravenous (5:5 emulsion E/P iv) : According to the hormone-containing emulsion of Example 2 in Table 4 above, and administered intravenously.

9：1 乳劑 靜脈注射(9：1 emulsion i.v.)：係根據實例3之不含 荷爾蒙的乳劑，並經靜脈注射投與。 9:1 Intravenous emulsion (9:1 emulsion iv) : A hormone-free emulsion according to Example 3, administered intravenously.

9：1 乳劑 ***/助孕激素 靜脈注射(9：1 emulsion E/P i.v.)：係根據如上述之表4中實例3之含有荷爾蒙的乳劑，並經靜脈注射投與。 9:1 emulsion estrogen/progestin intravenous (9:1 emulsion E/P iv) : according to the hormone-containing emulsion of Example 3 in Table 4 above, and administered intravenously.

由結果可知，與荷爾蒙助孕激素以及***一起使用的富含ω-3脂肪酸的魚油乳劑(實例2以及實例3)，展現了協同作用以及意外的效果。 From the results, it was revealed that the omega-3 fatty acid-rich fish oil emulsion (Example 2 and Example 3) used together with the hormone progestin and estrogen exhibited synergistic effects and unexpected effects.

Claims (15)

一種非經口投與之含有荷爾蒙的水包油型乳劑，其係包含：a)助孕激素(progestogen)及/或***(estrogen)；以及b)魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸重量之至少45%的二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)。 A non-orally administered hormone-containing oil-in-water emulsion comprising: a) a progestogen and/or an estrogen; and b) a fish oil triglyceride, wherein the fish oil The triglyceride is composed of a fatty acid esterified glycerol, wherein the fatty acid comprises eicosapentaenoic acid (EPA) and docosahexaenoic acid in an amount of at least 45% by weight of the fatty acid. (DHA). 如請求項1所述之含有荷爾蒙的水包油型乳劑，進一步包含中鏈三酸甘油酯(medium chain triglycerides，MCT)。 The hormone-containing oil-in-water emulsion according to claim 1, further comprising medium chain triglycerides (MCT). 如請求項1或2所述之含有荷爾蒙的水包油型乳劑，其中以油成分的總重量計，該魚油三酸甘油酯係以至少25重量%，較佳為至少35重量%，更佳為至少50重量%，尤其為至少75重量%，以及特別為至少85重量%的含量存在。 The hormone-containing oil-in-water emulsion according to claim 1 or 2, wherein the fish oil triglyceride is at least 25% by weight, preferably at least 35% by weight, more preferably, based on the total weight of the oil component. It is present in an amount of at least 50% by weight, in particular at least 75% by weight, and in particular at least 85% by weight. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中以油成分的總重量計，該乳劑係包含5至75重量%，較佳為10至55重量%，以及特別為15至45重量%的含量範圍之中鏈三酸甘油酯。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises from 5 to 75% by weight, preferably from 10 to 55% by weight, based on the total weight of the oil component, and The chain triglyceride is in the range of 15 to 45% by weight. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該乳劑係包含重量比較佳為2：1至500：1，更佳為2：1至200：1之助孕激素及***。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a weight ratio of preferably from 2:1 to 500:1, more preferably from 2:1 to 200:1. Progesterone and estrogen. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該乳劑係包含重量比範圍為1：1至9：1之魚油三酸甘油酯及中鏈三酸甘油酯。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises fish oil triglyceride and medium chain triglyceride in a weight ratio ranging from 1:1 to 9:1. . 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳 劑，其中，該乳劑係包含***(estradiol)及/或助孕激素。 Hormone-containing oil-in-water emulsion as described in one or more of the preceding claims And the emulsion comprises estradiol and/or progestogen. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該乳劑係包含其含量範圍為0.15至12公克/公升之助孕激素及/或其含量範圍為0.015至1.5公克/公升之***。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a progestin having a content ranging from 0.15 to 12 g/liter and/or a content ranging from 0.015 to 1.5 G/L of estradiol. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，以該經酯化脂肪酸的總含量計，ω-3脂肪酸的總含量為至少50重量%，較佳為至少55重量%，更佳為至少60重量%，以及最佳為至少65重量%。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the fish oil triglyceride is composed of a fatty acid esterified glycerol, wherein the total of the esterified fatty acid is The total content of omega -3 fatty acids is at least 50% by weight, preferably at least 55% by weight, more preferably at least 60% by weight, and most preferably at least 65% by weight. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該乳劑係包含選自以下所組成群組之乳化劑：蛋卵磷脂、大豆卵磷脂、衍生自海洋甲殼動物之磷脂質及其混合物。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises an emulsifier selected from the group consisting of egg lecithin, soy lecithin, derived from marine crustaceans Phospholipids and mixtures thereof. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其中，該乳劑係包含磷脂質，該磷脂質係包含ω-3脂肪酸部分，較佳為自磷蝦(磷蝦目(Euphausiacea))獲得之磷脂質。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a phospholipid comprising an omega-3 fatty acid moiety, preferably from krill (Krill (Euphausiacea)) obtained phospholipids. 如前述請求項之一或多項所述之含有荷爾蒙的水包油型乳劑，其係包含：a)其含量範圍為1.0至2.0公克/公升之助孕激素及/或其含量範圍為0.05至1.0公克/公升之***；b)以該水包油型乳劑計，100至300公克/公升的油成分，其係包含：i)以該油成分之總重量計，至少50重量%之魚油三酸甘油酯，其中，該魚油三酸甘油酯係由經脂肪酸酯化之甘油所組成，其中，該脂肪酸係包含其含量為該脂肪酸 重量之至少45%的二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)，以及較佳ω-3脂肪酸的總含量為該脂肪酸重量的至少50%；以及ii)以該油成分之總重量計，10至50重量%之中鏈三酸甘油酯；c)4至20公克/公升之磷脂質；以及d)10至50公克/公升之甘油。 A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, which comprises: a) a progestin having a content ranging from 1.0 to 2.0 g/l and/or a content ranging from 0.05 to 1.0克/L of estradiol; b) 100 to 300 g/L of oil component based on the oil-in-water emulsion, comprising: i) at least 50% by weight of fish oil based on the total weight of the oil component a triglyceride, wherein the fish oil triglyceride is composed of a fatty acid esterified glycerol, wherein the fatty acid comprises eicosapentaenoic acid (EPA) in an amount of at least 45% by weight of the fatty acid. And docosahexaenoic acid (DHA), and preferably the total content of the omega -3 fatty acid is at least 50% by weight of the fatty acid; and ii) from 10 to 50% by weight based on the total weight of the oil component Medium chain triglyceride; c) 4 to 20 grams per liter of phospholipid; and d) 10 to 50 grams per liter of glycerol. 一種醫藥組合物，其係包含如前述請求項之一或多項所述之水包油型乳劑、或係由如請求項之一或多項所述之水包油型乳劑所組成。 A pharmaceutical composition comprising an oil-in-water emulsion as claimed in one or more of the preceding claims, or an oil-in-water emulsion as claimed in one or more of the claims. 如請求項13所述之醫藥組合物，其係用於治療或預防中風及/或創傷後之神經傷害。 The pharmaceutical composition according to claim 13 for use in the treatment or prevention of nerve damage after stroke and/or trauma. 如請求項13所述之醫藥組合物，其係用於治療或預防腦震盪後之神經傷害，或用於治療或預防創傷性事件。 The pharmaceutical composition according to claim 13, which is for treating or preventing nerve damage after a concussion, or for treating or preventing a traumatic event.