TW201334808A - Hormone containing emulsion comprising krill phospholipids - Google Patents

Abstract

The invention relates to hormone containing oil-in-water emulsion for parenteral administration comprising progestogen and/or estrogen; a phospholipid comprising one or two omega-3 fatty acid moieties; and an oil as well as a pharmaceutical composition comprising or consisting of said oil-in-water emulsion. The pharmaceutical is especially for use in the treatment or prophylaxis of neurological damage after strokes and/or trauma and/or for use in the treatment or prophylaxis of neurological damage after concussion and/or traumatic injury to the central nervous system.

Description

An emulsion containing krill phospholipids containing hormones

The present invention relates to a hormone-containing oil-in-water emulsion for parenteral administration comprising a progestogen and/or an estrogen, a phospholipid comprising one or two omega-3 fatty acid moieties The present invention also relates to a pharmaceutical composition comprising the aforementioned oil-in-water emulsion or consisting of the aforementioned oil-in-water emulsion, which is particularly useful for treating or preventing stroke and/or Or post-traumatic nerve damage, and / or used to treat or prevent neurological damage after concussion and / or traumatic injury of the central nervous system.

Krill has been used as an important source of omega-3 fatty acids for humans over the past decade, and sales of krill in the international market are rapidly increasing. Traditional omega-3 supplements on the market today rely on omega-3 fatty acids linked to triglycerides (such as cod liver oil and fish oil) or ethyl esters containing a high proportion of omega-3 fatty acids linked to phospholipids. Krill oil.

There are many preclinical studies and clinical research departments that explore krill oil, and there is increasing evidence that the molecular form of omega-3 fatty acids (ie, triglycerides, ethyl esters, phospholipids) versus omega-3 The biological effects of fatty acids in the body and Distribution can be very important. It has been demonstrated in an animal study that krill oil and fish oil are administered together with an equimolar dose of Eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA). In Zucker rats, krill oil has a higher specificity than fish oil and, in some cases, fish oils associated with metabolic symptoms. Rats fed krill oil had significantly lower amounts of oil in the heart and liver than rats fed fish oil. The authors believe that this difference may be related to the difference in the distribution of omega-3 fatty acids in the cell membrane, and that the subsequent inflammatory molecules and endocannabinoids are reduced, and may also be related to the observed differences between krill oil and fish oil. In addition, the same study has confirmed that the amount of DHA in the brain is significantly increased after administration of krill oil compared to the control group, but does not increase after administration of fish oil. Therefore, the distribution of omega-3 fatty acids attached to phospholipids in the body may be different compared to omega-3 fatty acids in other molecular forms. In the clinical safety study, EPA and DHA were detected in plasma after 4 weeks of administration of 2 g of krill oil or 2 g of cod oil per day.

Traumatic brain injury (TBI) is a non-degenerate, non-congenital, temporary or permanent 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.

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 and that progesterone can reduce mortality after treatment of TBI patients. In addition, the patent application WO2006/102644, WO2006102596, WO2008/039898, US 2011/0262494 and US 2011/0262495 outline a method of orally administering progestogen to treat TBI.

In addition, Alkayed et al., Stroke 31, 161 (2003), describe the positive effects of subcutaneous administration of estrogen and progesterone in stroke patients.

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.

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.

The most effective route of administration of progestogens (eg progesterone) and/or estrogens (eg estradiol) is non-oral (eg intravenous administration) And the way. However, due to the low solubility of progesterone and/or estradiol molecules in water, and the limitations of current formulations, aqueous solutions do not provide effective treatment for delivery of progesterone and/or estradiol. The dosage is given 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.

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 mixture It is briefly mixed (eg, shaken) manually before being administered via the vein. This preparation method has the following disadvantages: First, it is not ideal to administer alcohol solution to patients with TBI; second, although the presence of alcohol increases the solubility of progesterone and/or estradiol, low cut (low) Manual mixing of shear does not allow all progesterone/estradiol to enter 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.

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.

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 and mixed a few hours before use) because 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).

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 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, sputum. Measles and allergic reactions (pruritic dermatitis, erythema).

It is known in the art to use an organic solvent to increase the solubility of progesterone and/or estradiol in an oil emulsion. Progesterone is highly soluble in benzoic acid or a derivative thereof. For example, JP 60-258110 describes the use of benzyl benzoate to increase the solubility of progesterone in oil-and-fat 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.

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.

Surprisingly, it has been discovered that the prior art problem can be solved by a non-orally administered hormone-containing oil-in-water emulsion comprising progestogen and/or estrogen, oil, and one or more, especially It is a phospholipid of one or two omega-3 fatty acid moieties.

definition:

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. Unless otherwise stated herein, the term "oil" as used herein does not include phospholipids.

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) as small droplets. (discrete phase).

As used herein, the term "phospholipid" refers to a glyceride having one or two fatty acids and a phosphate group. In addition to glycerol-derived phospholipids, the term "phospholipid" as used herein also encompasses sphingomyelin.

As used herein, the term "aqueous medium" means a liquid containing water.

The singular forms "a", "the" and "the"

As used herein, the term "therapeutically effective amount" refers to a drug dose that provides a particular medicinal response when administered to a subject in need of treatment. It is also emphasized that a therapeutically effective amount or level of treatment of a drug is not limited to being effective in treating the condition/disease 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 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.

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).

Photon Correlation (Photon Correlation) Spectroscopy, PCS) refers to PCS measured by the Zetasizer 1000 HAS (Malvern Instruments) method described in Method I of Chapter 729 of the United States Pharmacopoeia United States Pharmacopoeia, USP.

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).

As used herein, "zeta-potential" refers to the electrokinetic potential measured experimentally using a Zetasizer 1000 HAS (Malvern instrument) in a colloidal system.

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).

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; b) an emulsifier (emulsifer), Containing a phospholipid comprising one or two omega-3 fatty acid moieties or consisting of a phospholipid comprising one or two omega-3 fatty acid moieties; c) oil.

The oil-in-water emulsion of the present invention comprises an oil phase and an aqueous phase.

The oil-in-water emulsion of the present invention comprises a progesterone and/or an estrogen as an active pharmaceutical ingredient (API).

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; 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.

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.

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.

In a specific embodiment, the progestogen is selected from the group consisting of 5-α-dihydroprogesterone, medroxyprogesterone, dehydroprogesterone, and progesterone and/or a mixture thereof .

In another embodiment, the progestogen is selected from the group consisting of pregnelonone, progesterone, medroxyprogesterone, and pharmaceutically acceptable derivatives thereof.

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.

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.

Progesterone (eg any progestin, including progesterone) can Its pharmaceutically acceptable salt form is suitable for use in the present invention.

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.

In a preferred embodiment, the oil-in-water emulsion comprises a progestogen at a level of from 0.15 to 12 grams per liter.

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.

According to an alternative embodiment of the invention, the oil-in-water emulsion comprises one or more estrogens.

In a preferred embodiment, the emulsion comprises estriol (1,3,5(10)-estratriene-3,16α,17β-triol) of the following formula III:

In another embodiment, the emulsion comprises estradiol (1,3,5(10)-estratriene-3,17β-diol) of the following formula IV:

In another embodiment, the emulsion comprises an estrone of the following formula V:

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.

Particularly preferred is estradiol.

The estrogen is preferably from 0.015 to 5 g/liter, more preferably from 0.015 to 1.5 g/L, and most preferably from 0.05 to 0.3 g/L (per liter) in the oil-in-water emulsion. The content of grams is present.

In a preferred embodiment, the emulsion comprises a content of From 0.015 to 1.5 g/l, preferably from 0.05 to 1 g/l, more preferably from 0.08 to 0.5 g/l, especially from 0.1 to 0.3 g/l estradiol.

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 more preferably 10: 1 to 20:1.

Preferably, the oil-in-water emulsion comprises estradiol and/or progesterone.

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.

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.

The oil used in the oil-in-water emulsion of the present invention may be any oil or oil mixture suitable for intravenous administration.

Preferred are oils derived from plants or animals. In a preferred embodiment of the invention, the oil is selected from the group consisting of vegetable oils and/or aquatic oils.

Preferred vegetable oils are soybean oil and safflower seed oil.

Vegetable oil, especially oil of soybean and safflower, characterized by high The content of omega-6 polyunsaturated fatty acids (mainly linolic acid, 18:2 ω-6), while its omega-3 fatty acids (actually, only alpha-linolenic acid (α-linolenic) Acid), 18:3 ω-3) is low in content.

A preferred aqueous oil is selected from the group consisting of fish oil. Fish oil obtained from cold water fish, characterized by high levels of polyunsaturated fatty acids (mainly eicosapentaenoic acid, EPA, 20:5 ω-3; and docosahexaenoic acid, DHA, 22: 6 omega-3), while its omega-6 fatty acid content is low. For example, suitable fish oils are commercially available in large quantities from cold water fish. In general, fish oils are triglycerides containing fatty acids having from 12 to 22 carbon atoms. For example, highly purified fish oil concentrates obtained from sardine oil, salmon oil, salmon oil and/or salmon oil are particularly preferred.

In one aspect of the invention, the oil-in-water emulsion comprises a vegetable oil, preferably a medium chain triglycerides (MCT). In another aspect of the invention, the oil-in-water emulsion comprises fish oil and MCT, and optionally a vegetable oil different from MCT. In another alternative embodiment, the oil is different from the vegetable oil of MCT, and/or the aquatic oil, and additionally comprises medium chain triglyceride (MCT).

In a preferred embodiment of the present invention, the oil phase of the oil-in-water emulsion comprises fish oil triglyceride, wherein the fish oil triglyceride is esterified by fatty acid. Composition, 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 the total content of omega-3 fatty acids is Preferably at least 50% by weight of the fatty acid, more preferably at least 55% by weight, and most preferably at least 60% by weight, And preferably at least 65% by weight.

In the European Pharmacopeia (EP), there are two monographs EP1352 and EP1912 on fish oil that can be used in non-oral emulsions. The topics are "omega-3 acid triglyceride" and "fish oil, rich". Containing 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 omega-3 fatty acids in an amount 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.

According to the present invention, the fish oil triglyceride comprises, by weight of all omega-3 fatty acid content, eicosapentaenoic acid having a content of 30% or more, and the content thereof is 30% or less. Doctopentaenoic acid, and an omega-3 fatty acid composed of docosapentaenoic acid (DPA) in an amount of 40% or less.

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%.

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 comprises 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. Individual doses, such as the total daily dose of docosapentaenoic acid (DPA), can range from 0 to 300 mg/kg of formula, for example 50 To 250 mg / kg, for example 100 to 200 mg / kg. For example, EPA, DHA, and/or DPA can be present in an amount effective to provide neuroprotection of a vital organ.

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.

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. .

According to a preferred embodiment of the invention, the oil-in-water emulsion additionally comprises medium chain triglycerides (MCT).

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 MCTs, the amount of esterified omega-3 fatty acid delivered to the human body can be increased. For example, using the 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 human body while still achieving beneficial metabolic clearance and physicochemical stability characteristics of the emulsion.

For example, the MCT can comprise a saturated medium chain fatty acid, such as a plurality of saturated medium chain fatty acids. In a specific embodiment of the demonstration, the MCT system is A triglyceride having a fatty acid of 6 to 12 carbon atoms. The MCT is derived from a plant such as a vegetable, such as a plurality of plants. The MCT may contain an 8 carbon saturated fatty acid (8:0), caprylic acid (e.g., a content of from about 50% to about 80% by weight of the 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 triglycerides in an amount of at least 90% caprylic acid and capric acid in an amount of 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).

The oil system 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).

According to a preferred embodiment of the present invention, the emulsion comprises an MCT composed of a fatty acid esterified glycerin, comprising at least 50% by weight of a fatty acid selected from the group consisting of fatty acids having 7, 9 and 11 carbon atoms. The group formed.

The combination of MCT and fish oil triglyceride as defined above is an advantage of the oil-in-water emulsion of the present invention.

According to a preferred embodiment of the present invention, each of the oil components The oil-in-water emulsion comprises a chain triglyceride in an amount of from 5 to 75% by weight, preferably from 10 to 55% by weight, especially from 15 to 45% by weight, based on the total weight.

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.

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.

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.

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.

In a more specific embodiment, the oil phase additionally comprises long-chain triglycerides (LCT).

In certain embodiments, the oil can comprise a vegetable oil. "Vegetable oil" means an oil derived from the seeds or nuts of a plant. 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 specific implementations In the sample, a vegetable oil of high purity grade (also referred to as "super-refining") is used to ensure the safety and stability of the oil-in-water emulsion. In certain embodiments, hydrogenated vegetable oils produced by the hydrogenation of controlled vegetable oils may be used.

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.

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.

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.

High amounts of omega-3 fatty acid residues were found to enhance the effects of hormone-treated patients. Thus, in accordance with certain embodiments of the present invention, the oil-in-water emulsion The agent is substantially free of vegetable oil and/or oil other than fish oil and MCT. By substantially no meaning in the context of the invention is meant that the content is less than 10% by weight, preferably less than 5% by weight, more preferably less than 2% by weight, especially less than 1% by weight, based on the total weight of the emulsion. For example, less than 0.1% by weight.

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. .

Differently manifested, in a specific embodiment, the emulsion contains no more than 30%, including no more than 20%, no more than 10%, or no more than 5% of phospholipids, polar modifiers, which are selected From the following groups: monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides, and/or mixtures of the foregoing. The use of a polar modifier having a high concentration relative to the phospholipid content in the emulsion may have side effects on the stable properties of the phospholipid.

In certain embodiments, a substantial proportion of progestogen and/or estrogen is included in the oil droplets of the oil-in-water emulsion. In certain embodiments, more than 80% of the progestogen and/or estrogen are dissolved and retained in the oil droplets. In some embodiments, more than 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% of progestogen and/or estrogen is dissolved. to In the oil phase (measured at 20 ° C).

The oil-in-water emulsion of the present invention comprises an emulsifier comprising a phospholipid comprising one or two omega-3 fatty acid moieties or a phospholipid comprising a moiety comprising one or two omega-3 fatty acids Quality composition.

The oil-in-water emulsion of the present invention preferably comprises an emulsifier which is present in an amount of up to 20 g/l, preferably 2 to 15 g/l.

The emulsifier may additionally comprise other lecithins, preferably naturally occurring lecithins such as soy lecithin, egg lecithin, sunflower oil lecithin, sphingosine, ganglioside , phytosphingosine, and combinations thereof. Hydrogenated lecithin, a product of the regulated hydrogenation of lecithin, can also be used in addition to the emulsifier.

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 one or more omega-3 fatty acid moieties. The phospholipid component of the composition is a single phospholipid or a mixture of a plurality of phospholipids. The phospholipids used may be natural or synthetic, but should be acceptable for parenteral administration, especially intravenous injection.

A not-to-be-listed list of suitable phospholipids that may be additionally present in the emulsifier is as follows: phosphatidic acid , including 1,2-Dimyristoyl-sn-glycero-3- phosphatidic acid, sodium salt, DMPA -Na), 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid (sodium salt, DPPA-Na), distearyl phospholipid sodium salt (1,2-Distearoyl- Sn-glycero-3-phosphatidic acid, sodium salt, DSPA-Na); phospholipid choline , including 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC), two flesh 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), di-hard 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC); phospholipid醯ethanolamine , including 1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine, DLPE), 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), dipalmitoside phospholipid, ethanolamine (1,2-Dip) Almitoyl-sn-glycero-3-phosphoethanolamine, DPPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); phosphoglycerol: including dilaurin phosphatidylglycerol Sodium salt (1,2-Dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt, DLPG-Na), 1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt, DMPG-Na), 1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonium salt, DMP-sn-1-G, NH4, dipalmitine 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt, DPPG-Na, distearoyl-sn-glycero-3-phosphoglycerol , sodium salt, DSPG-Na), distearoyl-sn-glycero-3-phospho-sn-1-glycerol, sodium salt, DSP-sn- 1G-Na); phosphosrine , including 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt, DPPS-Na; mixed chain phospholipids, including palm oil acyl phospholipid acyl Choline (1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC), palmetto oil, sodium phosphatidylglycerol (1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt, POPG-Na), palm oil acyl glycerol phosphate acyl ammonium salt (1-palmitoyl-2-oleoyl -sn-glycero-3-phosphoglycerol, ammonium salt, POPG-NH4); lysophospholipids (lysophospholipid), comprising palmitic acyl lysophospholipid Choline (1-Palmitoyl-2-lyso-sn-glycero-3-phosphocholine, P-lyso-PC), stearin lysophosphatidylcholine (1-Stearoyl-2-lyso-sn-glycero-3- phosphocholine, S-lyso-PC) ; phospholipid polyethylene glycol (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-methoxy polyethylene glycol 5000)-MPEG-5000-DSPE sodium salt (N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000 -DSPE, sodium salt), nitro-(carbonyl-methoxypolyethylene glycol 5000)-MPEG-5000-DPPE sodium salt (N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DPPE, sodium salt), Nitro-(carbonyl- Methoxy polyethylene glycol 750)-MPEG-750-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).

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 20 grams per liter, such as from 1 to 15 grams per liter.

In a further specific embodiment, the source of the phospholipid emulsifier is lecithin, such as krill phospholipids. According to the United States Pharmacopoeia (USP), lecithin is a non-owner's name, which is described mainly by phospholipid choline, phospholipid, ethanolamine, phospholipidylserine, and phospholipidinositol. A mixture of acetone-insoluble phospholipids composed of a combination of a substance such as triglyceride, a fatty acid, and a carbohydrate.

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, the amount is 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 grams per liter Litre, especially for 10 to 20 grams / liter, for example 11 to 15 grams / liter.

The emulsion comprises a phospholipid comprising an omega-3 fatty acid moiety, preferably a phospholipid obtained from krill (Euphausiacea).

In a preferred embodiment, the emulsion comprises phospholipids selected from the group consisting of phospholipid choline comprising one or two omega-3 fatty acid moieties, lysophospholipids comprising an omega-3 fatty acid moiety Choline, and mixtures thereof.

In one embodiment, the emulsion additionally comprises egg lecithin, which comprises 60% to 80% by weight, such as 67% by weight of phospholipid choline; 10% to 20% by weight, For example, 15% w/w phospholipid ethanolamine; 3% w/w or less, for example 2% w/g sphingomyelin; and 3% w/w or less, for example 1% w/g lysophospholipid Alkali.

"Fresenius Kabi AB" is an example of egg lecithin having such a phospholipid content.

Omega-3 fatty acid residues were found to improve the effects of hormones during treatment and prevention. Accordingly, the oil-in-water emulsion comprises a phospholipid having an omega-3 fatty acid moiety, preferably a phospholipid obtained from krill (Krill).

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 not substantially contain omega-3 fatty acids. Triglyceride. 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 a phosphate linked to an alcohol such as choline, ethanolamine, serine, inositol, etc., which significantly changes the molecule, giving it two characteristics of hydrophilicity and hydrophobicity. Also known as amphiphilic compounds. As part of a modified biomodel structure and exhibiting amphiphilic properties, PLs play an integral role in many metabolic processes.

In an exemplary embodiment, a predetermined amount of the phospholipid comprising an omega-3 fatty acid comprises an omega-3 fatty acid that is attached to the first and second positions of the phospholipid but not to the 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 -3 fatty acid, which may be present at a level of from about 70% to about 80%, for example from about 80% to about 95%.

According to another exemplary aspect, there is provided a method of parenterally administering the oil-in-water emulsion, the method comprising: comprising a non-orally aqueous oil-in-water emulsion A composition of phospholipid obtained from marine crustaceans is administered orally to a human body. The oil-in-water emulsion contains a protective concentration of the naturally occurring antioxidant astaxanthin to counteract the presence of unsaturation. Chemical disintegration or oxidation of omega-3 fatty acids. Oxidation of polyunsaturated omega-3 fatty acids can lead to the formation of reactive oxygen species, which can cause damage in the veins. 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. Therefore, as the aquaculture-based phospholipid system found in krill oil contains a high concentration of n3-FAs, it can uniquely enhance the physical stability of the emulsion, and therefore, there is shrimp red in krill oil. The pigment also uniquely enhances the chemical stability of the oil-in-water emulsion. As an exemplary aspect 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.

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 described above; and b) Phospholipids obtained from marine crustaceans as described above.

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) polyethylene glycol-pentadecyl stearate (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.

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.

An oil-in-water emulsion according to the present invention may comprise one or more other therapeutic components (APIs), such as other neurotrophic and/or neuroprotective agents.

Aqueous medium

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.

The oil-in-water emulsion of the present invention may comprise from 70 to 98% by weight, preferably from 70 to 90% by weight, based on the total weight of the emulsion.

In several embodiments, the emulsion may comprise a physiologically compatible buffer at a concentration of from 0 to 4 millimolar.

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 capable of preventing flocculation and/or agglomeration of oil-and-fat emulsions. Use (coalescence). 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) 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.

In several embodiments, the co-surfactant may be present in the composition at a level greater than or equal to 0.005%, greater than or equal to 0.01%, or greater than or equal to 0.02% (weight/volume). 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%.

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.

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 In one such embodiment, the co-surfactant can be present at a level (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 infusion. 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).

Penetrant

The oil-in-water emulsion according to the present invention may comprise a penetrant and/or a tonicity modulator. Such compositions may have an osmolality of from 200 to 1000 milliosmoles per kilogram (mOsm/kg).

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.

Suitable reagents for permeation and/or liquid permeability regulators 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.

In one embodiment, the penetrant is a physiologically acceptable polyol such as glycerol, sorbitol or xylitol. In a particular embodiment, the penetrant is glycerin.

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 penetrant, the glycerin may be present at a level of from 2% to 5% (weight/volume), such as 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 regulator

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 buffer will have a negative effect on the zeta potential of the emulsion, so high ionic strength is not desired of. In a specific embodiment, the pH is adjusted to the desired value by means of 1 N sodium hydroxide.

Additives as needed

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.

Proportion of composition ingredients

While exemplary amounts of different ingredients that the compositions of the present invention may contain have been previously described, other aspects of the invention pertain to ratios of particular ingredients as discussed below.

Emulsifier (phospholipid): oil

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 in turn adversely affects emulsion stability.

In a preferred embodiment, expressed as % (weight/weight) of the total oil component, the emulsion comprises a content of 6.8% to 43%, such as 8.4% to 42.5%, including 12% to 26%, For example, 14% to 25%, including 15% to 22% emulsifier. 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.

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, expressed as % by weight of oil. Phospholipids at 8.4%, greater than or equal to 12%, greater than or equal to 14%, or greater than or equal to 15%. 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.

In another preferred embodiment of the present invention, for example, wherein the source of the phospholipid is a phospholipid obtained from krill, the composition comprises a content ranging from 3% to 20% (w/w) of the oil. For example, from 4% to 18% (w/w) of the oil, including from 6% to 16% (w/w) of the oil, for example from 8% to 14% (w/w) 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.

Common interfacial active agent: oil

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 in an amount of 0.5% (weight/weight) of the oil.

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 % of oil (weight/weight). . In other specific embodiments, the concentration of the co-surfactant is less than or expressed as % of oil (weight/weight). Equal to 0.2%, less than or equal to 0.9%, or less than or equal to 0.7%.

Common interfacial surfactant: emulsifier (phospholipid)

In a preferred embodiment of the invention, the composition comprises krill phospholipid as an emulsifier, and a co-surfactant such as 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.

In a preferred embodiment, the co-surfactant and the krill 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 A ratio of greater than or 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.

In another preferred embodiment of the invention, the composition comprises krill phospholipids as emulsifiers, and a co-surfactant such as 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).

In a specific embodiment, the co-surfactant and the lecithin system Ratio of 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 1:50 (weight/weight) (auxactuator: egg) Phospholipids are 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.

In a specific embodiment, wherein the co-surfactant is oleate, and the emulsifier is a phospholipid (krill phospholipid) obtained from krill, the ratio of co-surfactant to emulsifier The range is 1:45 to 1:20, for example 1:40 to 1:25 (weight/weight). In a more specific embodiment, wherein the co-surfactant is an oleate, and the emulsifier is egg lecithin, the ratio of the co-surfactant to the emulsifier ranges from 1:51 to 1:30, for example 1:51 to 1:34 (weight/weight).

package

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.

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 specific embodiment, the emulsion is packaged in a sealed In the 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.

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. To extend shelf life, the packaging material helps to prevent oxygen in the atmosphere from diffusing into the compositions of the present invention to prevent the formation of oxygen degradants in the composition.

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 quick and easy 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.

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. Demonstration of insulin pumping system by MiniMed And sales of 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.

Specific embodiment

In a specific embodiment, the emulsion of the present invention comprises: a) a progestogen 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 of fish oil and/or a vegetable oil selected from the group consisting of soybean oil, safflower seed oil, and mixtures thereof, based on the total weight of the oil component; ii) the total weight of the oil component 10 to 50% by weight of MCT; c) 4 to 20 grams per liter of phospholipid obtained from krill; and d) 10 to 50 grams per liter of glycerol.

More specifically, the emulsion of the present invention comprises: a) a progestin having a content ranging from 1.0 to 2.0 g/l; b) an oil component of from 100 to 300 g/liter in terms of an oil-in-water emulsion, which comprises : i) at least 50% by weight of fish oil triglyceride, based on the total weight of the oil component, wherein the triglyceride is composed of glycerol esterified with a fatty acid, wherein the fatty acid comprises a content thereof At least 45% by weight of the fatty acid 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; 10 to 50% by weight of MCT; c) 4 to 20 g/L of phospholipid obtained from krill; and d) 10 to 50 g/L of glycerol, based on the total weight of the oil component.

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 from 100 to 300 g/liter, based on the oil-in-water emulsion, comprising: i) at least 50% by weight of fish oil and/or one selected from soybean oil, safflower seed, based on the total weight of the oil component a vegetable oil of oil, and mixtures thereof; and ii) 10 to 50% by weight of MCT based on the total weight of the oil component; c) 4 to 20 grams per liter of phospholipid obtained from krill; and d) 10 to 50 G/L of glycerol.

More specifically, the emulsion of the present invention comprises: a) estradiol in an amount ranging from 0.05 to 1.0 g/l and a progesterone in an amount ranging from 1.0 to 2.0 g/l; b) an oil-in-water emulsion An oil component of 100 to 300 g/liter, which comprises: i) at least 50% by weight of fish oil triglyceride based on the total weight of the oil component, wherein the fish oil triglyceride is derived from fatty acid a composition of glycerol after esterification, 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 omega-3 The total content of fatty acids is preferably 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 grams per liter of phospholipid obtained from krill And d) 10 to 50 grams per liter of glycerin.

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 in an oil-in-water emulsion, from 100 to 300 g/liter, comprising: i) based on the total weight of the oil component , at least 50% by weight of fish oil and/or a vegetable oil selected from the group consisting of soybean oil, safflower seed oil, and mixtures thereof; and ii) 10 to 50% by weight of MCT based on the total weight of the oil component; c) 4 to 20 Glucose obtained from krill in grams per liter; and d) glycerol from 10 to 50 grams per liter.

More specifically, 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 in an oil-in-water emulsion, 100 to 300 g/liter, which comprises : i) at least 50% by weight of fish oil triglyceride, based on the total weight of the oil component, wherein the fish oil triglyceride is composed of glycerol esterified with a fatty acid, wherein the fatty acid comprises The content is at least 45% by weight of the fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and the total content of the omega-3 fatty acid is preferably 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 grams per liter of phospholipid obtained from krill; and d) 10 to 50 grams per liter of glycerol

The nature of the emulsion

The compositions of the present invention are typically milky white in appearance and are visually homogeneous emulsions.

Emulsion Droplet Particle Size Distribution) PFAT5 value

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. The PFAT5 value of the emulsion is affected by a number of factors, including the total amount of oil in the emulsion, the type and amount of phospholipid, the choice of co-surfactant, the ratio of co-surfactant to oil, and the effect of emulsion droplets on coalescence. / or the stability of flocculation.

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%.

In one embodiment, the 100% emulsion droplets of the compositions 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.

Photon correlation method (PCS)

In one embodiment, droplets having a diameter of less than or equal to 1 micron have a PCS z-average of a maximum of 350 nanometers, and/or a PCS polydispersity value of no more than 0.25. In a specific embodiment, the liquid having a diameter of less than or equal to 1 micrometer Drops have a z-average of a maximum of 250 nm and/or a polydispersity value of no more than 0.20. In a more specific embodiment, droplets having a size of less than or equal to 1 micrometer have a z-average of a maximum of 220 nanometers and/or a polydispersity value of no more than 0.15.

Median Droplet Size

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 The drop 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 surfactant, and the type of co-surfactant, the presence of the active component, the amount of oil, the ratio of oil to surfactant, and the oil and The proportion of co-surfactant.

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. , 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.

Mean Droplet Size

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 nm, 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 240 to 320 nm.

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. , 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 potential (zeta-potential)

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.

In one embodiment, the Zeta potential of the compositions of the present invention ranges from -30 millivolts to -70 millivolts, such as from -40 millivolts to -65 millivolts, including from -51 millivolts to -60 millivolts. Further, the zeta potential of the emulsion composition of the present invention may be -30 mV, -35 mV, -40 mV, -45 mV, -50 mV, -55 mV, -60 mV, -65 m Volts, or -70 millivolts, or higher.

Particulate matter

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 0 to 12 per ml, etc. Particles at or above 10 microns and 0 to 2 particles equal to or greater than 25 microns.

Emulsion stability Sterility

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 certain embodiments, the composition meets the requirements of Chapter 85 (Bacterial Endotoxin Test) of the United States Pharmacopoeia and, if necessary, additionally complies with the requirements of Chapter 151 (pyrogenic test) of the United States Pharmacopoeia.

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.

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 containing less progesterone and/or estrogen crystallization; (b) the composition has a lower PFAT5 value (as discussed in detail above); (c) the composition contains Low chemical impurities; (d) for microbiological safety, the composition can be autoclaved in gold standard methods; and/or (e) the composition is free of alcohol or toxic possible organic solvents.

One or more of the above combinations compared to prior art compositions Among the advantages of the present invention, the emulsion provides improved progestogen and/or estrogen availability (e.g., good pharmacokinetics and bioavailability, which can reflect the concentration of hormones and/or plasma in serum), and The emulsion administration system provides improved patient dose constancy.

Finally, the emulsion compositions of the present invention are advantageous in that they are convenient and safe to use, and because they have a sterile ready-to-use form and have a shelf life of 1 or 2 years at room temperature.

Manufacturing process

Another embodiment of the invention is a method of preparing an oil-in-water emulsion of the invention.

The method comprises the steps of: a) dissolving progestogen and/or estrogen in an oil phase, preferably comprising an aqua oil or a vegetable oil, in particular a fish oil triglyceride, wherein the fish oil triglyceride is a 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; Preferably, the total content of omega-3 fatty acids is at least 60% by weight of the fatty acid; and b) is preferably emulsified in the aqueous phase in the presence of an emulsifier.

In another aspect, the invention relates to a method of making an oil-in-water emulsion composition as described above, the method comprising the steps of:

a) combining water with a phospholipid comprising one or two omega-3 fatty acid moieties and optionally a penetrant to produce an aqueous composition.

b) combining a progestogen and/or an estrogen with an oil to make an oleaginous composition;

c) combining the aqueous composition with the oleaginous composition, followed by homogenization to form a homogeneous oil-in-water emulsion.

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 advantageous embodiment, progestogen and/or estrogen is added to an oil having a temperature of at least 40 ° C to promote dilution of the progestogen and/or estrogen. In another specific embodiment, the oleaginous composition is filtered prior to combining the oleaginous composition with the aqueous composition.

In a number of very specific embodiments, the method of manufacture comprises the steps of: A) dissolving a desired penetrant dissolved in an aqueous medium and stirring; B) adding an emulsifier and stirring; C) It is necessary to add a total of a surfactant and a pH adjuster and mix; D) dissolve the progestogen and/or estrogen in the oil to form an oil phase; E) filter the oil phase, and then add the filtered oil Phase to the aqueous phase, and mix; F) homogenize to form a homogeneous emulsion G) add water as needed; H) add sufficient 1N sodium hydroxide (NaOH) as needed to 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.

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.

In a specific embodiment, the method of making the emulsion involves dissolving the krill phospholipid in an aqueous medium (rather than dissolving in the oil), adding the oil phase to the aqueous phase (rather than adding the aqueous phase to The oil phase is subjected to a homogenization step at a temperature greater than or equal to 350 bar. These steps are believed to produce emulsions that are advantageous in terms of particle size and emulsion stability.

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.

In other very specific embodiments, the manufacturing method comprises the steps of: A) dissolving a penetrant dissolved in an aqueous medium and stirring; B) adding a phospholipid, especially a krill phospholipid, and stirring ; C) if necessary, add a total of surfactant and a pH adjuster, and mix; D) dissolve progesterone and / or estrogen in fish oil triglyceride to form an oil phase; E) filter the oil phase And then 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 (NaOH) as needed ) to 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.

Detailed manufacturing method examples are provided below. Modifications and variations that can be made and still be within the scope of the invention are readily apparent to those skilled in the art.

treatment method

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.

Preferably, the pharmaceutical composition of the present invention is for the treatment or prevention of nerve damage after stroke and/or trauma.

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.

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.

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, Child's head injury, degenerative diseases of the CNS, such as Parkinson's disease, dementia, including Alzheimer's disease, myelin's disease (demyelinating conditions), such as multiple sclerosis and chronic diabetic peripheral neuropathology.

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 cardiopulmonary during cardiac surgery Neurocognitive impairment of cardiopulmonary bypass, such as post-perfusion syndrome. Other examples include aphasia, sleep disorders, and anxiety disorders such as post-traumatic stress disorders.

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.

According to a specific embodiment, the present invention provides a method of treating a mammalian individual having a traumatic CNS injury, such as 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 invention to a mammalian subject in need thereof to deliver a therapeutically effective concentration of a progestogen and/or an estrogen Sex hormones. In a particular embodiment, the mammalian system is a human. For example, the methods of the invention can comprise administering a pharmaceutical composition comprising a progestogen and/or estradiol of the invention in a non-oral manner to an individual having a traumatic CNS injury (e.g., TBI). According to the method of the present invention, the pharmaceutical composition is for promoting a traumatic central nervous system Positive treatment response to systemic injuries.

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 classified as open and closed. 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 brain acceleration and deceleration.

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. The different methods of measuring the complete or partial reactions that have taken place are discussed in detail in the patent applications WO2006/102644, WO2006/102596, and WO2008/039898.

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 dosage unit is effective for treating or preventing nerve damage after the traumatic injury of the CNS, thereby causing a Neuroprotection. 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 Such as progesterone and / or estrogen specific activity, severity of traumatic injury and morphology, caused by nerve damage, patient responsiveness, patient weight, other personal internal factors, the type of administration And/or methods, and pharmaceutical compositions used.

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 particular embodiment, the composition is administered intravenously, such as an IV injection. When administered intravenously, the composition can be administered as an infusion solution over a period of from 1 to 144 hours.

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.

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.

In another embodiment of the present invention, at least one additional neuroprotective agent can be administered together with the progestogen and/or estrogen (either as part of the same composition or as a separate combination) ()) to enhance the neuroprotective effects of traumatic CNS injury.

The present invention is to be understood as being limited by the scope of the present invention.

Example General procedure for preparing oil emulsions containing hormones

After mixing of glycerol and part of the water, a cell homogenizer Ultra Turrax ^® emulsifier (phospholipid krill) oil dispersion of sodium and co-emulsifier (solution I). 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.

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.

Table 1 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⁾ 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⁾ 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.

It has been found that the krill phospholipid-containing emulsion of the present invention exhibits improved safety compared to the corresponding krill phospholipid-based emulsion substituted with egg phospholipid (hereinafter referred to as "comparative emulsion"). The emulsion of the present invention exhibited a smaller average droplet particle size than the comparative emulsion containing egg phospholipids.

Furthermore, it has been unexpectedly discovered that the effect of the hormone synergistically improves the emulsion of the present invention. The improvement effect of krill phospholipids can be confirmed by an infarct model.

Claims (15)

An oil-in-water emulsion containing a hormone which is orally administered, comprising: a) a progestogen and/or an estrogen; b) comprising one or two omega-3 fatty acid moieties Phospholipids; and c) oils. A hormone-containing oil-in-water emulsion according to claim 1, wherein the oil is a vegetable oil and/or a marine oil. The hormone-containing oil-in-water emulsion according to claim 1 or 2, wherein the oil comprises medium chain triglycerides (MCT). A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises the amount of 5 to 75% by weight, preferably 10 to 55% by weight based on the total weight of the oil component. %, especially 15 to 45% by weight of medium chain triglyceride. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a progestogen having a weight ratio of preferably from 2:1 to 500:1, more preferably from 2:1 to 200:1. And estrogen. A hormonal-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises an aqueous oil having a weight ratio of 1:1 to 9:1, especially fish oil, and medium chain triglyceride. . A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises estradiol and/or progestogen. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a progestogen in an amount of 0.15 to 12 g/liter and/or an estrogen of 0.015 to 1.5 g/liter Glycol. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the phospholipid system is derived from marine crustaceans. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a phospholipid obtained from krill. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, wherein the emulsion comprises a phospholipid selected from the group consisting of phospholipid choline comprising one or two omega-3 fatty acid moieties ( Phosphatidylcholine), a lyso-phosphatidylcholine comprising an omega-3 fatty acid moiety, and mixtures thereof. A hormone-containing oil-in-water emulsion according to one or more of the preceding claims, which comprises: a) a progestogen in an amount of from 1.0 to 2.0 g/l and/or from 0.05 to 1.0 g/l Estradiol; 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 of fish oil and/or one selected from the total weight of the oil component a vegetable oil of soybean oil, safflower seed oil, and a mixture thereof; and ii) 10 to 50% by weight of a medium chain triglyceride based on the total weight of the oil component; c) 4 to 20 grams per liter of the krill obtained from the krill Phospholipids; and d) 10 to 50 grams per liter of glycerol. A pharmaceutical composition comprising an oil-in-water emulsion according to one or more of the preceding claims, or an oil-in-water emulsion as claimed in one or more of the preceding claims. The pharmaceutical composition according to claim 13 for use in the treatment or prevention of nerve damage after stroke and/or trauma. 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.